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Physiological response to long-term peripheral and central leptin infusion in lean and obese mice
Abstract
Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue.
High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin
insensitivity. This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among
lean and three obese strains of mice: diet-induced obese AKR/J, New Zealand Obese (NZO), and Ay. Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels.
Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng/hr or greater resulted in complete depletion
of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion. Direct measurement of energy
balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows
reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean
mice. NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. Ay mice did not respond to subcutaneous leptin and were 1/100 as sensitive to i.c.v. leptin. The decreased response to leptin
in diet-induced obese, NZO, and Ay mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the
result of decreased transport of leptin into the cerebrospinal fluid, whereas in Ay mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.
... The male mice develop type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance (100). This strain was specifically developed to serve as a model for the etiology of T2D and for studying human obesity induced T2D and metabolic syndrome (99)(100)(101). Type 2 diabetes in males of this strain results from polygenic interactions producing a moderate obesity rather than the massive obesity elicited by mutations in the leptin or leptin receptor axis, such as ob/ob or db/db mice. Unlike mice with monogenic obesity syndromes, NONcNZO10/LtJ, males do not display hypercortisolism, hyperphagia, or obvious thermoregulatory defects (129). ...
... Unlike mice with monogenic obesity syndromes, NONcNZO10/LtJ, males do not display hypercortisolism, hyperphagia, or obvious thermoregulatory defects (129). When male mice from this strain are weaned onto a chow diet containing 10-11% fat by weight, they develop visceral obesity, maturity-onset hyperglycemia, dyslipidemia, moderate liver steatosis, and pancreatic islet atrophy (99)(100)(101). This mouse is quite useful as a model to study the etiology of obesity induced T2D and metabolic syndrome (99)(100)(101). ...
... When male mice from this strain are weaned onto a chow diet containing 10-11% fat by weight, they develop visceral obesity, maturity-onset hyperglycemia, dyslipidemia, moderate liver steatosis, and pancreatic islet atrophy (99)(100)(101). This mouse is quite useful as a model to study the etiology of obesity induced T2D and metabolic syndrome (99)(100)(101). In addition, NONcNZO10/LtJ appears to be a superior model for wound healing impairment studies, as it closely resembles the defects in wound healing that is characteristic of diabetic patients (99). There are also limitations for the use of this animal model. ...
Diabetes mellitus, commonly referred to as diabetes, is a group of metabolic disorders characterized by chronic elevation in blood glucose levels, resulting from inadequate insulin production, defective cellular response to extracellular insulin, and/or impaired glucose metabolism. The two main types that account for most diabetics are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), each with their own pathophysiological features. T1D is an autoimmune condition where the body’s immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to lack of insulin, a vital hormone for regulating blood sugar levels and cellular glucose uptake. As a result, those with T1D depend on lifelong insulin therapy to control their blood glucose level. In contrast, T2DM is characterized by insulin resistance, where the body’s cells do not respond effectively to insulin, coupled with a relative insulin deficiency. This form of diabetes is often associated with obesity, sedentary lifestyle, and/or genetic factors, and it is managed with lifestyle changes and oral medications. Animal models play a crucial role in diabetes research. However, given the distinct differences between T1DM and T2DM, it is imperative for researchers to employ specific animal models tailored to each condition for a better understanding of the impaired mechanisms underlying each condition, and for assessing the efficacy of new therapeutics. In this review, we discuss the distinct animal models used in type 1 and type 2 diabetes mellitus research and discuss their strengths and limitations.
... It is also produced by other tissues, such as stomach, placenta, brown adipose tissue (BAT) and breast (Klingenspor et al., 1996;Hoggard et al., 1997;Bado et al., 1998;Picó et al., 2022). Leptin plays an important role in regulating animal food intake, energy expenditure and body mass (Campfield et al., 1995;Halaas et al., 1995;Pelleymounter et al., 1995;Halaas et al., 1997). Secretion of leptin is mainly regulated by body fat content, and serum leptin levels in rodent or human were positively correlated with fat storage (Considine et al., 1996;Rousseau et al., 2003;Li and Wang, 2005), therefore, leptin serves as an indicator of energy availability (Nedergaard et al., 2022). ...
... Animals that lack leptin become grossly obese, purportedly for two reasons: increased food intake (Fischer et al., 2020;Nedergaard et al., 2022) and decreased energy expenditure (Commins et al., 1999). In mice, peripheral and central injection of leptin reduced food intake and body fat (Halaas et al., 1997). It found that in seasonal small mammals such as Microtus brandti, Dichotonyx groenlandicus, and Phodopus sungorus, seasonal changes in food intake, body mass and body fat content have been found to be related to seasonal changes in leptin levels, which showed that leptin is involved in regulating the seasonal changes of animal body mass and energy balance (Klingenspor et al., 2000;Johnson et al., 2004;Li and Wang, 2005). ...
Leptin is a hormone mainly synthesized and secreted by white adipose tissue (WAT), which regulates various physiological processes. To investigate the role of leptin in energy balance and thermoregulation in Eothenomys miletus , voles were randomly divided into leptin-injected and PBS-injected groups and placed at 25°C ± 1°C with a photoperiod of 12 L:12 D. They were housed under laboratory conditions for 28 days and compared in terms of body mass, food intake, water intake, core body temperature, interscapular skin temperature, resting metabolic rate (RMR), nonshivering thermogenesis (NST), liver and brown adipose tissue (BAT) thermogenic activity, and serum hormone levels. The results showed that leptin injection decreased body mass, body fat, food intake, and water intake. But it had no significant effect on carcass protein. Leptin injection increased core body temperature, interscapular skin temperature, resting metabolic rate, non-shivering thermogenesis, mitochondrial protein content and cytochrome C oxidase (COX) activity in liver and brown adipose tissue, uncoupling protein 1 (UCP1) content and thyroxin 5′-deiodinase (T 4 5′-DII) activity in brown adipose tissue significantly. Serum leptin, triiodothyronine (T 3 ), thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH) concentrations were also increased significantly. Correlation analysis showed that serum leptin levels were positively correlated with core body temperature, body mass loss, uncoupling protein 1 content, thyroxin 5′-deiodinase activity, nonshivering thermogenesis, and negatively correlated with food intake; thyroxin 5′-deiodinase and triiodothyronine levels were positively correlated, suggesting that thyroxin 5′-deiodinase may play an important role in leptin-induced thermogenesis in brown adipose tissue. In conclusion, our study shows that exogenous leptin is involved in the regulation of energy metabolism and thermoregulation in E. miletus , and thyroid hormone may play an important role in the process of leptin regulating energy balance in E. miletus .
... Obesity is associated with compromised leptin sensitivity 35 , so we hypothesized that RA may exert its function(s) by enhancing leptin sensitivity, perhaps acting as a -leptin sensitizer‖ 8,9 . The normal lean mice (~22 g; with low leptin levels), db/db mice (lacking functional leptin receptors) and ob/ob mice (leptin deficiency) represent three distinct experimental models to assess leptin sensitivity. ...
... Beyond its known role in reducing food intake, leptin has also been reported to maintain high-energy expenditure 35,36 . Our observations about RA reduced the fat mass in DIO model mice supported our reasoning that RA, despite its robust effects on reducing food intake, may actually enhance energy expenditure. ...
The occurrence of obesity is associated with age. But their interplay remains mysterious. Here, we discovered that rotundic acid (RA), a plant-derived pentacyclic triterpene, was a powerful agent for both anti-aging and treating obesity. Considering that obese individuals decrease the appetite-suppressing and energy-expenditure-enhancing functions of leptin leading to obesity, we found RA was a leptin sensitizer, evidenced by observations that RA enhanced the leptin sensitivity to normal diet-induced obese (DIO) mice, and had minimal or no use to normal lean mice, leptin receptor-deficient (db/db) mice and leptin-deficient (ob/ob) mice. Simultaneously, RA significantly increased energy expenditure, BAT thermogenesis and glucose metabolism in DIO mice, as the results of enhancing leptin sensitivity. Regarding mode of action, we demonstrated that RA is a noncompetitive inhibitor of leptin negative regulators protein tyrosine phosphatase 1B (PTP1B) and T-cell PTP (TCPTP) through interaction with their C-terminus, thus leading to weight loss through enhancing leptin sensitivity. Besides, we showed that deletion of yPTP1 in yeast completely abolished the lifespan extension effect of RA, celstrol and withaferin A, while these compounds exhibited PTP1B inhibition activity. Furthermore, PTP1B knockdown extend lifespan in yeast and human cells, indicating PTP1B is an important factor regulating cellular aging.
... 29 Leptin plays a role in reducing food intake and decreasing body weight. 30 Basic, translational, and clinical studies on childhood and teenage obesity still have many knowledge gaps. 9 For example, adopted children and parents have a paradoxically weak BMI association. ...
This study aimed to examine the prevalence of adolescent obesity in urban areas and the potential association with parental body mass index (BMI). A cross-sectional design was used and participants were selected from institutions of higher education in Jakarta City. Anthropometric data were obtained by trained volunteers while other variables were acquired through a self-administered questionnaire completed using a Google online form. Among the 420 questionnaires distributed, 370 (88%) were retrieved and completed. Data were analyzed by bivariate and multivariate analysis using chi-square and logistic regression adjusted for lifestyle covariates. The results showed that 59.65% and 63.16% of participants had a father or mother who was overweight and obese. The tendency to acquire obesity was higher when the father was obese compared to the mother (OR=1.42; 95% CI=0.92-2.19). A correlation was found between parental BMI and overweight/obesity in adolescents, with the father being a stronger predictor than the mother. Although there was no significant association, this study underscored the significance of adolescent obesity and overweight as a public health issue, suggesting the need for urgent preventive measures.
... Obesity can inhibit the transport of leptin across the BBB, making it impossible for the brain to receive the "satiety signal" emitted by leptin, leading to overeating and worsening of obesity, which may lead to a series of metabolic diseases. Of notice, with the development of obesity, obese mice modeling by 56 days of HFD respond to leptin for central administration (intracerebroventricularly) rather than peripheral administration (intraperitoneally or subcutaneously) [111,112]. This suggests that. ...
Obesity, a burgeoning global health issue, is increasingly recognized for its detrimental effects on the central nervous system, particularly concerning the integrity of the blood-brain barrier (BBB). This manuscript delves into the intricate relationship between obesity and BBB dysfunction, elucidating the underlying phenotypes and molecular mechanisms. We commence with an overview of the BBB’s critical role in maintaining cerebral homeostasis and the pathological alterations induced by obesity. By employing a comprehensive literature review, we examine the structural and functional modifications of the BBB in the context of obesity, including increased permeability, altered transport mechanisms, and inflammatory responses. The manuscript highlights how obesity-induced systemic inflammation and metabolic dysregulation contribute to BBB disruption, thereby predisposing individuals to various neurological disorders. We further explore the potential pathways, such as oxidative stress and endothelial cell dysfunction, that mediate these changes. Our discussion culminates in the summary of current findings and the identification of knowledge gaps, paving the way for future research directions. This review underscores the significance of understanding BBB dysfunction in obesity, not only for its implications in neurodegenerative diseases but also for developing targeted therapeutic strategies to mitigate these effects.
... An essential enzyme in the production of fatty acids is fatty acid-synthase (FAS). In the VMH, fasting specifically lowers FAS messenger ribonucleic acid mRNA have high amounts of circulating leptin rather than being leptin deficient [37], and increasing leptin does not prevent the development of obesity [24,38]. ...
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. In recent years, there has been growing interest in the role of hunger and satiety hormones such as ghrelin and leptin in the development and progression of T2DM. In this context, the present literature review aims to provide a comprehensive overview of the current understanding of how ghrelin and leptin influences food intake and maintain energy balance and its implications in the pathophysiology of T2DM.
A thorough literature search was performed using PubMed and Google Scholar to choose the studies that associated leptin and ghrelin with T2DM. Original articles and reviews were included, letters to editors and case reports were excluded.
This narrative review article provides a comprehensive summary on mechanism of action of leptin and ghrelin, its association with obesity and T2DM, how they regulate energy and glucose homeostasis and potential therapeutic implications of leptin and ghrelin in managing T2DM.
Ghrelin, known for its appetite-stimulating effects, and leptin, a hormone involved in the regulation of energy balance, have been implicated in insulin resistance and glucose metabolism. Understanding the complexities of ghrelin and leptin interactions in the context of T2DM may offer insights into novel therapeutic strategies for this prevalent metabolic disorder. Further research is warranted to elucidate the molecular mechanisms underlying these hormone actions and to explore their clinical implications for T2DM prevention and management.
... [1][2][3][4][5][6] Through suppression of orexigenic pathways, as well as stimulation of anorexigenic neuronal networks, leptin reduces food consumption, increases energy expenditure (EE), and promotes fat utilization as the body's main energy source. 2,4,7,8 Leptin has these manifold effects by acting on multiple leptin receptor (LepR)-expressing neuronal populations in the central nervous system (CNS), 4,[9][10][11][12][13][14][15] where it acts as a key peripheral messenger to communicate the abundance and availability of energy stores in the body. This system is well preserved in mammalian species, including in mice and humans. ...
... Leptin is mainly involved in the decrease in appetite [29]. Administration of recombinant leptin in individuals or mice leads to a decrease in food intake and body weight [30]. As a result of these studies, it had been thought that leptin could be used as well as insulin [31]. ...
Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese—650 million adults, 340 million adolescents, and 39 million children. The WHO estimates that, by 2025, approximately 167 million people—adults and children—will become less healthy because they are overweight or obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer. These are among the leading causes of preventable, premature death. The estimated annual medical cost of obesity in the United States was nearly $173 billion in 2019 dollars. Obesity is considered the result of a complex interaction between genes and the environment. Both genes and the environment change in different populations. In fact, the prevalence changes as the result of eating habits, lifestyle, and expression of genes coding for factors involved in the regulation of body weight, food intake, and satiety. Expression of these genes involves different epigenetic processes, such as DNA methylation, histone modification, or non-coding micro-RNA synthesis, as well as variations in the gene sequence, which results in functional alterations. Evolutionary and non-evolutionary (i.e., genetic drift, migration, and founder’s effect) factors have shaped the genetic predisposition or protection from obesity in modern human populations. Understanding and knowing the pathogenesis of obesity will lead to prevention and treatment strategies not only for obesity, but also for other related diseases.
... Leptin, which is an adipocyte-secreted hormone, was discovered more than 20 years and primarily acts on the hypothalamic neurons to activate the regulation of a balance between food intake and energy expenditure (Zhang et al., 1994;Halaas et al., 1995;Ingalls et al., 1996;Moon & Friedman, 1997;Friedman & Halaas, 1998). Obviously the discovery of leptin created much interest in its potential use for the treatment of obesity, but the hope was soon lost after leptin failed to counteract common diet-induced obesity (Halaas et al., 1997;Widdowson et al., 1997;Heymsfield et al., 1999;Levin et al., 2002). Nevertheless, overcoming resistance to the leptin therapy continues to challenge the researchers. ...
... The afferents to these AgRP neurons and their postsynaptic targets have been identified as key players in the regulation of energy balance and systemic insulin sensitivity Gropp et al., 2005;Luquet et al., 2005;Aponte et al., 2011;Könner et al., 2007;Steculorum et al., 2016). Leptin acts to decrease food intake and promote energy expenditure by suppressing the activity of AgRP neurons (Cowley et al., 2001;van den Top et al., 2004;Halaas et al., 1997;Friedman and Halaas, 1998). Selective ablation of LepR in AgRP neurons gives rise to an obese phenotype and diabetes (Xu et al., 2018;van de Wall et al., 2008). ...
The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptin-mediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptin-responsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities.
... Our finding that ob/ ob mice have reduced food intake and body weight after DRN Vglut3 activation suggests that these neurons can reduce weight independently of leptin. We next tested the effect of activating DRN Vglut3 neurons in leptin-resistant DIO mice that have high circulating levels and a diminished response to exogenous hormone 38 (Fig. 1). ...
Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders. Schneeberger et al. show that glutamatergic neurons within the dorsal raphe nucleus of the brainstem are enriched with the orexin 1 receptor Hcrtr1, which can be pharmacologically targeted to treat obesity in mice.
... 50 When compared to ob/ob mice, which lack lep completely, lep role in weight regulation has not been fully replicated in dio mice; in this context, dio mice represent a better animal model reflecting the common human obesity biology. 56 The observations obtained from the dio mice and the results obtained from human obese patients, suggest the presence of lep resistance similar to insulin resistance recognized in obesity and cardiometabolic disorders. anyway, while high doses of insulin can decrease glucose concentration in diabetic patients, very high doses of Lep do not produce significant changes in body weight. ...
The human male infertility has several causes interconnected to improper lifestyles such as smoking, sedentarism, environmental factors, toxins accumulation and energy imbalances. All these factors contribute to the obesity accompanied metabolic syndrome and hormonal alterations in the leptin-ghrelin axis. The leptin (Lep) has many pleiotropic effects in several biological systems, directly on the peripheral tissues or through the central nervous system (CNS). Many studies suggest that Lep is a key player in gonadal functions beside its documented role in reproductive regulation, however, further investigations are still necessary to elucidate all the molecular pathways involved in these mechanisms. Keeping into account that increased Lep levels in obese men are positively correlated with altered sperm parameters and testicular oxidative stress, evidences refer to Lep as a potential link between obesity and male infertility. This review represents an updated version on the concept of the Lep roles in mediating the male reproductive functions in obese patients.
... In support, partially leptin-deficient heterozygote ob/+ mice adapt to partial leptin deficiency by increasing adipose tissue mass until achieving leptin levels similar to B6 WT mice (62). Treatment of ob/ob mice with leptin resulted in dosedependent decreases in appetite (35,63). This finding contrasts with B6 mice fed a high fat diet; when treated with leptin, obese mice exhibit an attenuated response, attributable to leptin resistance (64). ...
Bone marrow adipose tissue (BMAT) levels are higher in distal femur metaphysis of female mice housed at thermoneutral (32°C) than in mice housed at 22°C, as are abdominal white adipose tissue (WAT) mass, and serum leptin levels. We performed two experiments to explore the role of increased leptin in temperature-enhanced accrual of BMAT. First, we supplemented 6-week-old female C57BL/6J (B6) mice with leptin for 2 weeks at 10 µg/d using a subcutaneously implanted osmotic pump. Controls consisted of ad libitum (ad lib) fed mice and mice pair fed to match food intake of leptin-supplemented mice. The mice were maintained at 32°C for the duration of treatment. At necropsy, serum leptin in leptin-supplemented mice did not differ from ad lib mice, suggesting suppression of endogenous leptin production. In support, Ucp1 expression in BAT, percent body fat, and abdominal WAT mass were lower in leptin-supplemented mice. Leptin-supplemented mice also had lower BMAT and higher bone formation in distal femur metaphysis compared to the ad lib group, changes not replicated by pair-feeding. In the second experiment, BMAT response was evaluated in 6-week-old female B6 wild type (WT), leptin-deficient ob/ob and leptin-treated (0.3 μg/d) ob/ob mice housed at 32°C for the 2-week duration of the treatment. Compared to mice sacrificed at baseline (22°C), BMAT increased in ob/ob mice as well as WT mice, indicating a leptin independent response to increased temperature. However, infusion of ob/ob mice with leptin, at a dose rate having negligible effects on either energy metabolism or serum leptin levels, attenuated the increase in BMAT. In summary, increased housing temperature and increased leptin have independent but opposing effects on BMAT in mice.
... Most obese subjects exhibit resistance to leptin, and this resistance impedes sustained weight loss [3]. Intriguingly, many mouse models of obesity are still responsive to intracerebroventricularly delivered leptin with high sensitivity compared to peripheral infusion, indicating that impaired brain access via diminished BBB transport may contribute to leptin resistance and other biological conditions [4,5]. ...
Background:
The hormone leptin exerts its function in the brain to reduce food intake and increase energy expenditure to prevent obesity. However, most obese subjects reflect the resistance to leptin even with elevated serum leptin. Considering that leptin must cross the blood-brain barrier (BBB) in several regions to enter the brain parenchyma, altered leptin transport through the BBB might play an important role in leptin resistance and other biological conditions. Here, we report the use of a human induced pluripotent stem cell (iPSC)-derived BBB model to explore mechanisms that influence leptin transport.
Methods:
iPSCs were differentiated into brain microvascular endothelial cell (BMEC)-like cells using standard methods. BMEC-like cells were cultured in Transwell filters, treated with ligands from a nuclear receptor agonist library, and assayed for leptin transport using an enzyme-linked immune sorbent assay. RNA sequencing was further used to identify differentially regulated genes and pathways. The role of a select hit in leptin transport was tested with the competitive substrate assay and after gene knockdown using CRISPR techniques.
Results:
Following a screen of 73 compounds, 17β-estradiol was identified as a compound that could significantly increase leptin transport. RNA sequencing revealed many differentially expressed transmembrane transporters after 17β-estradiol treatment. Of these, cationic amino acid transporter-1 (CAT-1, encoded by SLC7A1) was selected for follow-up analyses due to its high and selective expression in BMECs in vivo. Treatment of BMEC-like cells with CAT-1 substrates, as well as knockdown of CAT-1 expression via CRISPR-mediated epigenome editing, yielded significant increases in leptin transport.
Conclusions:
A major female sex hormone, as well as an amino acid transporter, were revealed as regulators of leptin BBB transport in the iPSC-derived BBB model. Outcomes from this work provide insights into regulation of hormone transport across the BBB.
... To investigate whether FGF21 has any functional effects on leptin signaling, we treated weight-matched lean WT mice with vehicle, FGF21 (1 mg/kg/day), a low dose of leptin (250 ng/h) [45], or FGF21 in combination with leptin for 14 days utilizing osmotic minipumps (Supplemental Figure 5a). As expected, mice receiving leptin exhibited elevated plasma leptin levels (Supplemental Figure 5c), and administration of FGF21 significantly increased plasma FGF21 (Supplemental Figure 5b). ...
Objective
Fibroblast growth factor 21 (FGF21) is a peripherally-derived endocrine hormone that acts on the central nervous system (CNS) to regulate whole body energy homeostasis. Pharmacological administration of FGF21 promotes weight loss in obese animal models and human subjects with obesity. However, the central targets mediating these effects are incompletely defined.
Methods
To explore the mechanism for FGF21’s effects to lower body weight, we pharmacologically administer FGF21 to genetic animal models lacking the obligate FGF21 co-receptor, β-klotho (KLB), in either glutamatergic (Vglut2-Cre) or GABAergic (Vgat-Cre) neurons. In addition, we abolish FGF21 signaling to leptin receptor (LepR-Cre) positive cells. Finally, we examine the synergistic effects of FGF21 and leptin to lower body weight and explore the importance of physiological leptin levels in FGF21-mediated regulation of body weight.
Results
Here we show that FGF21 signaling to glutamatergic neurons is required for FGF21 to modulate energy expenditure and promote weight loss. In addition, we demonstrate that FGF21 signals to leptin receptor-expressing cells to regulate body weight, and that central leptin signaling is required for FGF21 to fully stimulate body weight loss during obesity. Interestingly, co-administration of FGF21 and leptin synergistically leads to robust weight loss.
Conclusions
These data reveal an important endocrine crosstalk between liver- and adipose-derived signals which integrate in the CNS to modulate energy homeostasis and body weight regulation.
... The prevailing view is that leptin mediates resistance to obesity by its levels rising in response to positive energy balance (Flier and Maratos-Flier, 2017). Indeed, longer-term application of recombinant leptin to wild-type lean mice (Halaas et al., 1997;Ohlsson et al., 2018) and lean humans (Chrysafi et al., 2020) entails body weight loss and in particular loss of fat mass. However, in the latter mean weight loss was only ~1 kg upon treatment for twelve weeks; some of the respective lean females even gained weight (Chrysafi et al., 2020). ...
This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.
... La leptine agit ensuite sur son récepteur hypothalamique afin de diminuer la prise alimentaire et d'augmenter la sensibilité centrale à l'insuline. Chez la souris rendue obèse par un régime HFD, la leptine n'est plus capable d'activer sa voie de signalisation hypothalamique, ce qui correspond à la leptino-résistance (Seeley et al. 1996;Halaas et al. 1997;Münzberg et al. 2004). ...
Le neuropeptide 26RFa et son récepteur GPR103 constituent un système peptidergique impliqué dans la régulation de la glycémie. Il a récemment été montré que le 26RFa exerce une activité de type incrétine. Le 26RFa est sécrété par le duodénum après une charge orale en glucose et active son récepteur pancréatique afin de stimuler la sécrétion d’insuline induite par le glucose. Parallèlement, il augmente la sensibilité à l’insuline. Enfin, nous avons montré que le 26RFa était aussi impliqué dans la régulation centrale de la glycémie. En effet, ce peptide constitue un des relais de l’insuline centrale, il exerce un effet anti-hyperglycémiant associé à une augmentation de la sécrétion d’insuline. Alors que la régulation de la glycémie est fortement altérée dans certaines pathologies telles que l’obésité associée au diabète de type 2, aucune étude n’a évalué le fonctionnement du système 26RFa/GPR103 dans ces conditions. Dans ce contexte, nous avons voulu déterminer l’impact d’un régime riche en graisse (régime high fat diet – HFD) sur les effets du 26RFa dans la régulation de la glycémie. Dans un premier temps, nous avons soumis des souris à un régime HFD auxquelles nous avons injecté par voie ip du 26RFa durant différents tests métaboliques. L’ensemble des résultats obtenus nous a permis de mettre en évidence que les effets anti-hyperglycémiants du 26RFa sont totalement abolis chez les souris HFD. En effet, dans ce contexte, le 26RFa ne semble plus capable de stimuler la sécrétion d’insuline par le pancréas et l’effet insulino-sensibilisateur du peptide est fortement réduit. De plus, la perte de l’effet insulinotropique du 26RFa peut être expliquée par une diminution de l’immunomarquage du GPR103 dans les îlots pancréatiques tandis que la diminution des effets insulino-sensibilisateurs du 26RFa peut être en partie liée à une réduction de l’expression du GPR103 dans les organes cibles de l’insuline : le muscle et le tissu adipeux. En conclusion de ce premier travail, les effets périphériques du 26RFa semblent totalement abolis chez la souris HFD. Dans une seconde étude, nous avons effectué des injections icv de 26RFa chez la souris HFD. Cette étude nous a permis de mettre en évidence que les effets centraux du 26RFa ne sont pas impactés par le régime HFD. En effet, dans ces conditions, le 26RFa exerce toujours un effet anti-hyperglycémiant en stimulant la sécrétion d’insuline. Dans ce contexte où le 26RFa conserve ses effets centraux, nous avons souhaité déterminer les effets d’une infusion chronique icv de 26RFa sur le phénotype obèse et hyperglycémique des souris HFD. Ainsi, l’utilisation de mini-pompes osmotiques nous a permis d’injecter de façon continue durant 4 semaines du 26RFa dans le cerveau des souris HFD. Les résultats de cette étude ne nous ont pas permis de mettre évidence un effet bénéfique du 26RFa sur l’homéostasie du glucose chez les souris HFD. En effet, le 26RFa exerce un effet orexigène puissant qui pourrait masquer les effets du 26RFa sur la régulation de la glycémie observés lors d’injections aiguës. Finalement l’ensemble des travaux de cette thèse nous révèle que le système 26RFa/GPR103 central et périphérique ne sont pas impactés de la même façon par le régime HFD. En effet, tandis que le système périphérique perd totalement ses effets gluco-régulateurs, le système central quant à lui conserve ses effets anti-hyperglycémiants. Face à ce constat, il apparait aujourd’hui nécessaire d’évaluer les possibles communications/interactions entre ces systèmes central et périphérique dans ce modèle HFD. Enfin, le traitement chronique central que nous avons effectué ne semble pas améliorer la régulation glycémique chez les souris traitées. Toutefois, s’agissant de la première étude à avoir évalué les effets chroniques du 26RFa dans un contexte d’obésité associée à l’hyperglycémie, d’autres protocoles d’expérimentation sont nécessaires pour poursuivre l’analyse du système 26RFa en situation physiopathologique.
... Moreover, adiponectin, an adipokine that improves insulin sensitivity and attenuates inflammation was elevated in Ablated mice. Hyperleptinemia in the absence of high fat diet and/or obesity improves insulin sensitivity and glucose uptake (42,43) and only elicits leptin-and insulin-resistance in the context of diet-induced obesity (44). Thus, while hyperleptinemia and hyperinsulinemia are frequently implicated in metabolic problems of obesity, their appearance together in our non-obese/non-high calorie diet model remains puzzling. ...
A subpopulation of adipocytes in the major adipose depots of mice is produced from hematopoietic stem cells rather than mesenchymal progenitors that are the source of conventional white and brown/beige adipocytes. To analyze the impact of hematopoietic stem cell-derived adipocytes (HSCDAs) in the adipose niche we transplanted HSCs in which expression of a diphtheria toxin gene was under the control of the adipocyte-specific adiponectin gene promoter into irradiated wild type recipients. Thus, only adipocytes produced from HSC would be ablated while conventional white and brown adipocytes produced from mesenchymal progenitor cells would be spared. Wild type mice transplanted with HSCs from mice containing a reporter gene, but not the diphtheria toxin gene, regulated by the adiponectin gene promoter served as controls. In mice in which HSCDA production was suppressed, adipocyte size declined while adipose depot weights were unchanged and the number of conventional adipocyte progenitors significantly increased. We also measured a paradoxical increase in circulating leptin levels while physical activity was significantly decreased in the HSCDA depleted mice. Finally, insulin sensitivity was significantly reduced in HSCDA depleted mice. In contrast, loss of HSCDA production had no effect on body weight, components of energy balance, or levels of several circulating adipokines and tissue-resident inflammatory cells. These data indicate that ablation of this low-abundance subpopulation of adipocytes is associated with changes in circulating leptin levels and leptin-regulated endpoints associated with adipose tissue function. How they do so remains a mystery, but our results highlight the need for additional studies to explore the role of HSCDAs in other physiologic contexts such as obesity, metabolic dysfunction or loss of sex hormone production.
... Agouti protein may be over-expressed ectopically in Ay/a obese mice, resulting in higher food intake and body weight due to the antagonistic impact of MC4 receptor that causes notable obesity in the abdomen region and leptin-resistant diabetes (32). Although leptin injection through the ICV route diminished food intake in wild-type mice, it did not happen in MC4 receptor knockout obese or Ay/a obese mice (29). ...
The present study aimed to assess the probable impact of the central histaminergic and melanocortin systems on leptin-induced hypophagia in neonatal layer chickens. In experiment 1, the chickens received intracerebroventricular (ICV) injections of the control solution, 250 nmol of α-FMH, 10 µg of leptin, and α-FMH+leptin. Experimental groups 2-8 were injected the same as experiment 1. Nonetheless, the chickens in experiments 2-8 received ICV injections of 300 nmol of chlorpheniramine (H1 receptor antagonist), 82 nmol of famotidine (H2 receptor antagonist), 300 nmol of thioperamide (H3 receptor antagonist), 0.5 nmol of SHU9119 (M3/M4 receptors antagonist), 0.5 nmol of MCL0020 (M4 receptor antagonist), 30 µg of astressin-B (CRF1/ CRF2 receptors antagonist), and 30 µg of astressin2-B (CRF2 receptor antagonist), instead of α-FMH, respectively. Food was provided for the birds immediately following the injection, and 30, 60, and 120 min after the injection, cumulative food intake (g) was measured. The findings pointed out that the ICV injection of leptin diminished food intake in neonatal chickens (P<0.05). The co-administration of M3/M4 receptor antagonist+leptin significantly decreased the hypophagic effect of leptin (P<0.05). A significant decrease was also detected in the hypophagic effect of leptin following the co-administration of the M4 receptor antagonist and leptin (P<0.05). Moreover, the co-injection of the antagonists of CRF1/CRF2 receptors and leptin significantly mitigated the hypophagic effect of leptin (P<0.05). The co-injection of CRF2 receptor antagonist and leptin led to a decrease in the hypophagic effect of leptin. As evidenced by the results of the current study the hypophagic effect of leptin is mediated by the receptors of H1, H3, M3/M4, and CRF1/CRF2 in neonatal layer chicken.
... Intriguingly, mouse models of obesity are still responsive to intracerebroventricularly delivered leptin with high sensitivity compared to peripheral infusion, indicating that impaired brain access via diminished BBB transport may contribute to leptin resistance and other biological conditions [4,5]. ...
Background
The peptide hormone leptin exerts its function in the brain to reduce food intake and increase energy expenditure to prevent obesity. However, most obese subjects reflect the resistance to leptin even with elevated serum leptin. Considering that leptin must cross the blood-brain barrier (BBB) in several regions to enter the brain parenchyma, altered leptin transport through the BBB might play an important role in leptin resistance and other biological conditions. Here, we report the use of a human induced pluripotent stem cell (iPSC)-derived BBB model to explore mechanisms that influence leptin transport.
Methods
iPSCs were differentiated into brain microvascular endothelial cell (BMEC)-like cells using standard methods. BMEC-like cells were cultured in Transwell filters, treated with ligands from a nuclear receptor agonist library, and assayed for leptin transport using an enzyme-linked immune sorbent assay. RNA sequencing was further used to identify differentially regulated genes and pathways. The role of a select hit in leptin transport was tested with the competitive substrate assay and after gene knockdown using CRISPR techniques.
Results
Following a screen of 73 compounds, 17β-estradiol was identified as a compound that could significantly increase leptin transport. RNA sequencing revealed many differentially expressed transmembrane transporters after 17β-estradiol treatment. Of these, cationic amino acid transporter-1 (CAT-1, encoded by SLC7A1) was selected for follow-up analyses due to its high and selective expression in BMECs in vivo . Treatment of BMEC-like cells with CAT-1 substrates, as well as knockdown of CAT-1 expression via CRISPR-mediated epigenome editing, yielded significant increases in leptin transport.
Conclusions
A major female sex hormone, as well as an amino acid transporter, were revealed as regulators of leptin BBB transport in the iPSC-derived BBB model. Outcomes from this work provide insights into regulation of peptide hormone transport across the BBB.
... Notably, elevating (repleting) leptin levels leads to profound behavioral changes and weight loss in ob/ob mice [65][66][67] and leptin-deficient humans [68]. However, in humans and mice that are not leptin deficient, it results in only rather modest reductions in food intake, increased expenditure, and loss of body fat [69,70]. To explain this asymmetrical response, researchers have proposed the concept of "leptin resistance" [59,71,72] (Fig. 2a). ...
People completely lacking body fat (lipodystrophy/lipoatrophy), and those with severe obesity, both show profound metabolic and other health issues. Regulating levels of body fat somewhere between these limits would therefore appear to be adaptive. Two different models might be contemplated. More traditional is a set-point where levels are regulated around a fixed level. Alternatively, is a system that tolerates fairly wide variation but is activated when critically high or low levels are breached - a dual intervention point (DIP) system. A DIP system seems to fit our experience much better than a set-point, and models suggest it is more likely to have evolved. A DIP system may have evolved because of two contrasting selection pressures. At the low end we may have been selected to avoid low levels of fat as a buffer against starvation, disease induced anorexia, and to support reproduction. At the upper end we may have been selected to avoid excess storage because of the elevated risks of predation. This upper limit of control seems to have malfunctioned because some of us deposit large fat stores, with important negative health effects. Why has evolution not protected us against this problem? One possibility is that because the system evolved as a protection against predation risks, then when we dramatically reduced the risk of being predated in our evolutionary history, the protective system slowly fell apart due to random mutations. By chance it fell apart more in some people than others, and these people are now unable to effectively manage their weight in the face of the modern food glut. To understand the evolutionary context of obesity it is important to separate the adaptive reason for storing some fat (i.e. the lower intervention point), from the non-adaptive reason for storing lots of fat (a broken upper intervention point). The DIP model has several consequences for how we understand the obesity problem and what happens when we attempt to treat it.
... ObRb KO mice are found to be hyperphagic, obese, and diabetic [100]. Several findings have shown that obese mice develop peripheral but not central responsiveness to leptin, thus suggesting the dysfunction of the BBB that reduces brain access to leptin and provokes increased body weight [101,102]. However, a specific transport system has shown direct access of leptin to the brain across the BBB; hypothalamic neurons within the arcuate nucleus sense leptin independently of this transport system, thus showing increased sensitivity to circulating leptin [103]. ...
Background
In the first section of this review, we examined the neuroanatomical and neurochemical data of hunger and satiety centers, glucose receptors, sensorial influences on eating behavior, and regulation of energy requirements. The second section is devoted to orexigenic and anorexigenic hormones.
Objective
The paper aims to overview and summarize data dealing with the role of neuroendocrine regulation of food intake and eating behavior.
Methods
Appropriate keywords and MeSH terms were identified and searched in MEDLINE/PubMed. References of original articles and reviews were examined.
Results
Hunger and satiety center are located in the lateral (LH) and medio-ventral hypothalamus (VMH). Lasting aphagia has been observed following lesion of LH, while hyperphagia is induced by LH stimulation. On the other hand, increased food intake after VMH lesion and aphagia following VMH stimulation also in hungry animals has been reported. Intracellular glucopenia triggers food intake by reducing neuronal activity at the satiety center level. Moreover, sensorial influences are regulated by food palatability as the positive hedonic evaluation of food and energy requirement indicates the average amount of food energy needed to balance energy expenditure. Orexigenic and anorexigenic hormones secreted from the gastrointestinal tract and adipose tissue regulate brain areas involved in eating behavior via gastric afferent vagal nerve, circumventricular organ area postrema, or transporter system. Finally, oxytocin (OT) plays a role in reward-related eating by inhibiting sugar intake and decreasing palatable food intake by suppressing the reward circuitry in the brain. Moreover, the anorectic effect of nesfatin-1 is abolished by an OT antagonist.
... Mice ObRb KO mice are found to be hyperphagic, obese, and diabetic [100]. Several findings have shown that obese mice develop peripheral but not central responsiveness to leptin, thus suggesting the dysfunction of BBB that reduces brain access to leptin and provokes increased body weight [101,102]. However, a specific transport system has shown direct access of leptin to the brain across the BBB; hypothalamic neurons within the arcuate nucleus sense leptin independently of this transport system, thus showing increased sensitivity to circulating leptin [103]. ...
Background: in the first section of this review, we examined the neuroanatomical and neurochemical data of hunger and satiety centers , glucose receptors, sensorial influences on eating behavior, and regulation of energy requirements. The second section is devoted to orexigenic and anorexigenic hormones.
Objective: the paper aims to overview and summarize date dealing with the role of neuroendocrine regulation of food intake and eating behavior.
Methods: appropriate keywords and MeSH terms were identified and searched in MEDLINE/PuMed. References of original articles and reviews were examined.
Results: hunger and satiety center are located in the lateral (LH) and medio-ventral hypothalamus (VMH). Lasting aphagia has been observed following lesion of LH, while hyperphagia is induced by LH stimulation. On the other hand, increased food intake after VMH lesion and aphagia following VMH stimulation also in hungry animals has been reported. Intracellular glucopenia triggers food intake by reducing neuronal activity at the satiety center level. Moreover, sensorial influences are regulated by food palatability as the positive edonic evaluation of food and energy requirement indicates the average amount of food energy needed to balance energy expediture. Orexigenic and anorexigenic hormones secreted from the gastrointestinal tract and adipose tissue regulate brain areas involved in eating behavior via gastric afferent vagal nerve, circumventricular organ area postrema, or transporter system. Finally, oxytocin (OT) plays a role in reward-related eating by inhibiting sugar intake and decreasing palatable food intake by suppressing the reward circuitry in the brain. Moreover, the anorectic effect of nesfatin-1 is abolished by an OT antagonist.
... Retinoic acid, β-carotene, and 25(OH)2D, the bioactive form of vitamin D, have shown anti-adipogenic effects through their activations of key transcription factors involved in adipocyte differentiation [30][31][32]. Vitamin C, vitamin E, and β-carotene deficiencies may alter the genetic expression of leptin important in regulating food intake energy expenditure and constancy of adipose tissue thus leading to leptin resistance and increased adiposity and obesity risk [33,34]. Zinc repletion also leads to increased tissue leptin secretion, which may subsequently lead to reduced adipose tissue mass and so modify the risk of obesity [35]. ...
Background
The prevalence of overweight and obesity is increasing among African children potentially predisposing them to greater obesity and non-communicable diseases (NCDs) in adulthood. This risk may be higher among growth-impaired children who may have greater fat mass. Therefore, we examined the effects of school-based physical activity (PA) promotion and multi-micronutrient supplementation (MMNS) on body composition among South African children enrolled in a longitudinal school-based randomized controlled trial.
Methods
Children were cluster-randomized by class to one of four groups: (a) a physical activity group (PA), (b) a multi-micronutrient supplementation group (MMNS), (c) a physical activity + multi-micronutrient supplementation group (PA + MMNS), and (d) control group, and were being followed for 3 years. Linear random effects regression models with random intercepts for school classes tested the associations of each intervention arm with overall fat mass (FM), fat-free mass (FFM), truncal fat mass (TrFM), and truncal fat-free mass (TrFFM) at 9 months (T2) for boys and girls. These differences were then explored among children who differed in height velocity (HV).
Results
A total of 1304 children (614 girls, 667 boys) in twelve clusters were assessed at baseline and after 9 months follow-up (T2). At baseline, approximately 15% of children were classified as overweight or obese while approximately 38% of children were classified as mildly stunted or moderately/severely stunted. Among girls, promotion of PA was associated with reduced FM and TrFM at T2 while MMNS was associated with increased FFM. Children with reduced HV in the PA arm had reduced FM while children in the MMNS arm with lower HV had increased FM compared to children in the control arm. Similarly, children with lower HV in the MM and PA groups had reduced TrFM compared to children in the control arm.
Conclusions
Our study suggests that the promotion of school-based physical activity programs and micronutrient supplementation can reduce childhood adiposity and so reduce the risk of obesity and chronic diseases later in adulthood.
Trial registration
ISRCTN, ISRCTN29534081. Registered on August 9, 2018. The trial was designed, analyzed, and interpreted based on the CONSORT protocol (Additional file 1: CONSORT checklist for randomized trial)
... In terms of WAT, circulating leptin concentrations can be used as an indirect measure of fat accumulation (96,(236)(237)(238). For example, higher leptin concentrations are observed in fat or ad libitum fed Syrian hamsters compared to their respective lean or feed-restricted counterparts (239). ...
Since its discovery as a novel gonadotropin inhibitory peptide in 2000, the central and peripheral roles played by gonadotropin-inhibiting hormone (GnIH) have been significantly expanded. This is highlighted by the wide distribution of its receptor (GnIH-R) within the brain and throughout multiple peripheral organs and tissues. Furthermore, as GnIH is part of the wider RF-amide peptides family, many orthologues have been characterized across vertebrate species, and due to the promiscuity between ligands and receptors within this family, confusion over the nomenclature and function has arisen. In this review, we intend to first clarify the nomenclature, prevalence, and distribution of the GnIH-Rs, and by reviewing specific localization and ligand availability, we propose an integrative role for GnIH in the coordination of reproductive and metabolic processes. Specifically, we propose that GnIH participates in the central regulation of feed intake while modulating the impact of thyroid hormones and the stress axis to allow active reproduction to proceed depending on the availability of resources. Furthermore, beyond the central nervous system, we also propose a peripheral role for GnIH in the control of glucose and lipid metabolism at the level of the liver, pancreas, and adipose tissue. Taken together, evidence from the literature strongly suggests that, in fact, the inhibitory effect of GnIH on the reproductive axis is based on the integration of environmental cues and internal metabolic status.
... The female rat groups had decreased leptin levels which could be adduced to the role of leptin in preventing the build-up of lipid in adipocytes by increasing the turnover of TGs, inhibiting basal and insulinstimulated de novo lipogenesis while stimulating glucose and free fatty acid oxidation [38]. This would however remove the inhibitory effect of Leptin on food intake (satiety), which can be traced to the increased palatability and Different physiological states are adduced to differences in feed intake and calorie content of each diet is another factor that could affect leptin signalling [39]. Soda, as a refined carbohydrate content drink, is low in fibre and easily digested resulting in major swings in blood sugar level, eventually contributing to hyperphagia by interfering with leptin satiety signalling to the brain [40]. ...
Aims
High carbohydrate diet and carbonated soda consumption have individually been associated with metabolic dysfunction, with links to glucose and insulin homeostasis, affecting metabolic variables associated with feeding, satiety and adiposity. Our objective is to determine the combined effect of a high carbohydrate and carbonated soda diet on metabolic variables in male and female Wistar rats.
Materials and methods
Thirty-two female and male weanlings were equally divided into four dietary groups; Control, Soda, High Carbohydrate diet (HCD), and High Carbohydrate diet/Soda (HCD/Soda), and fed ad libitum for fourteen weeks. Bodyweight, thoracic circumference, abdominal circumference and glucose was determined; Insulin, leptin, adiponectin, Tumor Necrotic Factor (TNF)-α, Interleukin (IL)-6 and lipid profile were assayed and used to determine the metabolic effects.
Key findings
Soda and HCD/Soda had increased body weight in male rats, while HCD-fed rats were reduced compared to respective controls. Abdominal circumference, total cholesterol and reduced HDL of Soda were elevated in both sexes. Although HCD/Soda groups had elevated abdominal circumference in both sexes, total cholesterol and reduced high-density lipoprotein (HDL) were both reduced in females. Insulin and malondialdehyde (MDA) concentrations in Soda-fed rats was significantly reduced, however, MDA was elevated in both sexes in HCD and HCD/Soda fed rats. Female HCD and HCD/Soda groups had a significant increase in glutathione (GSH) concentration and a significant reduction in catalase. TNF-α was increased in both Soda and HCD/Soda groups.
Significance
The results of this study suggest that HCD and Soda consumption results in alteration in phenotype and variables impacting metabolism.
... Leptin is a hormone secreted primarily from the adipose tissue to relay the status of the energy stores to the central nervous system [1,2]. Leptin acts by stimulating the anorexigenic pathways in the appetite-regulating nucleus of the human hypothalamus, transmitting this information as peripheral signals that cause appetite suppression, limit food intake/energy consumption, and regulate energy expenditure [3,4]. Ghrelin is a hormone secreted mainly in the fundus of the stomach in adults (though the main source of ghrelin expression during perinatal life is the pancreas [5,6]) in response to a negative energy balance such as during fasting and starvation. ...
Markers of iron metabolism are altered in new-onset diabetes, but their relationship with metabolic signals involved in the maintenance of energy balance is poorly understood. The primary aim was to explore the associations between markers of iron metabolism (hepcidin and ferritin) and markers of energy balance (leptin, ghrelin, and the leptin/ghrelin ratio) in both the fasted and postprandial states. These associations were also studied in the sub-groups stratified by diabetes status. This was a cross-sectional study of individuals without disorders of iron metabolism who were investigated after an overnight fast and, in addition, some of these individuals underwent a mixed meal test to determine postprandial responses of metabolic signals. The associations between hepcidin, ferritin, and leptin, ghrelin, leptin/ghrelin ratio were studied using several multiple linear regression models. A total of 76 individuals in the fasted state and 34 individuals in the postprandial state were included. In the overall cohort, hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −883.45 ± 400.94; p = 0.031) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −148.26 ± 61.20; p = 0.018) in the fasted state. The same associations were not statistically significant in the postprandial state. In individuals with new-onset prediabetes or diabetes (but not in those with normoglycaemia or longstanding prediabetes or diabetes), hepcidin was significantly inversely associated with leptin (in the most adjusted model, the β coefficient ± SE was −806.09 ± 395.44; p = 0.050) and the leptin/ghrelin ratio (in the most adjusted model, the β coefficient ± SE was −129.40 ± 59.14; p = 0.037). Leptin appears to be a mediator in the link between iron metabolism and new-onset diabetes mellitus. These findings add to the growing understanding of mechanisms underlying the derangements of glucose metabolism.
... Additionally, the administration of ARP and EX treatment sufficiently attenuated these levels. Long-term HFD feeding would cause a decrease in the sensitivity of central leptin (35). A 48.3% elevated leptin content was found in FIGURE 2 | Effects of ARP and EX on insulin sensitivity in HFD-fed mice. ...
Metabolic syndrome is a cluster of metabolic disorders that threatens public health. Nevertheless, its exact mechanism and relative intervention remain largely obscure. Accumulating evidence indicate that tither Anoectochilus roxburghii polysaccharide (ARP) or exercise (EX) exhibited the beneficial effects on metabolic health. However, the synergetic beneficial effects of ARP and EX as a combined intervention on obesity-induced metabolic disorders remain largely obscure. Male C57BL/6 mice were fed a high-fat diet (HFD) and intervened with ARP and EX for 12 continuous weeks. The results indicated that the ARP, EX, and ARP combined with EX treatment group regulated lipogenesis by suppressing the fatty acid pathway, dampening the system oxidative stress by stimulating Nrf2-mediated phase II enzyme system, and promoting the mitochondrial function by activating the mitochondrial complexes and PGC-1α in HFD mice. More importantly, the combination of ARP and EX showed an even greater beneficial effects relative to either ARP or EX alone, especially in decreasing reactive oxygen species (ROS) level and increasing adenosine triphosphate (ATP) content. Taken together, these findings further confirmed that ARP and EX could be effective interventions on obesity-induced metabolic abnormalities, and that the combination of ARP and EX exhibited the beneficial synergetic effects.
... Being a well-known biomarker for obesity, leptin correlated positively with MUO-related PP5. is adipocyte-derived hormone, increases with BMI and adipose tissue mass, suggesting that obese individuals develop an insensitivity to this hormone with increasing weight [43]. e hormone regulates the energy balance by inhibiting hunger mediated through the hypothalamus; hence, it works to reduce caloric intake and increase energy expenditure [44], suggesting that such obesity-promoting mechanisms might be more pronounced in MUO than in MHO. ...
Method:
Associations between different biomarkers (proteomics, lipidomics, and metabolomics) coupled to either MHO or metabolically unhealthy obese (MUO) individuals were analyzed through principal component analysis (PCA). Subjects were identified from a subsample of 416 obese individuals, selected from the Malmö Diet and Cancer study-Cardiovascular arm (MDCS-CV, n = 3,443). They were further divided into MHO (n = 143) and MUO (n = 273) defined by a history of hospitalization, or not, at baseline inclusion, and nonobese subjects (NOC, n = 3,027). Two distinctive principle components (PL2, PP5) were discovered with a significant difference and thus further investigated through their main loadings.
Results:
MHO individuals had a more metabolically favorable lipid and glucose profile than MUO subjects, that is, lower levels of traditional blood glucose and triglycerides, as well as a trend of lower metabolically unfavorable lipid biomarkers. PL2 (lipidomics, p=0.02) showed stronger associations of triacylglycerides with MUO, whereas phospholipids correlated with MHO. PP5 (proteomics, p=0.01) included interleukin-1 receptor antagonist (IL-1ra) and leptin with positive relations to MUO and galanin that correlated positively to MHO. The group differences in metabolite profiles were to a large extent explained by factors included in the metabolic syndrome.
Conclusion:
Compared to MUO individuals, corresponding MHO individuals present with a more favorable lipid metabolic profile, accompanied by a downregulation of potentially harmful proteomic biomarkers. This unique and extensive biomarker profiling presents novel data on potentially differentiating traits between these two obese phenotypes.
... Por otra parte, la leptina también es una adipocina producida en mayor cantidad por los adipocitos, actúa sobre receptores hipotalámicos para controlar la ingesta de alimentos, el gasto energético y el peso corporal (Zhang et al., 1994;Halaas et al., 1995;Halaas et al., 1997;Friedman y Halaas, 1998;Montez et al., 2005). Tamaño (µm 2 ) de los islotes pancreáticos de ratones alimentados con dieta Control (Control), dieta alta en grasa (DAG), dieta alta en grasa con 0.1% de metil galato (DAG+0.1% MG), dieta alta en grasa con 10% de harina de los frutos de Vachellia farnesiana (DAG+10% HFV), dieta alta en grasa con 0.5% del extracto de Vachellia farnesiana (DAG+0.5% EVF), dieta alta en grasa con 1% del extracto de Vachellia farnesiana (DAG+1% EVF), dieta alta en grasa con 2% del extracto de Vachellia farnesiana (DAG+2% EVF). ...
Alternativas dietarias para mitigar las alteraciones metabólicas de la obesidad, a partir de los frutos de Acacia farnesiana en ratones machos C57BL/6.
... In subjects with obesity, elevated leptin levels in blood are not paired by proportionally high leptin levels in the cerebrospinal fluid, suggesting a causal relationship between a deficit in the transport system that carries leptin to the CNS and obesity [62]. Studies in obese mice show that these animals are sensitive to central administration of leptin but not to subcutaneous or intraperitoneal administration, indicating that the lack of leptin effect could be due to impaired transport of blood leptin to the brain [63]. However, the contribution of the alteration of leptin transport through the BBB to leptin resistance is not clear. ...
Leptin is a hormone primarily produced by the adipose tissue in proportion to the size of fat stores, with a primary function in the control of lipid reserves. Besides adipose tissue, leptin is also produced by other tissues, such as the stomach, placenta, and mammary gland. Altogether, leptin exerts a broad spectrum of short, medium, and long-term regulatory actions at the central and peripheral levels, including metabolic programming effects that condition the proper development and function of the adipose organ, which are relevant for its main role in energy homeostasis. Comprehending how leptin regulates adipose tissue may provide important clues to understand the pathophysiology of obesity and related diseases, such as type 2 diabetes, as well as its prevention and treatment. This review focuses on the physiological and long-lasting regulatory effects of leptin on adipose tissue, the mechanisms and pathways involved, its main outcomes on whole-body physiological homeostasis, and its consequences on chronic diseases.
... [23][24][25]31 The secreted protein leptin is, of course, a LEPR agonist, and leptin treatment of adults with leptin deficiency dramatically lowered their BW, body fat and food intake. 205,206,292 However, treating common polygenic obesity with leptin achieved only modest weight loss, 293,294 consistent with studies in rodents [295][296][297] and inconsistent with broad use of leptin as a weight loss therapy. Also, agonists against the MC4R and HTR2C GPCRs have been developed. ...
Purpose
Obesity is a major public health problem. Understanding which genes contribute to obesity may better predict individual risk and allow development of new therapies. Because obesity of a mouse gene knockout (KO) line predicts an association of the orthologous human gene with obesity, we reviewed data from the Lexicon Genome5000TM high throughput phenotypic screen (HTS) of mouse gene KOs to identify KO lines with high body fat.
Materials and Methods
KO lines were generated using homologous recombination or gene trapping technologies. HTS body composition analyses were performed on adult wild-type and homozygous KO littermate mice from 3758 druggable mouse genes having a human ortholog. Body composition was measured by either DXA or QMR on chow-fed cohorts from all 3758 KO lines and was measured by QMR on independent high fat diet-fed cohorts from 2488 of these KO lines. Where possible, comparisons were made to HTS data from the International Mouse Phenotyping Consortium (IMPC).
Results
Body fat data are presented for 75 KO lines. Of 46 KO lines where independent external published and/or IMPC KO lines are reported as obese, 43 had increased body fat. For the remaining 29 novel high body fat KO lines, Ksr2 and G2e3 are supported by data from additional independent KO cohorts, 6 (Asnsd1, Srpk2, Dpp8, Cxxc4, Tenm3 and Kiss1) are supported by data from additional internal cohorts, and the remaining 21 including Tle4, Ak5, Ntm, Tusc3, Ankk1, Mfap3l, Prok2 and Prokr2 were studied with HTS cohorts only.
Conclusion
These data support the finding of high body fat in 43 independent external published and/or IMPC KO lines. A novel obese phenotype was identified in 29 additional KO lines, with 27 still lacking the external confirmation now provided for Ksr2 and G2e3 KO mice. Undoubtedly, many mammalian obesity genes remain to be identified and characterized.
... Experiments conducted in the early 1990s showed that defects in the transport of leptin through the BBB played a major role in the pathogenesis of obesity. In 1997, two studies showed that animals with diet-related obesity went through a period in which they did not respond to peripherally administered leptin but still responded to centrally administered leptin directly into the brain [28,29]. This was evidence not only that leptin exceeded the BBB in ineffective amounts but also that there was a period in which resistance to the BBB was dominant to insensitivity to leptin at the receptor/postreceptor level (referred to as central resistance). ...
The short form of the leptin receptor (LRa) plays a key role in the transport of leptin to the central nervous system (CNS). Here, the resistin (RSTN)-mediated expression of LRa in the preoptic area (POA), ventromedial and dorsomedial nuclei (VMH/DMH),arcuate nucleus (ARC) and the anterior pituitary gland (AP)was analyzed considering the photoperiodic (experiment 1) and nutritional status (experiment 2) of ewes. In experiment 1, 30 sheep were fed normally and received one injection of saline or two doses of RSTN one hour prior to euthanasia. RSTN increased LRa expression mainly in the ARC and AP during long days (LD) and only in the AP during short days (SD). In experiment 2, an altered diet for 5 months created lean or fat sheep. Twenty sheep were divided into four groups: the lean and fat groups were given saline, while the lean-R and fat-R groups received RSTN one hour prior to euthanasia. Changes in adiposity influenced the effect of RSTN on LRa mRNA transcript levels in the POA, ARC and AP and without detection of LRa in the VMH/DMH. Overall, both photoperiodic and nutritional signals influence the effects of RSTN on leptin transport to the CNS and are involved in the adaptive/pathological phenomenon of leptin resistance in sheep.
Extensive research is undertaken in rodents to determine the mechanism underlying obesity‐induced leptin resistance. While body weight is generally tightly controlled in these studies, the effect of age of experimental animals has received less attention. Specifically, there has been little investigation into leptin regulation of food intake in middle‐aged animals, which is a period of particular relevance for weight gain in humans. We investigated whether the satiety effects of leptin remained constant in young (3 months), middle‐aged (12 months) or aged (18–22 months) male mice. Although mean body weight increased with age, leptin concentrations did not significantly increase in male mice beyond 12 months of age. Exogenous leptin administration led to a significant reduction in food intake in young mice but had no effect on food intake in middle‐aged male mice. This loss of the satiety effect of leptin appeared to be transient, with leptin administration leading to the greatest inhibition of food intake in the aged male mice. Subsequently, we investigated whether these differences were due to changes in leptin transport into the brain with ageing. No change in leptin clearance from the blood or transport into the brain was observed, suggesting the emergence of central resistance to leptin in middle age. These studies demonstrate the presence of dynamic and age‐specific changes in the satiety effects of leptin in male mice and highlight the requirement for age to be carefully considered when undertaking metabolic studies in rodents.
Obesity rates are increasing almost everywhere in the world, although the pace and timing for this increase differ when populations from developed and developing countries are compared. The sharp and more recent increase in obesity rates in many Latin American countries is an example of that and results from regional characteristics that emerge from interactions between multiple factors. Aware of the complexity of enumerating these factors, we highlight eight main determinants (the physical environment, food exposure, economic and political interest, social inequity, limited access to scientific knowledge, culture, contextual behaviour and genetics) and discuss how they impact obesity rates in Latin American countries. We propose that initiatives aimed at understanding obesity and hampering obesity growth in Latin America should involve multidisciplinary, global approaches that consider these determinants to build more effective public policy and strategies, accounting for regional differences and disease complexity at the individual and systemic levels.
Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to “reduce food and avoid drinking to fullness” and begin “running during the night.” Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.
Previous studies have shown that very low dose, acute, single peripheral leptin injections fully activate arcuate nucleus STAT3, but ventromedial hypothalamus (VMH) pSTAT3 continues to increase with higher doses of leptin that inhibit food intake. The lowest dose that inhibited intake increased circulating leptin 300-fold whereas food intake is inhibited by chronic peripheral leptin infusions that only double circulating leptin. This study examined whether the pattern of hypothalamic pSTAT3 was the same in leptin infused rats as in leptin injected rats. Male Sprague Dawley rats received intraperitoneal infusions of 0, 5, 10, 20 or 40 mg leptin/day for 9 days. The highest dose of leptin increased serum leptin by 50-100%, inhibited food intake for 5 days, but inhibited weight gain and retroperitoneal fat mass for 9 days. Energy expenditure, respiratory exchange ratio and brown fat temperature did not change. pSTAT3 was quantified in hypothalamic nuclei and the nucleus of the solitary tract (NTS) when food intake was inhibited and when it had returned to control levels. There was no effect of leptin on pSTAT3 in the medial or lateral arcuate nucleus or in the dorsomedial nucleus of the hypothalamus. VMH pSTAT3 was increased only at day 4 when food intake was inhibited, but NTS pSTAT3 was increased at both 4 and 9 days of infusion. These results suggest that activation of leptin VMH receptors contributes to the suppression of food intake, but that hindbrain receptors contribute to a sustained change in metabolism that maintains a reduced weight and fat mass.
It is well established that decreases in plasma leptin levels, as with fasting, signal starvation and elicit appropriate physiological responses, such as increasing the drive to eat and decreasing energy expenditure. These responses are mediated largely by suppression of the actions of leptin in the hypothalamus, most notably on arcuate nucleus (ArcN) orexigenic neuropeptide Y neurons and anorexic pro-opiomelanocortin neurons. However, the question addressed in this review is whether the effects of increased leptin levels are also significant on the long-term control of energy balance, despite conventional wisdom to the contrary. We focus on leptin’s actions (in both lean and obese individuals) to decrease food intake, increase sympathetic nerve activity, and support the hypothalamic–pituitary–thyroid axis, with particular attention to sex differences. We also elaborate on obesity-induced inflammation and its role in the altered actions of leptin during obesity.
Leptin secreted mainly by white adipose tissues (WAT) plays an important role in immune responses. To understand the role of energy status and leptin in immunity, bilateral perigonadal fat pads were removed or sham-removed in male striped hamsters (Cricetulus barabensis). Half of these hamsters were injected with sterile saline, and another half were administrated with exogenous leptin each day, which lasted for 20 days. Fat removal reduced total body fat mass and leptin titers significantly, leptin administration increased leptin levels in the fat removed hamsters to the control levels, but did not affect total body fat mass. Body mass and gross energy intake were not affected by fat removal, leptin supplement or their interaction. Fat removal decreased thymus mass, phytohaemagglutinin (PHA) response at 12 h, and the levels of immunoglobin (Ig) G 5, IgG10, IgM5, IgM10, IL-2, IL-4, and TNF-α, indicating a reduction in fat mass suppressed cellular and humoral immunity and the production of cytokines. However, fat removal had no effect on spleen mass, bacteria killing activity and IFN-γ titers. Leptin supplement increased PHA response at 6 h and 12 h, and the levels of IgG5, IgG10, IL-4, and IFN-γ to the control levels, implying its boosting effects on these parameters. In addition, leptin level was positively correlated with body fat mass, PHA 6 h, 12 h, Ig G10, Ig M5, Ig M10, IL-2, IL-4, and TNF-α. Collectively, these findings implied leptin was a link between energy status and immunity, and leptin mediated the suppressive effects of reduced energy storage on cellular and humoral immunity.
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-Ay mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-Ay mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD. The presence of visceral obesity or type 2 diabetes mellitus is a major risk factor and potential therapeutic target for non-alcoholic fatty liver disease (NAFLD). A new murine NAFLD model established in this study had obesity and insulin resistance, and rapidly develop steatohepatitis and fibrosis. This model could be useful as preclinical models for drug development of NAFLD.
The hypothalamus is an essential component of brain circuits that control critical physiological functions. It plays a particularly important role in regulating energy balance and feeding behaviors. Accumulating evidence suggests that perturbations in hypothalamic development greatly contribute to obesity and metabolic diseases in later life. This chapter will discuss the timelines during which hypothalamic neurons develop, paying particular attention to neurons producing agouti-related peptide/neuropeptide Y, pro-opiomelanocortin, and oxytocin, because of their documented role in feeding regulation. It will also describe hormonal, molecular, and cellular factors related to the development of these neuronal systems. Finally, it will review the role of genetic and nutritional factors in hypothalamic development.KeywordsHypothalamusDevelopmentPro-opiomelanocortinOxytocinAgouti-related peptideNeuropeptide YObesity
Adipose tissue (AT) in the body plays a very important role in the regulation of energy metabolism. AT regulates energy metabolism by secreting adipokines. Some of the adipokines released are vaspin, resistin, adiponectin, visfatin and omentin, and leptin. In addition to regulating energy metabolism, leptin plays a role in the regulation of many physiological functions of the body such as regulation of blood pressure, inflammation, nutrition, appetite, insulin and glucose metabolism, lipid metabolism, coagulation, and apoptosis. Among all these physiological functions, the relationship between leptin, oxidative stress, and apoptosis has gained great importance recently due to its therapeutic effect in various types of cancer. For this reason, in this study, the release of leptin, its cellular effects and its effect on oxida-tive stress, and apoptosis are discussed in line with current information.
The obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show VSG confers weight loss and durable metabolic benefit where equivalent caloric intake in shams resulted in significant weight gain following surgery. Further, we show that VSG is associated with early, weight-independent increases in bile acids, short chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes towards highly regulatory myeloid cells and Tregs. These data demonstrate this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.
According to the Center for Disease Control (CDC), childhood obesity has tripled since 1970, and nearly one in five school-age children and young people (6–19 years) in the United States have obesity. Childhood obesity is a result of complex interactions between genetic and environmental factors. Although the genetic contribution to obesity is very important, the effect of environmental and behavioral factors is also gaining importance in childhood obesity-related studies. Genes when exposed to certain circumstances such as radiation, virus infection, and sudden environmental changes may lead to gene mutation or gene abnormal activation, which may further lead to changes in the gene expressions. The difference in gene expressions between two conditions on a single-gene level allows the detection of a disease-related gene from a statistical perspective. We aim to detect differentially expressed genes in a given sample by locating the changepoint of a gene expression profile. In this article, we propose a procedure to detect changepoint in gene expression based on a nonparametric method. The proposed procedure performs well for non-normal error distribution and does not require the assumption of normal distribution. A simulation study is conducted to compare the performance of the proposed procedure with the existing procedure, considering the error distribution as Laplace, Student’s t, and a mixture of normal distributions. The simulation study indicates that the proposed procedure outperforms its competitor. We use real data to show the working of the procedure.
Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:1-19, 2021.
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.
The gene product of the recently cloned mouse obese gene (ob) is important in regulating adipose tissue mass. ob RNA is expressed specifically by mouse adipocytes in vivo in each of several different fat cell depots, including brown fat. ob RNA is also expressed in cultured 3T3-442A preadipocyte cells that have been induced to differentiate. Mice with lesions of the hypothalamus, as well as mice mutant at the db locus, express a 20-fold higher level of ob RNA in adipose tissue. These data suggest that both the db gene and the hypothalamus are downstream of the ob gene in the pathway that regulates adipose tissue mass and are consistent with previous experiments suggesting that the db locus encodes the ob receptor. In db/db and lesioned mice, quantitative differences in expression level of ob RNA correlated with adipocyte lipid content. The molecules that regulate expression level of the ob gene in adipocytes probably are important in determining body weight, as are the molecules that mediate the effects of ob at its site of action.
No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly.
We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding.
Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects.
Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.
The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.
The effects of recombinantly produced ob protein were compared to those of food restriction in normal lean and genetically obese mice. Ob protein infusion into ob/ob mice resulted in large decreases in body and fat-depot weight and food intake that persisted throughout the study. Smaller decreases in body and fat-depot weights were observed in vehicle-treated ob/ob mice that were fed the same amount of food as that consumed by ob protein-treated ob/ob mice (pair feeding). In lean mice, ob protein infusion significantly decreased body and fat-depot weights, while decreasing food intake to a much lesser extent than in ob/ob mice. Pair feeding of lean vehicle-treated mice to the intake of ob protein-treated mice did not reduce body fat-depot weights. The potent weight-, adipose-, and appetite-reducing effects exerted by the ob protein in ob protein-deficient mice (ob/ob) confirm hypotheses generated from early parabiotic studies that suggested the existence of a circulating satiety factor of adipose origin. Pair-feeding studies provide compelling evidence that the ob protein exerts adipose-reducing effects in excess of those induced by reductions in food intake.
Leptin, encoded for by the mouse ob gene, regulates feeding behavior and energy metabolism. Its receptor (Ob-R) is encoded by the mouse diabetic (db) gene and is mutated in the db/db mouse so that it lacks the cytoplasmic domain. We show that the full-length leptin receptor (Ob-Rb), which is believed to transmit the leptin signal, is expressed in pancreatic islets of ob/ob and wild-type mice, as well as in hypothalamus, liver, kidney, spleen, and heart. Recombinant leptin inhibited basal insulin release in the perfused pancreas preparation from ob/ob mice but not in that from Zucker fa/fa rats. Leptin (1-100 nmol/l) also produced a dose-dependent inhibition of glucose-stimulated insulin secretion by isolated islets from ob/ob mice. In contrast, leptin at maximum effective concentration (100 nmol/l) did not inhibit glucose-stimulated insulin secretion by islets from db/db mice. These results provide evidence that a functional leptin receptor is present in pancreatic islets and suggest that leptin overproduction, particularly from abdominal adipose tissue, may modify directly both basal and glucose-stimulated insulin secretion.
The peripheral production of leptin by adipose tissue and its putative effect as a signal of satiety in the central nervous system suggest that leptin gains access to the regions of the brain regulating energy balance by crossing the brain capillary endothelium, which constitutes the blood-brain barrier in vivo. The present experiments characterize the binding and internalization of mouse recombinant leptin in isolated human brain capillaries, an in vitro model of the human blood-brain barrier. Incubation of 125I-leptin with isolated human brain capillaries resulted in temperature-dependent binding: at 37 degrees C, approximately 65% of radiolabeled leptin was bound per milligram of capillary protein. Two-thirds of the bound radioactivity was resistant to removal by acid wash, demonstrating endocytosis of 125I-leptin into capillary cells. At 4 degrees C, binding to isolated capillaries was reduced to approximately 23%/mg of protein, the majority of which was acid wash resistant. Binding of 125I-leptin to brain capillary endothelial plasma membranes was saturable, described by a two-site binding model with a high-affinity dissociation constant of 5.1+/-2.8 nM and maximal binding capacity of 0.34+/-0.16 pmol/mg of membrane protein. Addition of porcine insulin or insulin-like growth factor at a final concentration of 100 nM had a negligible effect on leptin binding. These results provide evidence for a leptin receptor that mediates saturable, specific, temperature-dependent binding and endocytosis of leptin at the human blood-brain barrier.
Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.
The Ob gene product, leptin, is secreted by adipocytes and is required for fertility in the mouse. Leptin-deficient mice are obese and infertile, symptoms reminiscent of polycystic ovary syndrome (PCOS). Prior studies have shown that serum leptin levels are elevated in a significant sub-population of anovulatory women with PCOS, suggesting that elevated leptin levels may adversely affect ovarian function. Since leptin receptor mRNA has been detected in the ovary, this study was designed to test the hypothesis that leptin may impair granulosa cell (GC) estradiol-17β (E2) production by a direct mechanism. GC were isolated from the ovaries of 26-day-old Sprague-Dawley rats, and were cultured (60,000 GC/well) in 96-well plates in the presence and absence of ovine FSH (0.001–100 ng/ml) and androstenedione (0.1 μM), with and without recombinant murine leptin (0.1–100 ng/ml) for 48 h. Leptin alone had no effect on E2 production. FSH caused a dose-related increase in E2 production by GC (ED50 = 1.9 ± 0.4 ng/ml). Addition of leptin did not alter FSH-stimulated E2 levels. Concomitant treatment with FSH and IGF-I (30 ng/ml) augmented maximal FSH-dependent E2 production five-fold. Leptin caused a dose-dependent (IC50 = 2.7 ± 0.6 ng/ml) inhibition (30–50%) of the IGF-I increase in FSH-stimulated E2 production. The inhibitory effect of leptin was specific for E2 production since there was no effect on basal, FSH-, or FSH + IGF-I-dependent progesterone levels. The results of this study demonstrate that leptin can directly impair the IGF-I-mediated augmentation of FSH-stimulated E2 synthesis by GC. These data raise the possibility that high leptin levels may contribute to infertility in some women with PCOS by counteracting the sensitizing effects of IGF-I in dominant follicles.
DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide1–6. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)7, thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R)7–9. To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors7, we identified cyclic melanocortin analogues10 that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and AY mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.
RECENTLY Zhang et al.1 cloned a gene that is expressed only
in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse
is linked to a mutation in the obese gene that results in expression of
a truncated inactive protein. Human and rat homolo-gues for this gene
are known1,2. Previous experiments3,4 predict such
a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y
stimulates food intake, decreases thermogenesis, and increases plasma
insulin and corticosterone levels making it a potential
target5. Here we express the obese protein in Escherichia
coli and find that it suppresses food intake and decreases body weight
dramatically when administered to normal and ob/ob mice but not db/db
(diabetic) mice, which are thought to lack the appropriate receptor.
High-affinity binding was detected in the rat hypo-thalamus. One
mechanism by which this protein regulated food intake and metabolism was
inhibition of neuropeptide-Y synthesis and release.
The influence of systemic or intracerebroventricular (icv) administration of angiotensin II on the intakes of NaCl solution, water, and food was investigated in BALB/c mice. Systemic administration of angiotensin II had little, if any, influence on these ingestive behaviors. On the other hand, icv infusion of angiotensin II at 70 ng/day increased (P less than 0.05) intakes of NaCl solution and water by the third day of infusion. The amount of NaCl ingested daily during the infusion was two to three times body sodium content. The mean daily water intake increased to 40-60% of body weight. The vast increase in NaCl intake was not secondary to a natriuresis caused by the icv infusion of angiotensin II. The results suggest that angiotensin II has a direct effect on neural systems involved in sodium appetite in this species.
Overnutrition manifested by obesity has emerged as a major health problem in affluent countries. In spite of increased interest in fitness, obesity is on the increase in the United States. This is particularly so among children and adolescents. Although obesity is associated with many risk factors for diseases, the mechanisms whereby it enhances disease risk are not fully understood. Such an understanding is needed to develop strategies for management of these conditions. In this report we suggest that overnutrition produces clinical diseases only in individuals who already possess a metabolic weakness or "defect" in a given system. In the absence of such underlying defects, overnutrition, or obesity, is well tolerated. One of the most common consequences of obesity is dyslipidemia, that is, elevations of very low-density lipoprotein (VLDL) triglycerides and low-density lipoprotein (LDL) cholesterol and low concentrations of high-density lipoprotein (HDL) cholesterol. The major effect of overnutrition on lipoprotein metabolism is to stimulate the production of VLDL. For patients who have an underlying defect in lypolysis of VLDL triglycerides, hypertriglyceridemia will develop in the obese state. For those who have defective clearance of LDL, obesity will accentuate hypercholesterolemia. Both of these effects can be explained by overproduction of VLDL, due to obesity, combined with a genetic defect in clearance of VLDL or LDL. The mechanism whereby obesity causes a lowering of HDL cholesterol is uncertain, although it could enhance removal of HDL by an excess of adipose tissue. Another disease associated with obesity is cholesterol gallstones. The presence of obesity more than doubles the risk for gallstones. Two underlying factors increase the danger for gallstones: a deficiency of hepatic secretion of bile acids and a tendency for formation of cholesterol crystals in bile. Overnutrition promotes the synthesis of whole-body cholesterol, and the only route for excretion of this excess cholesterol is through the biliary tree.(ABSTRACT TRUNCATED AT 400 WORDS)
This article contains a brief review of the problem posed by a fundamental physiological regulatory mechanism, and a new hypothesis.
The regulation of body weight and composition involves input from genes and the environment, demonstrated, for example, by the variable susceptibility of inbred strains of mice to obesity when offered a high-fat diet. The identification of the gene responsible for obesity in the ob/ob mouse provides a new approach to defining links between diet and genetics in the regulation of body weight. The ob gene protein product, leptin, is an adipocyte-derived circulating protein. Administration of recombinant leptin reduces food intake and increases energy expenditure in ob/ob mice, suggesting that it signals to the brain the magnitude of fat stores. Information on the regulation of this protein is limited. In several rodent models of obesity including db/db, fa/fa, yellow (Ay/a) VMH-lesioned, and those induced by gold thioglucose, monosodium glutamate, and transgenic ablation of brown adipose tissue, leptin mRNA expression and the level of circulating leptin are increased, suggesting resistance to one or more of its actions. We have assessed the impact of increased dietary fat on circulating leptin levels in normal FVB mice and FVB mice with transgene-induced ablation of brown adipose tissue. We find that high-fat diet evokes a sustained increase in circulating leptin in both normal and transgenic mice, with leptin levels accurately reflecting the amount of body lipid across a broad range of body fat. However, despite increased leptin levels, animals fed a high-fat diet became obese without decreasing their caloric intake, suggesting that a high content of dietary fat changes the 'set point' for body weight, at least in part by limiting the action of leptin.
Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.
Leptin, the gene product of the obese gene, may play an important role in regulating body weight by signalling the size of the adipose tissue mass. Plasma leptin was found to be highly correlated with body mass index (BMI) in rodents and in 87 lean and obese humans. In humans, there was variability in plasma leptin at each BMI suggesting that there are differences in its secretion rate from fat. Weight loss due to food restriction was associated with a decrease in plasma leptin in samples from mice and obese humans.
The recent positional cloning of the mouse ob gene and its human homology has provided the basis to investigate the potential
role of the ob gene product in body weight regulation. A biologically active form of recombinant mouse OB protein was overexpressed
and purified to near homogeneity from a bacterial expression system. Peripheral and central administration of microgram doses
of OB protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral
effects after brain administration suggest that OB protein can act directly on neuronal networks that control feeding and
energy balance.
The gene product of the ob locus is important in the regulation of body weight. The ob product was shown to be present as a 16-kilodalton protein in mouse and human plasma but was undetectable in plasma from C57BL/6J ob/ob mice. Plasma levels of this protein were increased in diabetic (db) mice, a mutant thought to be resistant to the effects of ob. Daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30 percent after 2 weeks of treatment with no apparent toxicity but had no effect on db/db mice. The protein reduced food intake and increased energy expenditure in ob/ob mice. Injections of wild-type mice twice daily with the mouse protein resulted in a sustained 12 percent weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7 percent. These data suggest that the OB protein serves an endocrine function to regulate body fat stores.
C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls, suggesting that the OB protein normalized the metabolic status of the ob/ob mice. Lean animals injected with OB protein maintained a smaller weight loss throughout the 28-day study and showed no changes in any of the metabolic parameters. These data suggest that the OB protein regulates body weight and fat deposition through effects on metabolism and appetite.
POMC, the precursor of ACTH, MSH, and beta-endorphin peptides, is expressed in the pituitary and in two sites in the brain, in the arcuate nucleus of the hypothalamus and the commissural nucleus of the solitary tract of the brain stem. Little is known regarding the functions of melanocortin (ACTH and MSH) peptides in the brain. We report here the detailed neuroanatomical distribution of the MC4-R mRNA in the adult rat brain. The melanocortin 3 receptor (MC3-R), characterized previously, was found to be expressed in arcuate nucleus neurons and in a subset of their presumptive terminal fields but in few regions of the brainstem. The highly conserved MC4-R is much more widely expressed than MC3-R and is pharmacologically distinct. MC4-R mRNA was found in multiple sites in virtually every brain region, including the cortex, thalamus, hypothalamus, brainstem, and spinal cord. Unlike the MC3-R, MC4-R mRNA is found in both parvicellular and magnocellular neurons of the paraventricular nucleus of the hypothalamus, suggesting a role in the central control of pituitary function. MC4-R is also unique in its expression in numerous cortical and brainstem nuclei. Together, MC3-R and/or MC-4R mRNA are found in every nucleus reported to bind MSH in the adult rat brain and define neuronal circuitry known to be involved in the control of diverse neuroendocrine and autonomic functions. The high degree of conservation, distinct pharmacology, and unique neuronal distribution of the MC4 receptor suggest specific and complex roles for the melanocortin peptides in neuroendocrine and autonomic control.
We describe a new multiple gene mouse model of differential sensitivity to dietary obesity that provides a tool for dissecting the genetic basis for body composition and obesity. AKR/J and SWR/J male mice, as well as male progeny of intercrosses between these strains, were fed a high-fat diet for 12 weeks beginning at 5 weeks of age. Body weight and energy intake were assessed weekly. At the conclusion of the dietary manipulation, an adiposity index was calculated by dividing the weight of seven dissected adipose depots by the carcass weight. AKR/J mice had approximately sixfold greater adiposity than SWR/J mice. Examination of the segregation of the adiposity trait in the progeny of crosses between these strains indicates that the trait is determined by a minimum of one to four genetic loci and that there is significant dominance of the AKR/J genotype. A preliminary analysis with markers linked to the known mouse obesity genes ob, db, tub, and fat showed no linkage with these loci. However, a quantitative trait locus was found that maps distal to the db gene on Chromosome (Chr) 4. This locus has been designated dietary obese 1 or Do1.
The mouse agouti gene controls the deposition of yellow and black pigment in developing hairs. Several dominant alleles, including lethal yellow (Ay), result in the exclusive production of yellow pigment and have pleiotropic effects that include obesity and increased tumor susceptibility. In an interspecific backcross, we established genetic limits for the agouti gene and found that the Ay and the lethal non-agouti (ax) allele were not separated from a previously identified probe at the breakpoint of the Is1GsO chromosomal rearrangement. Using the Is1GsO probe, we isolated the agouti gene, and find that it has the potential to code for a secreted protein expressed in hair follicles and the epidermis, and that the level of expression correlates with the synthesis of yellow pigment. In the Ay mutation, there is a chromosomal rearrangement that results in the production of a chimeric RNA expressed in nearly every tissue of the body. The 5' portion of this chimeric RNA contains highly expressed novel 5' sequences, but the 3' portion retains the protein-coding potential of the nonmutant allele. We speculate that dominant pleiotropic effects of Ay are caused by ectopic activation of a signaling pathway similar to that used during normal hair growth.
Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiologic actions of leptin in humans.
Using a newly developed radioimmunoassay, wer measured serum concentrations of leptin in 136 normal-weight subjects and 139 obese subjects (body-mass index, > or = 27.3 for men and > or = 27.8 for women; the body-mass index was defined as the weight in kilograms divided by the square of the height in meters). The measurements were repeated in seven obese subjects after weight loss and during maintenance of the lower weight. The ob messenger RNA (mRNA) content of adipocytes was determined in 27 normal-weight and 27 obese subjects.
The mean (+/- SD) serum leptin concentrations were 31.3 +/- 24.1 ng per milliliter in the obese subjects and 7.5 +/- 9.3 ng per milliliter in the normal-weight subjects (P < 0.001). There was a strong positive correlation between serum leptin concentrations and the percentage of body fat (r = 0.85, P < 0.001). The ob mRNA content of adipocytes was about twice as high in the obese subjects as in the normal-weight subjects (P < 0.001) and was correlated with the percentage of body fat (r = 0.68, P < 0.001) in the 54 subjects in whom it was measured. In the seven obese subjects studied after weight loss, both serum leptin concentrations and ob mRNA content of adipocytes declined, but these measures increased again during the maintenance of the lower weight.
Serum leptin concentrations are correlated with the percentage of body fat, suggesting that most obese persons are insensitive to endogenous leptin production.
The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.
The adipocyte hormone, leptin (OB protein), is proposed to be an "adiposity signal" that acts in the brain to lower food intake and adiposity. As plasma leptin levels are elevated in most overweight individuals, obesity may be associated with leptin resistance. To investigate the mechanisms underlying brain leptin uptake and to determine whether reduced uptake may contribute to leptin resistance, we measured immunoreactive leptin levels in plasma and cerebrospinal fluid (CSF) of 53 human subjects. Leptin concentrations in CSF were strongly correlated to the plasma level in a nonlinear manner (r = 0.92; p = 0.0001). Like levels in plasma, CSF leptin levels were correlated to body mass index (r = 0.43; p = 0.001), demonstrating that plasma leptin enters human cerebrospinal fluid in proportion to body adiposity. However, the efficiency of this uptake (measured as the CSF:plasma leptin ratio) was lower among those in the highest as compared with the lowest plasma leptin quintile (5.4-fold difference). We hypothesize that a saturable mechanism mediates CSF leptin transport, and that reduced efficiency of brain leptin delivery among obese individuals with high plasma leptin levels results in apparent leptin resistance.
Mutations in the mouse diabetes (db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity. Previous data suggest that the db gene encodes the receptor for the obese (ob) gene product, leptin. A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db. This receptor maps to the same 300-kilobase interval as db, and has at least six alternatively spliced forms. One of these splice variants is expressed at a high level in the hypothalamus, and is abnormally spliced in C57BL/Ks db/db mice. The mutant protein is missing the cytoplasmic region, and is likely to be defective in signal transduction. This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus.
Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension, psychiatric symptoms and, in the worst cases, quadriplegia. Acute attacks, often precipitated by inappropriate drug therapy, are potentially fatal. While earlier workers thought the distal haem biosynthetic enzyme ferrochelatase may be involved in the genesis of VP, it was shown in the early 1980's, and is now accepted, that VP is associated with decreased protoporphyrinogen oxidase activity (PPO) (E.C.1.3.3.4). VP prevalence is much higher in South Africa than elsewhere; probably due to a founder effect with patients descending from a 17th century Dutch immigrant. PPO cDNAs from Bacillus subtilis, Myxococcus xanthus, human placenta and mouse liver have been cloned, sequenced and expressed. Human and mouse cDNAs consist of open reading frames 1431 nucleotides long, encoding a 477 amino acid protein. The human PPO gene contains thirteen exons, spanning approximately 4.5 kb. We have identified a C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W). A protein expressed from an in vitro-mutagenized PPO construct exhibits substantially less activity than the wild type. The R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Since at least one of these families is descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa.
A total deficiency in or resistance to the protein leptin causes severe obesity. As leptin levels rise with increasing adiposity in rodents and man, it is proposed to act as a negative feedback 'adipostatic signal' to brain centres controlling energy homeostasis, limiting obesity in times of nutritional abundance. Starvation is also a threat to homeostasis that triggers adaptive responses, but whether leptin plays a role in the physiology of starvation is unknown. Leptin concentration falls during starvation and totally leptin-deficient ob/ob mice have neuroendocrine abnormalities similar to those of starvation, suggesting that this may be the case. Here we show that preventing the starvation-induced fall in leptin with exogenous leptin substantially blunts the changes in gonadal, adrenal and thyroid axes in male mice, and prevents the starvation-induced delay in ovulation in female mice. In contrast, leptin repletion during this period of starvation has little or no effect on body weight, blood glucose or ketones. We propose that regulation of the neuroendocrine system during starvation could be the main physiological role of leptin.
Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism. Leptin's precise sites of action are not known. The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus. Ob-R is a member of the gp130 family of cytokine receptors which are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, we assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor where they are phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The activation of STAT proteins in response to leptin was assayed in a variety of mouse tissues known to express Ob-R. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wild-type mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes. Our data indicate the hypothalamus is a direct target of leptin action and that this activation is critically dependent on the gp-130-like leptin receptor isoform missing in C57BLKS/J db/db mice. This is the first in vivo demonstration of leptin signal transduction.
Leptin, or OB protein, is produced by fat cells and may regulate body weight by acting on the brain. To reach the brain, circulating leptin must cross the blood-brain barrier (BBB). Intravenously injected radioiodinated leptin (125I-leptin) had an influx constant (Ki) into brain of (5.87)10(-4) ml/g-min, a rate 20 times greater than that of labeled albumin. Unlabeled leptin inhibited the influx of 125I-leptin in a dose-dependent manner whereas unlabeled tyrosine and insulin, which have saturable transport systems, were without effect. HPLC and acid precipitation showed that the radioactivity in brain and serum represented intact 125I-leptin. About 75% of the extravascular 125I-leptin in brain completely crossed the BBB to reach brain parenchyma. Autoradiography detected uptake at the choroid plexus, arcuate nuclei of the hypothalamus, and the median eminence. Saturable transport did not occur out of the brain. The results show that leptin is transported intact from blood to brain by a saturable system.
Journal limitations on the number of permissable citations have prevented us from citing many additional important contributions made by workers in these fields. We regret that these references could not be more exhaustive. We gratefully acknowledge the helpful discussions and critiques provided by Drs. Regina Brun, Bradford Lowell, Barbara Kahn, Rudolf Leibel, and Steve Farmer. We also thank the members of our laboratories for their many contributions to the ideas presented here. This work was supported by grants R37DK28082 (JSF) and R37DK315405 (BMS) from the National Institutes of Health.
The Ob gene product, leptin, is secreted by adipocytes and is required for fertility in the mouse. Leptin-deficient mice are obese and infertile, symptoms reminiscent of polycystic ovary syndrome (PCOS). Prior studies have shown that serum leptin levels are elevated in a significant sub-population of anovulatory women with PCOS, suggesting that elevated leptin levels may adversely affect ovarian function. Since leptin receptor mRNA has been detected in the ovary, this study was designed to test the hypothesis that leptin may impair granulosa cell (GC) estradiol-17 beta (E2) production by a direct mechanism. GC were isolated from the ovaries of 26-day-old Sprague-Dawley rats, and were cultured (60,000 GC/well) in 96-well plates in the presence and absence of ovine FSH (0.001-100 ng/ml) and androstenedione (0.1 microM), with and without recombinant murine leptin (0.1-100 ng/ml) for 48 h. Leptin alone had no effect on E2 production. FSH caused a dose-related increase in E2 production by GC (ED50 = 1.9 +/- 0.4 ng/ml). Addition of leptin did not alter FSH-stimulated B2 levels. Concomitant treatment with FSH and IGF-I (30 ng/ml) augmented maximal FSH-dependent E2 production five-fold. Leptin caused a dose-dependent (IC50 = 2.7 +/- 0.6 ng/ml) inhibition (30-50%) of the IGF-I increase in FSH-stimulated E2 production. The inhibitory effect of leptin was specific for E2 production since there was no effect on basal, FSH-, or FSH+ IGF-I-dependent progesterone levels. The results of this study demonstrate that leptin can directly impair the IGF-I-mediated augmentation of FSH-stimulated E2 synthesis by GC. These data raise the possibility that high leptin levels may contribute to infertility in some women with PCOS by counteracting the sensitizing effects of IGF-I in dominant follicles.
The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.
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