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The effect of the Western-type diet on body weight gain and adiposity in wildtype (WT) and heterozygous OE-NPYDBH mice. Body weight gain curves (a, b), total weight gain (c, d), and fat tissue weights (e–h) were measured as described in Experiment 1 in Section 2, and presented here with females in the left panel (a, c, e, g) and males on the right (b, d, f, h). (a, c) Heterozygous female OE-NPYDBH mice gained significantly more weight during the diet in comparison with their WT littermates. (b, d) The male mice were equally susceptible to weight gain in both genotypes. (e) Mean total WAT weights, (f) total WAT per body weight in percentages, and (g-h) different WAT subclass and BAT weights in female (e, g) and male (f, h) wildtype and OE-NPYDBH mice. Values are expressed as means ± SEM. n = 15, WT females; n = 16, OE-NPYDBH females; n = 9, WT males; n = 10, OE-NPYDBH males. White squares and bars = WT; Black squares and bars = OE-NPYDBH. *P < 0.05 with a Student's t-test; **P < 0.01 with a Bonferroni posthoc test in repeated measures two-way ANOVA (a) or with a Student's t-test (c–g); ***P < 0.001 with a Bonferroni posthoc test in repeated measures two-way ANOVA.
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Neuropeptide Y (NPY) is a neurotransmitter associated with feeding and obesity. We have constructed an NPY transgenic mouse model (OE-NPY(DBH) mouse), where targeted overexpression leads to increased levels of NPY in noradrenergic and adrenergic neurons. We previously showed that these mice become obese on a normal chow. Now we aimed to study the e...
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The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat, contrasting the expectation that very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they...
Citations
... The NPY system is strongly associated with the regulation of appetite and energy expenditure in the hypothalamus [39]. The Y2R is in the centre of NPY-associated anti-obesity research and, until recently, a central stimulation would have been assumed to reduce weight and be beneficial, while a blockage would have been assumed to increase body weight [25,26,40]. Despite its central, appetite-regulating actions, Y2R are also involved in oxidative fuel selection and lipid metabolism in peripheral tissues like fat, bones, and liver [41]. ...
(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY3-36, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY3-36) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.
... NPY derived from the brain and sympathetic nerves is a central factor in the regulation of orexigenic activity and energy homeostasis. The exogenous administration or overexpression of NPY stimulates food intake, increases body weight, and promotes adiposity [5][6][7]. More recently, NPY has also been shown to be expressed in adipose tissue and to impact adipocyte metabolism via the control of lipogenesis and lipolysis [8,9]. ...
Obesity is characterized by the expansion of the adipose tissue, usually accompanied by inflammation, with a prominent role of macrophages infiltrating the visceral adipose tissue (VAT). This chronic inflammation is a major driver of obesity-associated comorbidities. Four-and-a-half LIM-domain protein 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of various biological functions and the maintenance of the homeostasis of different tissues. In this study, we aimed to gain new insights into the expression and functional role of FHL2 in VAT in diet-induced obesity. We found enhanced FHL2 expression in the VAT of mice with Western-type diet (WTD)-induced obesity and obese humans and identified macrophages as the cellular source of enhanced FHL2 expression in VAT. In mice with FHL2 deficiency (FHL2KO), WTD feeding resulted in reduced body weight gain paralleled by enhanced energy expenditure and uncoupling protein 1 (UCP1) expression, indicative of activated thermogenesis. In human VAT, FHL2 was inversely correlated with UCP1 expression. Furthermore, macrophage infiltration and the expression of the chemokine MCP-1, a known promotor of macrophage accumulation, was significantly reduced in WTD-fed FHL2KO mice compared with wild-type (wt) littermates. While FHL2 depletion did not affect the differentiation or lipid metabolism of adipocytes in vitro, FHL2 depletion in macrophages resulted in reduced expressions of MCP-1 and the neuropeptide Y (NPY). Furthermore, WTD-fed FHL2KO mice showed reduced NPY expression in VAT compared with wt littermates, and NPY expression was enhanced in VAT resident macrophages of obese individuals. Stimulation with recombinant NPY induced not only UCP1 expression and lipid accumulation but also MCP-1 expression in adipocytes. Collectively, these findings indicate that FHL2 is a positive regulator of NPY and MCP-1 expression in macrophages and herewith closely linked to the mechanism of obesity-associated lipid accumulation and inflammation in VAT. Thus, FHL2 appears as a potential novel target to interfere with the macrophage–adipocyte crosstalk in VAT for treating obesity and related metabolic disorders.
... In sum, in mice with a high NPY level, these antagonists prevented obesity promoted by an energy-rich diet, but increased obesity in control animals [32] ( Table 2). In an NPY transgenic mouse model in which adrenergic and noradrenergic neurons expressed a high level of NPY, it has been reported that female mice, in comparison with males, showed a higher increase in body weight (obesity) and both white/brown fat depots and showed a decrease in insulin sensitivity and impaired glucose tolerance after a Western-type energy-dense diet [44]. In transgenic/wild type animals, no difference regarding obesity was observed, but transgenic mice were more susceptible to develop diabetes [44]. ...
... In an NPY transgenic mouse model in which adrenergic and noradrenergic neurons expressed a high level of NPY, it has been reported that female mice, in comparison with males, showed a higher increase in body weight (obesity) and both white/brown fat depots and showed a decrease in insulin sensitivity and impaired glucose tolerance after a Western-type energy-dense diet [44]. In transgenic/wild type animals, no difference regarding obesity was observed, but transgenic mice were more susceptible to develop diabetes [44]. The results suggest that females show a higher risk to increase body weight under high caloric conditions. ...
... The results suggest that females show a higher risk to increase body weight under high caloric conditions. Moreover, the authors suggest a relationship between rs16139 polymorphism, high levels of NPY, and several metabolic risks [44]. It has been reported that NPY neurons located in the central amygdala promoted an accelerated development of obesity with a high-fat diet and under chronic stress conditions, since the activation of these neurons reduced energy expenditure and enhanced food intake [33] ( Table 2). ...
Obesity leads to several metabolic disorders and, unfortunately, current pharmacological treatments for obesity are not very effective. In feeding mechanisms, the hypothalamus and some neuropeptides play an important role. Many data show that neuropeptide Y (NPY) is involved in these mechanisms. The aim of this review is to update the physiological actions mediated by the orexigenic peptide NPY, via its receptors, in the control of food intake and to review its involvement in food intake disorders. The relationships between NPY and other substances involved in food intake mechanisms, hypothalamic and extra-hypothalamic pathways involved in feeding and the potential pharmacological strategies to treat obesity will be discussed. Some research lines, focused on NPY, to be developed in the future are suggested. Neuropeptide systems are associated with redundancy and then therapies directed against a single target are generally ineffective. For this reason, other targets for the treatment of obesity are mentioned. It seems that combination therapies are the best option for successful anti-obesity treatments: new and more specific NPY receptor antagonists must be tested as anti-obesity drugs alone and in combination therapies.
... NPY is a crucial factor that regulates appetite and energy expenditure in the brain [10]. NPY increases food intake and promotes adiposity when administered exogenously or overexpressed [11,12]. Conversely, suppression of NPY decreases weigh gain and adiposity in obese mice [13,14]. ...
Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD.
... In addition, NPY neurons in the ventrolateral medulla almost completely colocalize with markers for catecholaminergic neurons (Everitt et al., 1984;Harfstrand et al., 1987;Sawchenko et al., 1985;Tseng, Lin, Wang, & Tung, 1993) (Li, Wang, Dinh, & Ritter, 2009). Also, Npy overexpression in catecholaminergic brainstem neurons alters body composition independent of changes in food intake (Ruohonen et al., 2008;Ruohonen, Vahatalo, & Savontaus, 2012;Zhang et al., 2014). Though catecholaminergic/NPY neurons in the A1/C1 regions project to the hypothalamus (Sawchenko et al., 1985), a role for their possible connection with the VTA in regulating the above-mentioned processes cannot be excluded, and despite the relatively small size of the VTA afferent projection, it may have a substantial impact on energy homeostasis. ...
The hypothalamic neuropeptide Y (NPY) circuitry is a key regulator of feeding behavior. NPY also acts in the mesolimbic dopaminergic circuitry, where it can increase motivational aspects of feeding behavior through effects on dopamine output in the nucleus accumbens (NAc) and on neurotransmission in the ventral tegmental area (VTA). Endogenous NPY in the NAc originates from local interneurons and afferent projections from the hypothalamic arcuate nucleus (Arc). However, the origin of endogenous NPY in the VTA is unknown. We determined, in normal‐weight male Wistar rats, if the source of VTA NPY is local, and/or whether it is derived from VTA‐projecting neurons. Immunocytochemistry, in situ hybridization and RT‐qPCR were utilized, when appropriate in combination with colchicine treatment or 24h fasting, to assess NPY/Npy expression locally in the VTA. Retrograde tracing using cholera toxin beta (CTB) in the VTA, fluorescent immunocytochemistry and confocal microscopy were used to determine NPY‐immunoreactive afferents to the VTA. NPY in the VTA was observed in fibers, but not following colchicine pre‐treatment. No NPY‐ or Npy‐expressing cell bodies were observed in the VTA. Fasting for 24h, which increased Npy expression in the Arc, failed to induce Npy expression in the VTA. Double‐labeling with CTB and NPY was observed in the Arc and in the ventrolateral medulla.
Thus, VTA NPY originates from the hypothalamic Arc and the ventrolateral medulla of the brainstem in normal‐weight male Wistar rats. These afferent connections link hypothalamic and brainstem processing of physiologic state to VTA‐driven motivational behavior.
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... Mice with inactivation of the dopamine beta-hydroxylase gene (Dbh-null mice) gain weight on a high fat diet comparing to the control mice [22]. Similarly, the mouse model overexpressing NPY driven by DBH gene promoter (OE-NPY DBH ) displays obesity and impaired glucose metabolism [23][24][25]. Among the 143 differentially methylated genes in this study, the HLA set is of particular interest. ...
Objective
Exposure to stress during pregnancy may program susceptibility to the development of obesity in offspring. Our goal was to determine whether prenatal maternal stress (PNMS) due to a natural disaster was associated with child obesity, and to compare the DNA methylation profiles in obese versus non-obese children at age 13½ years. Women and their children were involved in the longitudinal natural disaster study—Project Ice Strom, which served as a human model to study PNMS. Blood was collected from 31 children (including five obese children). Infinium HumanMethylation450 BeadChip Array was performed for genome-wide DNA methylation analyses.
Results
Results demonstrated a well-defined obesity-associated genome-wide DNA methylation pattern. There were 277 CpGs, corresponding to 143 genes, were differentially-methylated. IPA analyses revealed 51 canonical pathways, and enrichment of pathways was involved in immune function. Although no significant association was found between PNMS and child obesity, the preliminary data in the study revealed obesity-associated methylation patterns on a genome-wide level in children.
Electronic supplementary material
The online version of this article (10.1186/s13104-019-4189-0) contains supplementary material, which is available to authorized users.
... Neuropeptide Y (NPY) is expressed in the hypothalamus with agouti-related peptide (Agrp) and functions to regulate the energy balance in the brain (5). NPY stimulates feeding and weight gain, thereby promoting adiposity when administered or overexpressed in the brain (6,7). Consistent with its role as an orexigenic peptide, NPY is increased during fasting or caloric restriction and suppressed by feeding, leptin, and insulin (5). ...
The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice.
Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.
... Mice were divided into treatment groups based on their body weights, and at the initiation of the drug treatments the body compositions were similar between treatment groups within the same genotype (Supplementary Figure 2). As previously shown, NPY mice had increased body weight and fat mass, and decreased lean mass compared to WT on chow, whereas DIO-NPY and DIO-WT mice had similar body weights and adiposity at the beginning of drug treatment (Ruohonen et al., 2012). Energy intake was similar between groups during the habituation period (Supplementary Figure 2). ...
Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y2-receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y2-receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y2-receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPYDβH) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y2-receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPYDβH and WT mice feeding on chow or Western diet. Treatment with Y2-receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y2-receptors induced obesity in WT mice, whereas OE-NPYDβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y2-receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y2-receptor antagonism has beneficial effects on metabolic status.
... The susceptibility to T2D was studied by disrupting pancreatic insulin secretion with STZ in mice with IR due to high caloric diet that induces obesity in a similar manner in OE-NPY DBH and WT mice, but is not sufficient to induce T2D in OE-NPY DBH mice (Ruohonen et al. 2012). Homozygous male OE-NPY DBH of 16-week-old and WT mice (n = 7/group) subjected to western diet (41% kcal fat, 43% kcal carbohydrate, 17% kcal protein, D12079B, Research Diets, New Brunswick, NJ, USA) for 3 weeks were administered a low-dose [40 mg/kg in 7.5 mg/ml Na-Citrate solution (pH 4.5), i.p.) of STZ (Sigma-Aldrich] after a 4-h fast on 3 consecutive days (week 0), followed by a single dose every 4.5 weeks to maintain hyperglycemia. ...
A gain-of-function polymorphism in human neuropeptide Y (NPY) gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPY(DBH)) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome -like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4-7-month-old) OE-NPY(DBH) mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with a Y1-receptor antagonist, BIBO3304. Obese OE-NPY(DBH) mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deteriation of glucose metabolism of OE-NPY(DBH) mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPY(DBH) mice. Hepatic inflammation was not morphologically visible, but up-regulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPY(DBH) mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPY(DBH) mice. Instead, down-regulation of beta1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated via changes in sympathetic nervous system activity.
... Neuropeptide Y (NPY) is a key factor that regulates orexigenic activity and energy homeostasis in the brain (Mercer et al., 2011). Fasting stimulates NPY (Sahu et al., 1992), which increases food intake and body weight (BW), thereby promoting adiposity when NPY is administered exogenously or overexpressed (Zarjevski et al., 1993;Ruohonen et al., 2012). Conversely, suppression of NPY signaling decreases BW gain and adiposity in obese mice (Ishihara et al., 2006;Chao et al., 2011). ...
Neuropeptide Y (NPY) is an orexigenic peptide that plays an essential role in caloric restriction (CR)-mediated lifespan extension. However, the mechanisms underlying the NPY-mediated effects in CR are poorly defined. Here, we report that NPY deficiency in male mice during CR increases mortality in association with lipodystrophy. NPY−/− mice displayed a rapid decrease in body weight and fat mass, as well as increased lipolysis during CR. These alterations in fat regulation were inhibited by the lipolysis inhibitor, acipimox, a treatment associated with reduced mortality. The lipolytic/thermogenic signaling, β3-adrenergic receptor/hormone sensitive lipase, was markedly activated in white adipose tissue of NPY−/− mice compared with that of NPY+/+ mice, and thermogenesis was controlled by NPY under negative energy balance. These results demonstrate the critical role of NPY in the regulation of lipid metabolic homeostasis and survival via control of lipolysis and thermogenesis in a state of negative energy balance.
