Figure 1 - uploaded by Georgia Lahr
Content may be subject to copyright.
A Boy with a Novel Mutation in the Leptin Gene. Panel A shows the weight curve for the patient, as compared with normal percentiles for boys of his age, before and after the start of treatment with metreleptin. Panel B is a photograph of the patient at the age of 2 years 6 months. Panel C shows the results after human embryonic kidney 293 (HEK293) cells were transiently transfected with empty vector or vector encoding nonmutant or D100Y leptin. After 48 hours, culture medium was collected and protein lysates were prepared. Leptin immunoreactivity was examined by Western blot analysis in cell lysates or medium supernatants , with β-actin serving as a loading control. The results of one representative experiment out of three performed are shown.
Source publication
Mutations in the gene encoding leptin (LEP) typically lead to an absence of circulating leptin and to extreme obesity. We describe a 2-year-old boy with early-onset extreme obesity due to a novel homozygous transversion (c.298G→T) in LEP, leading to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y) and high immunoreactive...
Contexts in source publication
Context 1
... patient is the first child of two healthy, nor- mal-weight Turkish parents with known consan- guinity (first-degree cousins). He was born at 40 weeks of gestation with normal birth weight (3680 g); rapid weight gain started in the post- natal period (Fig. 1A and 1B). At presentation, the boy was 2 years 6 months of age and weighed 33.7 kg (>99.9th percentile; z score, 7.2), with a height of 93.5 cm (69.1st percentile; z score, 0.5). His body-mass index (the weight in kilograms divided by the square of the height in meters) was 38.6 (>99.9th percentile; z score, 5.8). Food- seeking behavior was ...
Context 2
... the hormone. Therefore, we studied the secretory behavior of the D100Y mutant in a heterologous cell system. Plasmids encoding nonmutant and mutant leptin were transiently introduced into HEK293 cells. Both nonmutant and mutant proteins were abun- dantly present in cell lysates and were also de- tected in the medium supernatants of intact cells (Fig. 1C). This clearly shows that the novel muta- tion interferes neither with protein expression nor with secretion of ...
Context 3
... lean body weight per day was chosen on the basis of previous experience with young pa- tients with congenital leptin deficiency. 13 Subcu- taneous metreleptin administration in our patient resulted in a rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss, as well as in metabolic and hormonal changes ( Fig. 1A and Table ...
Similar publications
In fish models, seasonal change in feeding is under the influence of water temperature. However, the effects of temperature on appetite control can vary among fish species and the mechanisms involved have not been fully characterized. Using goldfish (Carassius auratus) as a model, seasonal changes in feeding behavior and food intake were examined i...
The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressi...
Leptin is a hormone protein regulating food intake and energy expenditure. A number of studies have evaluated the genetic effect of leptin (
LEP
) and leptin receptor (
LEPR
) genes on T2DM. This study aimed to investigate the association between these gene polymorphisms and T2DM by a systematic review and meta-analysis. Published studies were iden...
![Figure I.8 Representation and results of [Horgan, 2011] model. A....](profile/Marine-Jacquier/publication/295932273/figure/fig4/AS:669457282252808@1536622462668/Representation-and-results-of-Horgan-2011-model-A-Schematic-representation-of-the_Q320.jpg)
The regulation of food intake and energy expenditure usually limits important loss or gain of body weight. Hormones (leptin, ghrelin, insulin) and nutrients (glucose, triglycerides) are among the main regulators of food intake. Leptin is also involved in leptin resistance, often associated with obesity and characterized by a reduced efficacy to reg...
Objectives
Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression.
Methods
Because STAT3 is crucial for physiologic leptin action, we...
Citations
... Antisense oligonucleotides (ASOs) that alter protein expression in debilitating diseases are another promising modality based on precise genetic diagnosis. Recombinant leptin therapy (metreleptin) is the first targeted therapy effective in individuals with either absent [9,10] or ineffective leptin [11,12]. Recently, FDA approved the use of setmelanotide, a second generation α-melanocyte stimulating hormone (α-MSH) analog for some genetic forms of obesity [13••, 14••]. ...
Purpose of Review
The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care.
Recent Findings
Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% –new variants in known genes as well as identification of novel genes– causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity.
Summary
While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier.
... Leptin is transported from the blood to the brain's interstitial tissue and cerebrospinal fluid through brain blood arteries that produce short versions of Lep-R, which bind to leptin [28]. The concentration of leptin in brain tissues and CSF fluid is maintained such that under normal conditions it does not rise above a range of 25-30 ng/mL in serum. ...
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.
... Metreleptin was approved by the United States Food and Drug Administration in 2014 as a replacement therapy to treat the complications of leptin deficiency [165]. In patients with congenital leptin deficiency, subcutaneous injection of human recombinant leptin leads to reduced food intake, fat mass, and body weight, as well as improved hyperinsulinemia, hyperlipidemia, liver steatosis, and hypogonadism [166][167][168][169]. Notably, leptin supplementation is ineffective in patients with LEPR deficiency, as dysfunctional LEPRs preclude the ability of increased leptin to activate the MC4R pathway [27]. ...
Background
Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies.
Methods
In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity.
Results
Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists.
Conclusion
Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.
... Overall, appetite-regulating adipokines in human milk are suggested to affect newborn's and infants' milk intake and possibly offspring growth [91,106,107]. According to Adamska-Patruno and coworkers [108], the shift in the balance between serum ghrelin and other appetite-regulating hormones affects energy homeostasis [109][110][111]. Taking the above into consideration, it seems that the imbalance between colostral ghrelin and other appetite-regulating hormones might translate into altered offspring metabolic homeostasis; however, more investigations in this field are needed. ...
Gestational diabetes mellitus (GDM) is a complex metabolic disorder that has short- and long-term effects on maternal and offspring health. This study aimed to assess the impact of maternal hyperglycemia severity, classified as GDM-G1 (diet treatment) and GDM-G2 (insulin treatment) on colostral appetite-regulating molecules. Colostrum samples were collected from hyperglycemic (N = 30) and normoglycemic (N = 21) mothers, and the concentrations of milk hormones were determined by immunoenzymatic assay. A difference was found for milk ghrelin, but not for molecules such as adiponectin, leptin, resistin, or IGF-I levels, in relation to maternal hyperglycemia. The colostral ghrelin in the GDM-G1 cohort (0.21 ng/mL) was significantly lower than for GDM-G2 (0.38 ng/mL) and non-GDM groups (0.36 ng/mL). However, colostral resistin was higher, but not significantly, for GDM-G1 (13.33 ng/mL) and GDM-G2 (12.81 ng/mL) cohorts than for normoglycemic mothers (7.89 ng/mL). The lack of difference in relation to hyperglycemia for milk leptin, adiponectin, leptin–adiponectin ratio, resistin, and IGF-I levels might be the outcome of effective treatment of GDM during pregnancy. The shift between ghrelin and other appetite-regulating hormones might translate into altered ability to regulate energy balance, affecting offspring’s metabolic homeostasis.
... The infrequent allele is associated with a lower BMI 21 . Further, we have to note that pathogenic variants typically are present homozygously 15,71 . For heterozygous MC4R variants, carrier develop obesity later in childhood 13 , while for heterozygous LEP variants, carriers are mainly unaffected 15,71 . ...
... Further, we have to note that pathogenic variants typically are present homozygously 15,71 . For heterozygous MC4R variants, carrier develop obesity later in childhood 13 , while for heterozygous LEP variants, carriers are mainly unaffected 15,71 . As we have exclusively detected heterozygous variants in both genes, the relevance remains unknown. ...
Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in LEP and MC4R, respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1) LEP: reduced/loss of function (p.Val94Met), (2) MC4R: gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211fsX) and without functional in vitro data (p.Val50Leut). In LEP, the variant p.Val94Met was detected in one patient with AN. For MC4R variants, one patient with AN carried the frameshift variant p.Leu211fsX. One patient with AN was heterozygous for two variants at the MC4R (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.
... Leptin loss-of-function missense variants have been described in humans with severe obesity (2,(12)(13)(14). These typically result in low serum leptin (2,12,15). ...
... Another class of leptin deficiency is associated with normal-to-high serum leptin, but these variants are biologically inactive due to structural alterations that affect receptor binding (13). Recently, variants that antagonise the leptin receptor have also been reported (16). ...
... The variants selected were linked to low serum leptin (p.L72S, p.N103K, p.R105W, p.C117Y, p.P23R) (12,(21)(22)(23)(24) and/or those associated with obesity with a less clear or debated mechanism-of-action (p.H118L, p.S141C, p.D100N) (25, 26) ( Table 1). As negative controls, we included three variants (p.G59S, p.P64S, p.D100Y) (13,16) previously characterised as biologically inactive with no secretory phenotype, and one variant (p.V110M) found in an overweight (BMI 27.2) individual with normal serum leptin (27). Each variant was cloned into a piggyBac RUSH plasmid system (28,29), and 12 stable cell lines were generated for analysis. ...
The hormone leptin, primarily secreted by adipocytes, plays a crucial role in regulating whole-body energy homeostasis. Homozygous loss-of-function mutations in the leptin gene (LEP) cause hyperphagia and severe obesity, primarily through alterations in leptin’s affinity for its receptor or changes in serum leptin concentrations. Although serum concentrations are influenced by various factors (e.g., gene expression, protein synthesis, stability in the serum), proper delivery of leptin from its site of synthesis in the endoplasmic reticulum via the secretory pathway to the extracellular serum is a critical step. However, the regulatory mechanisms and specific machinery involved in this trafficking route, particularly in the context of human LEP mutations, remain largely unexplored.
We have employed the Retention Using Selective Hooks (RUSH) system to elucidate the secretory pathway of leptin. We have refined this system into a medium-throughput assay for examining the pathophysiology of a range of obesity-associated LEP variants. Our results reveal that leptin follows the default secretory pathway, with no additional regulatory steps identified prior to secretion.
Through screening of leptin variants, we identified three mutations that lead to proteasomal degradation of leptin and one mutant that significantly decreased leptin secretion, likely through aberrant disulfide bond formation. These observations have identified novel pathogenic effects of leptin variants, which can be informative for therapeutics and diagnostics. Finally, our novel quantitative screening platform can be adapted for other secreted proteins.
... In 1999, leptin deficiency-diagnosed in homozygous LEP gene mutation carriers with severe obesity-was successfully treated with leptin administration [62]. Indeed, subcutaneous injection of human recombinant leptin (metreleptin) is notably beneficial for patients with leptin deficiency, leading to improved food control and weight reduction, as well as improvement of metabolic and endocrine dysregulations [63]. Reported side effects include the production of antibodies against leptin and an increased susceptibility to lymphomas [62]. ...
Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between December 2022 and December 2023. We used the terms “obesity”, “genetics”, “monogenic”, “syndromic”, “drugs”, “autosomal dominant”, “autosomal recessive”, “leptin-melanocortin pathway”, and “children” in different combinations. Recognizing the genetic background in obesity can enhance the effectiveness of treatment. During the last years, intense research in the field of obesity treatment has increased the number of available drugs. This review analyzes the main categories of syndromic and monogenic obesity discussing current data on genetic-based pharmacological treatment of genetic obesity and highlighting the necessity that cases of genetic obesity should follow specific, pharmacological treatment based on their genetic background.
... Patients with congenital leptin deficiency or dysfunction can be treated with hormone replacement therapy. In cases of leptin deficiency, subcutaneous administration of human recombinant leptin at a dose of 0.03 mg/kg of lean body mass daily has been shown to have prompt effects on eating behaviour, reducing food intake and leading to loss of adipose mass and body weight [29][30][31]. Metreleptin administration has also been associated with favourable metabolic outcomes, including improvements in hyperinsulinaemia, hyperlipidaemia, hepatic steatosis, and central hypogonadism, with the onset of puberty evidenced by gonadotropin secretion and menarche. These positive effects can be observed shortly after starting therapy, as demonstrated by rapid improvement in liver lipid content [32]. ...
The prevalence of obesity in children and adolescents is increasing, and it is recognised as a complex disorder that often begins in early childhood and persists throughout life. Both polygenic and monogenic obesity are influenced by a combination of genetic predisposition and environmental factors. Rare genetic obesity forms are caused by specific pathogenic variants in single genes that have a significant impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. Genetic testing is recommended for patients who exhibit rapid weight gain in infancy and show additional clinical features suggestive of monogenic obesity as an early identification allows for appropriate treatment, preventing the development of obesity-related complications, avoiding the failure of traditional treatment approaches. In the past, the primary recommendations for managing obesity in children and teenagers have been focused on making multiple lifestyle changes that address diet, physical activity, and behaviour, with the goal of maintaining these changes long-term. However, achieving substantial and lasting weight loss and improvements in body mass index (BMI) through lifestyle interventions alone is rare. Recently the progress made in genetic analysis has paved the way for innovative pharmacological treatments for different forms of genetic obesity. By understanding the molecular pathways that contribute to the development of obesity, it is now feasible to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms.
Conclusion: However, additional preclinical research and studies in the paediatric population are required, both to develop more personalised prevention and therapeutic programs, particularly for the early implementation of innovative and beneficial management options, and to enable the translation of these novel therapy approaches into clinical practice. What is Known:
• The prevalence of obesity in the paediatric population is increasing, and it is considered as a multifaceted condition that often begins in early childhood and persists in the adult life. Particularly, rare genetic forms of obesity are influenced by a combination of genetic predisposition and environmental factors and are caused by specific pathogenic variants in single genes showing a remarkable impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway.
• Patients who present with rapid weight gain in infancy and show additional clinical characteristics indicative of monogenic obesity should undergo genetic testing, which, by enabling a correct diagnosis, can prevent the development of obesity-related consequences through the identification for appropriate treatment.
What is New:
• In recent years, advances made in genetic analysis has made it possible to develop innovative pharmacological treatments for various forms of genetic obesity. In fact, it is now achievable to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms by understanding the molecular pathways involved in the development of obesity.
• As demonstrated over the last years, two drugs, setmelanotide and metreleptin, have been identified as potentially effective interventions in the treatment of certain rare forms of monogenic obesity caused by loss-of-function mutations in genes involved in the leptin-melanocortin pathway. Recent advancements have led to the development of novel treatments, including liraglutide, semaglutide and retatrutide, that have the potential to prevent the progression of metabolic abnormalities and improve the prognosis of individuals with these rare and severe forms of obesity. However, extensive preclinical research and, specifically, additional studies in the paediatric population are necessary to facilitate the translation of these innovative treatment techniques into clinical practice.
... Similarly, all of our previously published (#11, #13-16) patients of LEP deficiency experienced pubertal problems, such as pubertal delay or menstrual irregularities, which were completely reversed by metreleptin treatment. Given that the majority of individuals with LEP deficiency were diagnosed before puberty, and, even among them, some of the previously described (33,53,54,70) prepubescent patients also had low FSH levels, current estimations may not be conclusive. ...
... p.D100Y) may generate an inactive protein that circulates in plasma (resulting in high leptin levels) being biologically inoperative. [299]Body composition evaluation shows that congenital leptin deficiency is characterized by preferential deposition of fat mass. [300,301] Information on the degree of insulin sensitivity in patients with mutations in the leptin gene is limited. ...
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
