RARE DISEASE
Obesity due to congenital leptin deficiency
Obesity due to congenital leptin deficiency
Obesity due to congenital leptin deficiency
Drug discovery
169
papers
On emerging therapies
Overview
Obesity due to congenital leptin deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the LEP gene, leading to undetectable serum leptin levels. It presents with severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, recurrent infections, and metabolic abnormalities (hyperinsulinemia, dyslipidemia). Diagnosis involves genetic testing and low serum leptin levels. Daily recombinant leptin (metreleptin) therapy normalizes appetite, weight, and endocrine function, significantly improving prognosis [1][6][11][12].
Burden
Mortality: Up to 26% in untreated children due to severe infections (respiratory/gastrointestinal) [2][7].
Morbidity: Hypogonadism, immune dysfunction, insulin resistance, and developmental delays without treatment [1][11][12].
Psychosocial impact: Hyperphagia-driven food-seeking behaviors (hoarding, aggression) impair quality of life [6][11].
Therapies
Recombinant leptin (metreleptin): Subcutaneous administration reverses hyperphagia, induces weight loss, restores puberty, and improves immune/metabolic function [1][9][12][13].
Supportive care: Management of infections (e.g., pneumonia, gastrointestinal), metabolic complications (e.g., diabetes), and endocrine dysfunction (e.g., thyroid replacement) [2][7][10].
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders
Research Papers
169 drug discovery papers about Obesity due to congenital leptin deficiency, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
169 drug discovery papers about Obesity due to congenital leptin deficiency, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-21 | Can Leptin Responsiveness Be Restored in Common Human Obesity?
In 1994, leptin was identified as a hormone that signals the brain to reduce food intake and increase energy expenditure. Leptin was initially considered a breakthrough therapy for obesity. This was largely based on animal studies, showing that leptin reversed obesity in individuals with congenital leptin deficiency and normal leptin receptor sensitivity. However, due to leptin resistance, leptin therapy failed to reduce weight in common human obesity. Consequently, interest in leptin waned for many years. However, recent studies in animal models of common obesity show that combining leptin with other weight-loss-stimulating agents, can restore hypothalamic leptin sensitivity and induce a greater reduction of body weight than after single drug treatment. Moreover, after initially reducing weight by combination therapy, leptin monotherapy proved enough to maintain reduced body weight. The strongest evidence for restoring leptin’s weight-lowering actions in common obesity to date comes from mouse studies in which leptin was combined with other pharmacotherapies. However, it is unclear at this moment whether this strategy also can be used to treat common human obesity successfully. Overcoming leptin resistance, by combining leptin with other pharmacotherapies, is a promising strategy that needs to be further investigated in humans with obesity.
2026-08-01 | OC11.2 - ECE_2967 - Metreleptin therapy in pediatric and adult patients with congenital leptin deficiency: a multicenter real-world experience
Abstract Background Congenital leptin deficiency (CLD) is a rare monogenic cause of severe early-onset obesity and hyperphagia, with limited long-term real-world evidence on metreleptin therapy. In this study, we aimed to evaluate the long-term clinical outcomes and safety of metreleptin therapy in a large, multicenter cohort of pediatric and adult patients. Methods We conducted a multicenter, observational cohort study including 17 patients with CLD (10 pediatric, 7 adult) across 8 centers. Clinical characteristics, genetic findings, longitudinal anthropometric measurements, metabolic parameters, and total daily metreleptin doses were systematically evaluated. Pediatric and adult cohorts were analyzed separately to account for age- and growth-related trajectories. Repeated-measures analyses were performed in subgroups with complete longitudinal data. One patient who developed loss of efficacy due to neutralizing antibodies was presented separately. Results Obesity onset clustered within the first year of life in 87.5% of patients, and hyperphagia was present in all patients at baseline. Pathogenic or likely pathogenic LEP gene variants were identified in most cases; three individuals with ongoing genetic analyses were included based on markedly low leptin levels and a robust clinical response to metreleptin. Across the entire cohort, metreleptin induced a marked, time-dependent reduction in BMI (median −25.7% at month 6; −40.7% at month 18). In pediatric patients, BMI and BMI SDS decreased substantially (mean BMI SDS 5.52 ± 1.47 at baseline to 2.66 ± 1.37 by month 24) and remained stable long term; all children showed a net BMI SDS reduction at last follow-up. Linear growth was preserved, with stable height SDS and no evidence of growth attenuation. In adults, BMI decreased from 55.7 kg/m2 at baseline to 29.9 kg/m2 by month 18, with subsequent inter-individual variability but overall preservation of therapeutic gains. Glycemic and lipid parameters remained largely within reference ranges, no severe adverse events occurred, and total metreleptin doses remained stable without systematic escalation. A boy with a large deletion in the LEP gene started metreleptin at 24 months and initially lost 10 kg. By month 6, he began regaining weight and developed injection-site reactions. He tested strongly positive for neutralizing antibodies and was later treated with an investigational agent. Conclusions This multicenter cohort is among the largest real-world series jointly evaluating pediatric and adult patients with congenital leptin deficiency. Metreleptin was effective and well-tolerated during long-term follow-up in routine clinical practice. Neutralizing antibody–associated loss of efficacy occurred in one patient; otherwise, responses were sustained without clinically relevant safety signals.
2025-10-04 | Leptin: 30 Years Later.
The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.
2025-09-27 | Response to long-term pharmacological management of metreleptin in a patient with monogenic obesity due to mutation in the LEP gene.
The cases of obesity worldwide have increased significantly, with this condition being considered a global pandemic. This pathology poses a major health problem due to its high morbidity burden. Its cause in the majority of cases is multifactorial; however, there are various cases of monogenic obesity reported in the literature. Mutation in the leptin gene causes a marked decrease in leptin levels, leading to intense hyperphagia and associated morbid obesity. Substituting leptin with metreleptin is a treatment option for these patients. We present the case of a patient with morbid obesity due to a single mutation in the LEP gene and approximately four years of treatment with metreleptin as a substitute therapy. Weight decreased from 154 to 64 kg and BMI decreased from 68.4 to 28.4 kg/m2. The patient achieved a reduction of 40 kg/m2 in BMI, corresponding to a body weight loss of 90 kg, with a significant improvement in associated metabolic comorbidities, acne, and hirsutism.
2025-08-29 | Structural and functional characterization of the Pro64Ser leptin mutant: Implications for congenital leptin deficiency.
Congenital leptin deficiency or dysfunction is a form of monogenic childhood obesity. The disease is primarily caused by mutations in the LEP gene, which encodes for the expression of a hormone called leptin. The mutations typically impair leptin synthesis, secretion, or binding to the leptin receptor (LepR). The Pro64Ser mutation in leptin, despite not affecting the protein's stability or its binding affinity to the LepR, completely abolishes the protein's ability to mediate intracellular signaling via the LepR. To elucidate the mechanism underlying this signal inhibition and to further understand the mechanism of leptin-mediated LepR signal transduction, we performed extensive molecular dynamics simulations of both the wild-type and mutant (MT) leptins. Our simulations reveal that the Pro64Ser mutation increases the rigidity of AB loop N-terminus and thus prevents the loop's conformational changes required for interaction with the LepR immunoglobulin-like domain (IgD). Conversely, the CD loop of the MT exhibits increased flexibility compared with the wild-type. This elevated flexibility potentially hinders the protein's transition into helical structure and subsequent interaction with the IgD. Given that the interactions between leptin and the LepR IgD are crucial for the formation of higher-order leptin-LepR assembly and the following intracellular signal transduction, the observed changes in the MT leptin loop dynamics provide a mechanistic explanation for the signaling defects.
small molecules
2025-09-11 | Leptin and leptin resistance in obesity: current evidence, mechanisms and future directions.
Leptin, a key adipokine regulating energy homeostasis, has been extensively studied for its potential in the management of obesity. However, its therapeutic efficacy is often limited due to leptin resistance. This review synthesizes animal and clinical evidence on leptin's role in obesity, focusing on models such as genetically deficient mice (e.g., ob/ob, db/db), diet-induced obesity mice, and clinical conditions such as congenital leptin deficiency (CLD), leptin receptor deficiency (LRD), lipodystrophy, and common obesity. The mechanisms underlying leptin resistance are summarized, including hyperleptinemia, impaired JAK2-STAT3 signaling, reduced blood-brain barrier permeability, defective autophagy, endoplasmic reticulum stress, inflammation, decreased leptin receptor expression, leptin signaling pathway dysfunction, increased mTOR activity, and peripheral leptin resistance. Due to these leptin receptor and/or post-receptor signaling pathway defects, leptin or its analogs usually fail to produce the expected weight-loss effect in individuals with overweight or obesity, although they remain highly effective in individuals with CLD and lipodystrophy, as well as in ob/ob mice. Alternative strategies, such as melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide) for LRD treatment, are very promising. Future directions include enhancing leptin sensitization, combining leptin with other drugs, and exploring partial leptin reduction to mitigate compensatory responses during weight loss. The review emphasizes the complexity of leptin resistance and the necessity of targeted approaches in obesity therapy.
2023-09-07 | A Negative Feedback Loop Between TET2 and Leptin in Adipocyte Regulates Body Weight
Abstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a novel compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.
2022-08-07 | Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin
Abstract TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α−η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11- deficient mice phenocopies Trp73 -deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ, necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.
2022-08-01 | Role of Sodium dependent SLC13 transporter and its inhibitors in various metabolic disorders
The sodium dependent SLC13 family transporters comprise of the five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them the three NaDC1, NaDC3 and NaCT are sodium dependent transporters such as di-carboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, the information to the structures is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these receptors and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of the citrate present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporter are required for the development of citrate inhibitors. In this review the structure, function, and regulation of the NaCT receptors are discussed. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT receptors are succinctly summarized.
2022-03-03 | Conjugated linoleic acid ameliorates hepatic steatosis by modulating intestinal permeability and gut microbiota in ob/ob mice
Background: Conjugated linoleic acid (CLA) is an effective supplement for reducing fat mass, but its effect on hepatic steatosis remains controversial. Objective: This study aims to evaluate the effect of CLA on liver fat accumulation, inflammation, gut microbiome, and intestinal barrier integrity. Design: Wild-type (WT) mice and ob/ob (OB) mice were randomly divided into four groups according to the treatment with/without 1% CLA: WT, WT mice treated with CLA (WT-CLA), OB, and OB mice treated with CLA (OB-CLA). Lipid metabolism and hepatic fat accumulation were evaluated by changes in histological and biochemical parameters. Gene expressions related to liver inflammation and intestinal barrier integrity were examined. The effect of CLA on the gut microbiota population was investigated. Results: The body weight, fatty tissue mass, and serum lipid levels of the WT-CLA group and OB-CLA group were separately lower than those of the WT group and OB group, but the livers of the WT-CLA group had more fatty lipids, higher triglyceride properties, and saturated fatty acid (FA) composition than those of the WT group, which was contrary to the effect of CLA on OB mice. Real time quantitative PCR results showed that CLA increased hepatic inflammation and intestinal permeability in the WT mice, while it significantly decreased the mRNA expression of liver TNF-α, IFN-γ, and IL-1β and markedly ameliorated intestinal tight junction proteins in the OB mice. The gut microbiota testing indicated a higher abundance of beneficial bacteria (e.g., Lachnoclostridium, Roseburia, Dubosiella, Oscillibacter, and Anaerostipes) and a lower abundance of pro-inflammatory bacteria (e.g., Tyzzerella and Alistipes) in the OB-CLA group than those of the OB group. Correlation analysis suggested that gut microbiota correlated with liver inflammation, intestinal permeability, and hepatic FA composition. Conclusion: CLA potentially contributed to ameliorating hepatic steatosis in OB mice via modulating liver inflammation, intestinal permeability, and gut microbiota, which suggests CLA is more suitable for people with obesity or overweight.
gene therapies
2025-07-25 | Subcutaneous administration of adipose-tropic gene therapy for congenital leptin deficiency.
AAV-based gene therapy targeting adipose tissue has been underdeveloped due to lack of adipose-tropic AAV vectors with sufficient transduction efficiency. We previously demonstrated that an engineered capsid variant of Rec2 capsid with F503Y, Y708D and K709I substitution (named V7 capsid) exhibited highly selective adipo-tropism while ablating liver transduction upon intraperitoneal injection or intravenous injection. In this study, we investigated the feasibility of subcutaneous administration of V7 vector harboring human leptin (V7-LEP) in a congenital leptin deficiency model ob/ob mice. Subcutaneous administration of V7-LEP vector at a low dose of 4×1010 viral genome per mouse restored circulating leptin levels and completely normalized metabolic abnormalities associated with leptin deficiency. In an ongoing long-term experiment, one-time subcutaneous administration of V7-LEP to extreme obese ob/ob mice has led to sustained weight loss at least up to 9 months post injection associated with stable circulating human leptin levels throughout the long-term study. These data indicate subcutaneous injection is a feasible and relevant administration route for gene therapy targeting adipose tissue, and V7-LEP is highly efficacious for congenital leptin deficiency and potentially other lipodystrophy disorders with leptin deficiency.
2025-07-01 | Dose-finding and in vivo safety study of an adipose targeted leptin gene therapy for congenital leptin deficiency.
Congenital leptin deficiency is a monogenic disease originated from adipose tissue, causing hyperphagia, severe obesity, and hyperinsulinemia. Moreover, most forms of lipodystrophy syndromes exhibit leptin deficiency. Leptin replacement therapy with leptin protein analog requires frequent injection for life and is extremely expensive. We previously reported that a single intraperitoneal injection of an adipose-targeting Rec2-leptin adeno-associated virus (AAV) vector normalized metabolic syndromes in the leptin deficient ob/ob mice. Here, we conducted a dose-deescalating study with four doses (2E10, 1E10, 5E9, and 1E9 viral genome per mouse) in ob/ob mice and extended in vivo monitoring to 27 weeks post dosing. Rec2-leptin at all doses normalized excessive weight gain, hyperphagia, obesity, low core temperature, glucose intolerance, and hyperinsulinemia in the ob/ob mice. Transgene expression was restricted in the targeting visceral adipose tissues and sustained throughout the 27-weeks study. Rec2-leptin at the lowest dose 1E9 viral genome (vg)/mouse restored the circulating leptin level to 18% of the normal level of wild-type (WT) mice. Rec2-leptin at all doses reversed liver steatosis and pancreatic islet hyperplasia. Behavioral assessment, serum chemistry, and histopathology noted no significant adverse effects attributed to Rec2-leptin. This study demonstrates that Rec2-leptin is safe and highly efficacious, supporting further development for genetic or acquired leptin deficiency.
2024-02-24 | Syndromic and Monogenic Obesity: New Opportunities Due to Genetic-Based Pharmacological Treatment.
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.
2022-01-18 | Leptin gene-targeted editing in ob/ob mouse adipose tissue based on the CRISPR/Cas9 system.
Gene therapy has become the most effective treatment for monogenic diseases. Congenital LEPTIN deficiency is a rare autosomal recessive monogenic obesity syndrome caused by mutations in the Leptin gene. Ob/ob mouse is a monogenic obesity model, which carries a homozygous point mutation of C to T in Exon 2 of the Leptin gene. Here, we attempted to edit the mutated Leptin gene in ob/ob mice preadipocytes and inguinal adipose tissues using CRISPR/Cas9 to correct the C to T mutation and restore the production of LEPTIN protein by adipocytes. The edited preadipocytes exhibit a correction of 5.5% of Leptin alleles and produce normal LEPTIN protein when differentiated into mature adipocytes. The ob/ob mice display correction of 1.67% of Leptin alleles, which is sufficient to restore the production and physiological functions of LEPTIN protein, such as suppressing appetite and alleviating insulin resistance. Our study suggests CRISPR/Cas9-mediated in situ genome editing as a feasible therapeutic strategy for human monogenic diseases, and paves the way for further research on efficient delivery system in potential future clinical application.
2018-02-15 | Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C
Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg−1 day−1) and pair-fed]. Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.
antibodies
2023-11-24 | Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.
2020-07-01 | Selection of a Full Agonist Combinatorial Antibody that Rescues Leptin Deficiency In Vivo
Abstract Growth factor deficiency in adulthood constitutes a distinct clinical syndrome with significant morbidities including abnormal body composition, reduced energy, affective disturbances, dyslipidemia, and increased cardiovascular risk. Protein replacement therapies using recombinant proteins or enzymes represent the only approved treatment. Combinatorial antibodies have shown great promise as a new class of therapeutic molecules because they act as “mechanism‐based antibodies” with both agonist and antagonist activities. Using leptin, a key hormone in energy metabolism, as an example, a function‐guided approach is developed to select combinatorial antibodies with high potency and full agonist activity that substitute natural growth factors in vivo. The identified antibody shows identical biochemical properties and cellular profiles as leptin, and rescues leptin‐deficiency in ob/ob mice. Remarkably, the antibody activates leptin receptors that are otherwise nonfunctional because of mutations (L372A and A409E). Combinatorial antibodies have significant advantages over recombinant proteins for chronical usage in terms of immunological tolerance and biological stability.
2018-02-21 | Genetics of Obesity in Consanguineous Populations: Toward Precision Medicine and the Discovery of Novel Obesity Genes
Objective Consanguinity has been instrumental in the elucidation of many Mendelian genetic diseases. Here, the unique advantage of consanguineous populations was considered in the quest for genes causing obesity. Methods PubMed was searched for articles relevant to consanguinity and obesity published between 1995 and 2016. Some earlier articles of interest were also consulted. Results Although obesity is the most heritable disorder, even in outbred populations, only 2% to 5% of severe obesity cases have so far been proven to be caused by single gene mutations. In some highly consanguineous populations, a remarkably higher proportion of obesity cases because of known and novel monogenic variants has been identified (up to 30%). Conclusions Combining the power conferred by consanguinity with current large‐capacity sequencing techniques should bring new genetic factors and molecular mechanisms to the fore, unveiling a large part of the yet‐elusive neurohumoral circuitry involved in the regulation of energy homeostasis and appetite. Importantly, the undertaking of such initiatives is destined to unfold novel targets for the development of precision medicine relevant to different forms of obesity.
2016-06-21 | An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse.
Objective Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half‐life and low immunogenicity could be useful in the treatment of this condition. Methods Phage display technology coupled with flow cytometry and cell‐based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP‐deficient Lep ob /Lep ob mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured. Results XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep ob /Lep ob mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects. Conclusions Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency.
2012-03-01 | Structure of the Human Obesity Receptor Leptin-Binding Domain Reveals the Mechanism of Leptin Antagonism by a Monoclonal Antibody
Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR. We describe the structure of the LBD-9F8 Fab complex and the conformational changes in 9F8 associated with LBD binding. A molecular model of the putative leptin-LBD complex reveals that 9F8 Fab blocks leptin binding through only a small (10%) overlap in their binding sites, and that leptin binding is likely to involve an induced fit mechanism. This crystal structure of the leptin-binding domain of the obesity receptor will facilitate the design of therapeutics to modulate leptin signaling.
other
2021-12-29 | Pinch Loss Ameliorates Obesity, Glucose Intolerance, and Fatty Liver by Modulating Adipocyte Apoptosis in Mice.
The mammalian focal adhesion proteins Pinch1/2 activate integrins and promote cell-extracellular matrix adhesion and migration; however, their roles in adipose tissue and metabolism are unclear. Here we find that high-fat diet (HFD) feeding dramatically increases expression of Pinch1/2 proteins in white adipose tissue (WAT) in mice. Furthermore, expression of Pinch1 is largely upregulated in WAT in leptin-deficient ob/ob type 2 diabetic mice and obese humans. While mice with loss of Pinch1 in adipocytes or global Pinch2 do not display any notable phenotypes, deleting Pinch1 in adipocytes and Pinch2 globally significantly decreases body weight and WAT mass, but not brown adipose tissue mass, in HFD-fed, but not normal chow diet-fed, mice. Pinch loss ameliorates HFD-induced glucose intolerance and fatty liver. After HFD challenge, Pinch loss slightly but significantly accelerates energy expenditure. While Pinch loss decreases adipocyte size and alters adipocyte size distribution, it greatly accelerates cell apoptosis primarily in epididymal WAT and to a lesser extent in subcutaneous WAT. In vitro studies demonstrate that Pinch loss accelerates adipocyte apoptosis by activating the Bim/Caspase-8 pathway. In vivo, genetic ablation of Caspase-8 expression in adipocytes essentially abolishes the ameliorating effects of Pinch deficiency on obesity, glucose intolerance, and fatty liver in mice. Thus, we demonstrate a previously unknown function of Pinch in control of adipose mass, glucose, and fat metabolism via modulation of adipocyte apoptosis. We may define a novel target for the prevention and treatment of metabolic diseases, such as obesity and diabetes.
2016-11-18 | Knockdown of PTRF ameliorates adipocyte differentiation and functionality of human mesenchymal stem cells
Healthy expansion of human adipose tissue requires mesenchymal stem cells (hMSC) able to proliferate and differentiate into mature adipocytes. Hence, characterization of those factors that coordinate hMSC-to-adipocyte transition is of paramount importance to modulate the adipose tissue expansion. It has been previously reported that the adipogenic program of hMSC can be disrupted by upregulating caveolar proteins, and polymerase I and transcript release factor (PTRF) is an integral component of caveolae, highly expressed in adipose tissue. Here, we hypothesized that the role of PTRF in adipocyte functionality might stem from an effect on hMSC. To test this hypothesis, we isolated hMSC from the subcutaneous fat depot. We found an upregulated expression of the PTRF associated with decreased adipogenic potential of hMSC, likely due to the existence of senescent adipocyte precursors. Employing short hairpin RNA-based constructs to stably reduce PTRF, we were able to restore insulin sensitivity and reduced basal lipolysis and leptin levels in human adipocytes with high levels of PTRF. Additionally, we pinpointed the detrimental effect caused by PTRF on the adipose tissue to the existence of senescent adipocyte precursors unable to proliferate and differentiate into adipocytes. This study provides evidence that impaired adipocyte functionality can be corrected, at least partially, by PTRF downregulation and warrants further in vivo research in patients with dysfunctional adipose tissue to prevent metabolic complications.
proteins
2026-08-21 | Can Leptin Responsiveness Be Restored in Common Human Obesity?
In 1994, leptin was identified as a hormone that signals the brain to reduce food intake and increase energy expenditure. Leptin was initially considered a breakthrough therapy for obesity. This was largely based on animal studies, showing that leptin reversed obesity in individuals with congenital leptin deficiency and normal leptin receptor sensitivity. However, due to leptin resistance, leptin therapy failed to reduce weight in common human obesity. Consequently, interest in leptin waned for many years. However, recent studies in animal models of common obesity show that combining leptin with other weight-loss-stimulating agents, can restore hypothalamic leptin sensitivity and induce a greater reduction of body weight than after single drug treatment. Moreover, after initially reducing weight by combination therapy, leptin monotherapy proved enough to maintain reduced body weight. The strongest evidence for restoring leptin’s weight-lowering actions in common obesity to date comes from mouse studies in which leptin was combined with other pharmacotherapies. However, it is unclear at this moment whether this strategy also can be used to treat common human obesity successfully. Overcoming leptin resistance, by combining leptin with other pharmacotherapies, is a promising strategy that needs to be further investigated in humans with obesity.
2026-08-01 | OC11.2 - ECE_2967 - Metreleptin therapy in pediatric and adult patients with congenital leptin deficiency: a multicenter real-world experience
Abstract Background Congenital leptin deficiency (CLD) is a rare monogenic cause of severe early-onset obesity and hyperphagia, with limited long-term real-world evidence on metreleptin therapy. In this study, we aimed to evaluate the long-term clinical outcomes and safety of metreleptin therapy in a large, multicenter cohort of pediatric and adult patients. Methods We conducted a multicenter, observational cohort study including 17 patients with CLD (10 pediatric, 7 adult) across 8 centers. Clinical characteristics, genetic findings, longitudinal anthropometric measurements, metabolic parameters, and total daily metreleptin doses were systematically evaluated. Pediatric and adult cohorts were analyzed separately to account for age- and growth-related trajectories. Repeated-measures analyses were performed in subgroups with complete longitudinal data. One patient who developed loss of efficacy due to neutralizing antibodies was presented separately. Results Obesity onset clustered within the first year of life in 87.5% of patients, and hyperphagia was present in all patients at baseline. Pathogenic or likely pathogenic LEP gene variants were identified in most cases; three individuals with ongoing genetic analyses were included based on markedly low leptin levels and a robust clinical response to metreleptin. Across the entire cohort, metreleptin induced a marked, time-dependent reduction in BMI (median −25.7% at month 6; −40.7% at month 18). In pediatric patients, BMI and BMI SDS decreased substantially (mean BMI SDS 5.52 ± 1.47 at baseline to 2.66 ± 1.37 by month 24) and remained stable long term; all children showed a net BMI SDS reduction at last follow-up. Linear growth was preserved, with stable height SDS and no evidence of growth attenuation. In adults, BMI decreased from 55.7 kg/m2 at baseline to 29.9 kg/m2 by month 18, with subsequent inter-individual variability but overall preservation of therapeutic gains. Glycemic and lipid parameters remained largely within reference ranges, no severe adverse events occurred, and total metreleptin doses remained stable without systematic escalation. A boy with a large deletion in the LEP gene started metreleptin at 24 months and initially lost 10 kg. By month 6, he began regaining weight and developed injection-site reactions. He tested strongly positive for neutralizing antibodies and was later treated with an investigational agent. Conclusions This multicenter cohort is among the largest real-world series jointly evaluating pediatric and adult patients with congenital leptin deficiency. Metreleptin was effective and well-tolerated during long-term follow-up in routine clinical practice. Neutralizing antibody–associated loss of efficacy occurred in one patient; otherwise, responses were sustained without clinically relevant safety signals.
2025-10-04 | Leptin: 30 Years Later.
The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.
2025-09-27 | Response to long-term pharmacological management of metreleptin in a patient with monogenic obesity due to mutation in the LEP gene.
The cases of obesity worldwide have increased significantly, with this condition being considered a global pandemic. This pathology poses a major health problem due to its high morbidity burden. Its cause in the majority of cases is multifactorial; however, there are various cases of monogenic obesity reported in the literature. Mutation in the leptin gene causes a marked decrease in leptin levels, leading to intense hyperphagia and associated morbid obesity. Substituting leptin with metreleptin is a treatment option for these patients. We present the case of a patient with morbid obesity due to a single mutation in the LEP gene and approximately four years of treatment with metreleptin as a substitute therapy. Weight decreased from 154 to 64 kg and BMI decreased from 68.4 to 28.4 kg/m2. The patient achieved a reduction of 40 kg/m2 in BMI, corresponding to a body weight loss of 90 kg, with a significant improvement in associated metabolic comorbidities, acne, and hirsutism.
2025-08-29 | Structural and functional characterization of the Pro64Ser leptin mutant: Implications for congenital leptin deficiency.
Congenital leptin deficiency or dysfunction is a form of monogenic childhood obesity. The disease is primarily caused by mutations in the LEP gene, which encodes for the expression of a hormone called leptin. The mutations typically impair leptin synthesis, secretion, or binding to the leptin receptor (LepR). The Pro64Ser mutation in leptin, despite not affecting the protein's stability or its binding affinity to the LepR, completely abolishes the protein's ability to mediate intracellular signaling via the LepR. To elucidate the mechanism underlying this signal inhibition and to further understand the mechanism of leptin-mediated LepR signal transduction, we performed extensive molecular dynamics simulations of both the wild-type and mutant (MT) leptins. Our simulations reveal that the Pro64Ser mutation increases the rigidity of AB loop N-terminus and thus prevents the loop's conformational changes required for interaction with the LepR immunoglobulin-like domain (IgD). Conversely, the CD loop of the MT exhibits increased flexibility compared with the wild-type. This elevated flexibility potentially hinders the protein's transition into helical structure and subsequent interaction with the IgD. Given that the interactions between leptin and the LepR IgD are crucial for the formation of higher-order leptin-LepR assembly and the following intracellular signal transduction, the observed changes in the MT leptin loop dynamics provide a mechanistic explanation for the signaling defects.
small molecules
2025-09-11 | Leptin and leptin resistance in obesity: current evidence, mechanisms and future directions.
Leptin, a key adipokine regulating energy homeostasis, has been extensively studied for its potential in the management of obesity. However, its therapeutic efficacy is often limited due to leptin resistance. This review synthesizes animal and clinical evidence on leptin's role in obesity, focusing on models such as genetically deficient mice (e.g., ob/ob, db/db), diet-induced obesity mice, and clinical conditions such as congenital leptin deficiency (CLD), leptin receptor deficiency (LRD), lipodystrophy, and common obesity. The mechanisms underlying leptin resistance are summarized, including hyperleptinemia, impaired JAK2-STAT3 signaling, reduced blood-brain barrier permeability, defective autophagy, endoplasmic reticulum stress, inflammation, decreased leptin receptor expression, leptin signaling pathway dysfunction, increased mTOR activity, and peripheral leptin resistance. Due to these leptin receptor and/or post-receptor signaling pathway defects, leptin or its analogs usually fail to produce the expected weight-loss effect in individuals with overweight or obesity, although they remain highly effective in individuals with CLD and lipodystrophy, as well as in ob/ob mice. Alternative strategies, such as melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide) for LRD treatment, are very promising. Future directions include enhancing leptin sensitization, combining leptin with other drugs, and exploring partial leptin reduction to mitigate compensatory responses during weight loss. The review emphasizes the complexity of leptin resistance and the necessity of targeted approaches in obesity therapy.
2023-09-07 | A Negative Feedback Loop Between TET2 and Leptin in Adipocyte Regulates Body Weight
Abstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a novel compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.
2022-08-07 | Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin
Abstract TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α−η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11- deficient mice phenocopies Trp73 -deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ, necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.
2022-08-01 | Role of Sodium dependent SLC13 transporter and its inhibitors in various metabolic disorders
The sodium dependent SLC13 family transporters comprise of the five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them the three NaDC1, NaDC3 and NaCT are sodium dependent transporters such as di-carboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, the information to the structures is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these receptors and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of the citrate present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporter are required for the development of citrate inhibitors. In this review the structure, function, and regulation of the NaCT receptors are discussed. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT receptors are succinctly summarized.
2022-03-03 | Conjugated linoleic acid ameliorates hepatic steatosis by modulating intestinal permeability and gut microbiota in ob/ob mice
Background: Conjugated linoleic acid (CLA) is an effective supplement for reducing fat mass, but its effect on hepatic steatosis remains controversial. Objective: This study aims to evaluate the effect of CLA on liver fat accumulation, inflammation, gut microbiome, and intestinal barrier integrity. Design: Wild-type (WT) mice and ob/ob (OB) mice were randomly divided into four groups according to the treatment with/without 1% CLA: WT, WT mice treated with CLA (WT-CLA), OB, and OB mice treated with CLA (OB-CLA). Lipid metabolism and hepatic fat accumulation were evaluated by changes in histological and biochemical parameters. Gene expressions related to liver inflammation and intestinal barrier integrity were examined. The effect of CLA on the gut microbiota population was investigated. Results: The body weight, fatty tissue mass, and serum lipid levels of the WT-CLA group and OB-CLA group were separately lower than those of the WT group and OB group, but the livers of the WT-CLA group had more fatty lipids, higher triglyceride properties, and saturated fatty acid (FA) composition than those of the WT group, which was contrary to the effect of CLA on OB mice. Real time quantitative PCR results showed that CLA increased hepatic inflammation and intestinal permeability in the WT mice, while it significantly decreased the mRNA expression of liver TNF-α, IFN-γ, and IL-1β and markedly ameliorated intestinal tight junction proteins in the OB mice. The gut microbiota testing indicated a higher abundance of beneficial bacteria (e.g., Lachnoclostridium, Roseburia, Dubosiella, Oscillibacter, and Anaerostipes) and a lower abundance of pro-inflammatory bacteria (e.g., Tyzzerella and Alistipes) in the OB-CLA group than those of the OB group. Correlation analysis suggested that gut microbiota correlated with liver inflammation, intestinal permeability, and hepatic FA composition. Conclusion: CLA potentially contributed to ameliorating hepatic steatosis in OB mice via modulating liver inflammation, intestinal permeability, and gut microbiota, which suggests CLA is more suitable for people with obesity or overweight.
gene therapies
2025-07-25 | Subcutaneous administration of adipose-tropic gene therapy for congenital leptin deficiency.
AAV-based gene therapy targeting adipose tissue has been underdeveloped due to lack of adipose-tropic AAV vectors with sufficient transduction efficiency. We previously demonstrated that an engineered capsid variant of Rec2 capsid with F503Y, Y708D and K709I substitution (named V7 capsid) exhibited highly selective adipo-tropism while ablating liver transduction upon intraperitoneal injection or intravenous injection. In this study, we investigated the feasibility of subcutaneous administration of V7 vector harboring human leptin (V7-LEP) in a congenital leptin deficiency model ob/ob mice. Subcutaneous administration of V7-LEP vector at a low dose of 4×1010 viral genome per mouse restored circulating leptin levels and completely normalized metabolic abnormalities associated with leptin deficiency. In an ongoing long-term experiment, one-time subcutaneous administration of V7-LEP to extreme obese ob/ob mice has led to sustained weight loss at least up to 9 months post injection associated with stable circulating human leptin levels throughout the long-term study. These data indicate subcutaneous injection is a feasible and relevant administration route for gene therapy targeting adipose tissue, and V7-LEP is highly efficacious for congenital leptin deficiency and potentially other lipodystrophy disorders with leptin deficiency.
2025-07-01 | Dose-finding and in vivo safety study of an adipose targeted leptin gene therapy for congenital leptin deficiency.
Congenital leptin deficiency is a monogenic disease originated from adipose tissue, causing hyperphagia, severe obesity, and hyperinsulinemia. Moreover, most forms of lipodystrophy syndromes exhibit leptin deficiency. Leptin replacement therapy with leptin protein analog requires frequent injection for life and is extremely expensive. We previously reported that a single intraperitoneal injection of an adipose-targeting Rec2-leptin adeno-associated virus (AAV) vector normalized metabolic syndromes in the leptin deficient ob/ob mice. Here, we conducted a dose-deescalating study with four doses (2E10, 1E10, 5E9, and 1E9 viral genome per mouse) in ob/ob mice and extended in vivo monitoring to 27 weeks post dosing. Rec2-leptin at all doses normalized excessive weight gain, hyperphagia, obesity, low core temperature, glucose intolerance, and hyperinsulinemia in the ob/ob mice. Transgene expression was restricted in the targeting visceral adipose tissues and sustained throughout the 27-weeks study. Rec2-leptin at the lowest dose 1E9 viral genome (vg)/mouse restored the circulating leptin level to 18% of the normal level of wild-type (WT) mice. Rec2-leptin at all doses reversed liver steatosis and pancreatic islet hyperplasia. Behavioral assessment, serum chemistry, and histopathology noted no significant adverse effects attributed to Rec2-leptin. This study demonstrates that Rec2-leptin is safe and highly efficacious, supporting further development for genetic or acquired leptin deficiency.
2024-02-24 | Syndromic and Monogenic Obesity: New Opportunities Due to Genetic-Based Pharmacological Treatment.
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.
2022-01-18 | Leptin gene-targeted editing in ob/ob mouse adipose tissue based on the CRISPR/Cas9 system.
Gene therapy has become the most effective treatment for monogenic diseases. Congenital LEPTIN deficiency is a rare autosomal recessive monogenic obesity syndrome caused by mutations in the Leptin gene. Ob/ob mouse is a monogenic obesity model, which carries a homozygous point mutation of C to T in Exon 2 of the Leptin gene. Here, we attempted to edit the mutated Leptin gene in ob/ob mice preadipocytes and inguinal adipose tissues using CRISPR/Cas9 to correct the C to T mutation and restore the production of LEPTIN protein by adipocytes. The edited preadipocytes exhibit a correction of 5.5% of Leptin alleles and produce normal LEPTIN protein when differentiated into mature adipocytes. The ob/ob mice display correction of 1.67% of Leptin alleles, which is sufficient to restore the production and physiological functions of LEPTIN protein, such as suppressing appetite and alleviating insulin resistance. Our study suggests CRISPR/Cas9-mediated in situ genome editing as a feasible therapeutic strategy for human monogenic diseases, and paves the way for further research on efficient delivery system in potential future clinical application.
2018-02-15 | Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C
Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg−1 day−1) and pair-fed]. Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.
antibodies
2023-11-24 | Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.
Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.
2020-07-01 | Selection of a Full Agonist Combinatorial Antibody that Rescues Leptin Deficiency In Vivo
Abstract Growth factor deficiency in adulthood constitutes a distinct clinical syndrome with significant morbidities including abnormal body composition, reduced energy, affective disturbances, dyslipidemia, and increased cardiovascular risk. Protein replacement therapies using recombinant proteins or enzymes represent the only approved treatment. Combinatorial antibodies have shown great promise as a new class of therapeutic molecules because they act as “mechanism‐based antibodies” with both agonist and antagonist activities. Using leptin, a key hormone in energy metabolism, as an example, a function‐guided approach is developed to select combinatorial antibodies with high potency and full agonist activity that substitute natural growth factors in vivo. The identified antibody shows identical biochemical properties and cellular profiles as leptin, and rescues leptin‐deficiency in ob/ob mice. Remarkably, the antibody activates leptin receptors that are otherwise nonfunctional because of mutations (L372A and A409E). Combinatorial antibodies have significant advantages over recombinant proteins for chronical usage in terms of immunological tolerance and biological stability.
2018-02-21 | Genetics of Obesity in Consanguineous Populations: Toward Precision Medicine and the Discovery of Novel Obesity Genes
Objective Consanguinity has been instrumental in the elucidation of many Mendelian genetic diseases. Here, the unique advantage of consanguineous populations was considered in the quest for genes causing obesity. Methods PubMed was searched for articles relevant to consanguinity and obesity published between 1995 and 2016. Some earlier articles of interest were also consulted. Results Although obesity is the most heritable disorder, even in outbred populations, only 2% to 5% of severe obesity cases have so far been proven to be caused by single gene mutations. In some highly consanguineous populations, a remarkably higher proportion of obesity cases because of known and novel monogenic variants has been identified (up to 30%). Conclusions Combining the power conferred by consanguinity with current large‐capacity sequencing techniques should bring new genetic factors and molecular mechanisms to the fore, unveiling a large part of the yet‐elusive neurohumoral circuitry involved in the regulation of energy homeostasis and appetite. Importantly, the undertaking of such initiatives is destined to unfold novel targets for the development of precision medicine relevant to different forms of obesity.
2016-06-21 | An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse.
Objective Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half‐life and low immunogenicity could be useful in the treatment of this condition. Methods Phage display technology coupled with flow cytometry and cell‐based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP‐deficient Lep ob /Lep ob mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured. Results XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep ob /Lep ob mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects. Conclusions Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency.
2012-03-01 | Structure of the Human Obesity Receptor Leptin-Binding Domain Reveals the Mechanism of Leptin Antagonism by a Monoclonal Antibody
Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR. We describe the structure of the LBD-9F8 Fab complex and the conformational changes in 9F8 associated with LBD binding. A molecular model of the putative leptin-LBD complex reveals that 9F8 Fab blocks leptin binding through only a small (10%) overlap in their binding sites, and that leptin binding is likely to involve an induced fit mechanism. This crystal structure of the leptin-binding domain of the obesity receptor will facilitate the design of therapeutics to modulate leptin signaling.
other
2021-12-29 | Pinch Loss Ameliorates Obesity, Glucose Intolerance, and Fatty Liver by Modulating Adipocyte Apoptosis in Mice.
The mammalian focal adhesion proteins Pinch1/2 activate integrins and promote cell-extracellular matrix adhesion and migration; however, their roles in adipose tissue and metabolism are unclear. Here we find that high-fat diet (HFD) feeding dramatically increases expression of Pinch1/2 proteins in white adipose tissue (WAT) in mice. Furthermore, expression of Pinch1 is largely upregulated in WAT in leptin-deficient ob/ob type 2 diabetic mice and obese humans. While mice with loss of Pinch1 in adipocytes or global Pinch2 do not display any notable phenotypes, deleting Pinch1 in adipocytes and Pinch2 globally significantly decreases body weight and WAT mass, but not brown adipose tissue mass, in HFD-fed, but not normal chow diet-fed, mice. Pinch loss ameliorates HFD-induced glucose intolerance and fatty liver. After HFD challenge, Pinch loss slightly but significantly accelerates energy expenditure. While Pinch loss decreases adipocyte size and alters adipocyte size distribution, it greatly accelerates cell apoptosis primarily in epididymal WAT and to a lesser extent in subcutaneous WAT. In vitro studies demonstrate that Pinch loss accelerates adipocyte apoptosis by activating the Bim/Caspase-8 pathway. In vivo, genetic ablation of Caspase-8 expression in adipocytes essentially abolishes the ameliorating effects of Pinch deficiency on obesity, glucose intolerance, and fatty liver in mice. Thus, we demonstrate a previously unknown function of Pinch in control of adipose mass, glucose, and fat metabolism via modulation of adipocyte apoptosis. We may define a novel target for the prevention and treatment of metabolic diseases, such as obesity and diabetes.
2016-11-18 | Knockdown of PTRF ameliorates adipocyte differentiation and functionality of human mesenchymal stem cells
Healthy expansion of human adipose tissue requires mesenchymal stem cells (hMSC) able to proliferate and differentiate into mature adipocytes. Hence, characterization of those factors that coordinate hMSC-to-adipocyte transition is of paramount importance to modulate the adipose tissue expansion. It has been previously reported that the adipogenic program of hMSC can be disrupted by upregulating caveolar proteins, and polymerase I and transcript release factor (PTRF) is an integral component of caveolae, highly expressed in adipose tissue. Here, we hypothesized that the role of PTRF in adipocyte functionality might stem from an effect on hMSC. To test this hypothesis, we isolated hMSC from the subcutaneous fat depot. We found an upregulated expression of the PTRF associated with decreased adipogenic potential of hMSC, likely due to the existence of senescent adipocyte precursors. Employing short hairpin RNA-based constructs to stably reduce PTRF, we were able to restore insulin sensitivity and reduced basal lipolysis and leptin levels in human adipocytes with high levels of PTRF. Additionally, we pinpointed the detrimental effect caused by PTRF on the adipose tissue to the existence of senescent adipocyte precursors unable to proliferate and differentiate into adipocytes. This study provides evidence that impaired adipocyte functionality can be corrected, at least partially, by PTRF downregulation and warrants further in vivo research in patients with dysfunctional adipose tissue to prevent metabolic complications.
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