RARE DISEASE
Obesity due to congenital leptin deficiency
Obesity due to congenital leptin deficiency
Obesity due to congenital leptin deficiency
Drug discovery
0
drugs
With orphan designations
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
167 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:
167 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:
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.
2025-09-11 | 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.
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.
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.
2025-10-04 | 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.
2025-09-11 | 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.
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.
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.
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