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.

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.

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.

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.

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.