Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

Abstract

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg͞kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ؎ 2.5 (mean ؎ SEM) at baseline to 26.9 ؎ 2.1 kg͞m 2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.T he increasing rates of obesity and consequent morbidity represent a major epidemic worldwide and threaten to bankrupt health care systems (1-3). While prevention is of great importance, it is medically relevant to identify biological pathways with the potential to treat obesity and related disorders, particularly in adults with fully established obesity and comorbid conditions, such as type 2 diabetes mellitus. Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4). Mutations in the leptin pathway can be a cause of human obesity (5-7). In children with complete leptin deficiency and who are still in the process of gaining weight and developing obesity, leptin replacement therapy can lead to substantial weight reduction (8,9).It is still unknown whether the leptin pathway is relevant to the treatment of established morbid obesity and its endocrine and metabolic consequences in adults. We addressed this question by treating three homozygous leptin-deficient adults with morbid obesity. Morbid obesity had been fully established for two to four decades in those patients, and they had been at a stable (but very high) weight for Ͼ10 years. They were hypogonadal, and one of them had type 2 diabetes mellitus. We report here the results of the first 18 months of replacement therapy with recombinant human leptin, showing that leptin is highly effective in dramatically reducing...

Microsatellite polymorphism of the human leptin gene (LEP) and risk of cardiovascular disease

“…3, OMIM #164160) has been found mutated in very rare forms of human obesity. 2,3 The identification of a polymorphic tetranucleotide repeat in the 3 0 flanking region of the LEP gene (LEP-tet) provided an useful marker for linkage and association studies between this gene and a number of phenotypes other that obesity, such as noninsulin-dependent diabetes mellitus, hypertension and insulin resistance syndrome. 4,5 LEP-tet is composed by 15 alleles, which can be divided into two groups with different size distribution: a shorter one (class I) and a longer one (class II).…”

Body weight is regulated by the brain: a link between feeding and emotion

“…Accordingly, mutations in the ob gene encoding leptin produce hyperphagia and morbid obesity in mice (ob/ob mice) 5,17 and humans. [36][37][38][39][40] Similar to states of starvation, leptin deficiency also leads to deficits in the reproductive, thyroid, and adrenal axes. [41][42][43][44] Moreover, exogenous leptin corrects these manifestations in leptin-deficient mice [45][46][47][48] and humans.…”

“…[41][42][43][44] Moreover, exogenous leptin corrects these manifestations in leptin-deficient mice [45][46][47][48] and humans. 38,40 Finally, the significance of leptin in adaptive endocrine and metabolic responses to fasting was demonstrated in healthy subjects. 49 In this study, a replacement dose of recombinant human leptin administered during fasting prevented the starvation-induced changes of endocrine axes.…”

Detrimental Effects of Leptin on Intracerebral Hemorrhage via the STAT3 Signal Pathway

“…The doses of leptin were determined on the basis of a previous experiment in a rodent stroke model 17 and a leptin replacement study in leptin-deficient adults. 18 …”