Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy

Abstract

SUMMARY To describe our 10-year experience in treating leptin-deficient humans. Three adults and one boy presented with childhood-onset morbid obesity, hypogonadism and family history of obesity and early death. Serum leptin was inappropriately low. A recessive C105T leptin gene mutation was identified. Metabolic and endocrine assessments were conducted, before and while on and off leptin. The adults’ body mass index decreased from 51.2 ± 2.5 to 29.5 ± 2.8 kg/m2. Serum lipids normalized, insulin resistance decreased, and one of the initially diabetic females became normoglycemic. Hypogonadotropic hypogonadism was reversed, and other changes were observed in the adrenal, sympathetic, somatotropic and thyroid functions. Leptin replacement therapy reverses endocrine and metabolic alterations associated with leptin deficiency. Some of these results may be extrapolated to other diseases.

Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis

“…Consistent with the study by Glasow et al, 31 we demonstrated that human and rat adrenal glands coexpress leptin receptors and CYP11B2, in zona glomerulosa cells, implying that leptin could regulate the function of zona glomerulusa cells. In agreement with the literature reporting low aldosterone levels in obese individuals 32,33 and animals [34][35][36][37][38][39] deficient in leptin receptors, we reported that leptin deficiency in ob/ob mice, deletion in leptin receptor in db/db mice, or nonfunctional mutation of the leptin receptors in obese Zucker rats blunted obesity-induced increases in adrenal CYP11B2 expression and plasma aldosterone levels. These data support a role for leptin and leptin receptors in obesity-mediated increases in plasma aldosterone levels and minimize the contribution of obesity per se in the control of aldosterone secretion.…”

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints

“…Leptin also plays important roles on lipid and glucose metabolism, the gonadal, adrenal, somatotropic and thyroid axes, sympathetic tone, biomarkers of cardiovascular disease, immunity, inflammation, and brain structure and function (5,6,(32)(33)(34). In humans, leptin deficiency is observed in cases of hypothalamic amenorrhea, anorexia nervosa, genetic deficiency due to mutations in the leptin gene, and LS.…”

“…It is an important metabolic regulator responsible for not only controlling food intake and energy expenditure, but also for maintaining glucose, insulin and lipid homeostasis (5,6). Impaired leptin action, due to leptin resistance or leptin deficiency, results in several metabolic abnormalities such as insulin resistance, hyperinsulinemia, diabetes, and hypertriglyceridemia, which are similar to those that are observed in LS.…”

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

“…Leptin levels are directly correlated with fat mass and are elevated in obese patients, who are also leptin resistant. Leptin deficient mice and humans are severely obese and have several metabolic and endocrine altera tions, such as hyperglycemia, insulin resistance, hyper triglyceridemia, hypogonadotropic hypogonadism, and central hypothyroidism (6,7).…”