Abstract

Most known types of nonsyndromic monogenic obesity are caused by rare mutations in genes of the leptin-melanocortin pathway controlling appetite and adiposity. In contrast, congenital generalized lipodystrophy represents the most extreme form of leanness in humans caused by recessive mutations in four genes involved in phospholipid/triglyceride synthesis and lipid droplet/caveolae structure. In this disease, the inability to store triglyceride in adipocytes results in hypoleptinemia and ectopic hepatic and muscle fat accumulation leading to fatty liver, hypertriglyceridemia and severe insulin resistance. As a result of hypoleptinemia, patients with lipodystrophy show alterations in eating behaviour characterized by constant increased energy intake. As it occurs in obesity caused by genetic leptin deficiency, exogenous leptin rapidly reduces hunger scores in patients with congenital generalized lipodystrophy, with additional beneficial effects on glucose homeostasis and metabolic profile normalization. The melanocortin-4 receptor agonist setmelanotide has been used in the treatment of monogenic obesities. There is only one report on the effect of setmelanotide in a patient with partial lipodystrophy resulting in mild reductions in hunger scores, with no improvements in metabolic status. The assessment of contrasting phenotypes of obesity/leanness represents an adequate strategy to understand the pathophysiology and altered eating behaviour associated with adipose tissue excessive accumulation/paucity.