Clinical perspectives: leptin replacement therapy for the treatment of lipodystrophy-associated non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride accumulation in the liver, not associated with excessive alcohol use. It is frequently observed in patients with common obesity, but it also affects patients with lipodystrophy syndrome (LS), a rare, but serious set of conditions presenting insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. The phenotype of patients with lipodystrophy is attributed to the deficiency of the adipose tissue-derived hormone leptin, which is an important regulator of energy metabolism. Human and animal studies of diseases characterized by low leptin levels such as lipodystrophy, functional hypothalamic amenorrhea, and genetic deficiency due to mutations in the leptin gene, have shown that leptin supplementation improves several metabolic parameters. Recently, the United States Food and Drug Administration (FDA) approved the use of the recombinant form of leptin, metreleptin, to treat generalized forms of lipodystrophy, which shares physiopathological features with other leptin-deficient conditions. Several clinical studies have demonstrated that leptin improves glucose and lipid profiles, as well as liver function, volume and fat content, in patients with lipodystrophy. This review will provide insight into the molecular biology of leptin in treating lipodystrophy, and summarize the findings from clinical studies where leptin was used to treat patients with lipodystrophy.