NIH Reporter #1ZIADK047052-19

Clinical utility of leptin therapy in syndromic forms of insulin resistance.

This award funds research on the clinical utility of leptin therapy for syndromic insulin resistance, focusing on leptin's role in obesity and lipodystrophy treatment, including clinical trials and development of novel leptin receptor agonists.

Description

Leptin was discovered when the gene mutation in the ob/ob mouse, an animal model of obesity, was identified. Leptin is a polypeptide of 167 amino acids encoded by the obese (ob) gene. Ob/ob mice produce a defective leptin product and are extremely obese and hyperphagic. Leptin administration causes a dramatic reduction in weight and food intake in these mice, leading to the hypothesis that leptin could treat obesity in humans. Leptin levels are proportional to fat tissue mass and are high in obese humans, but exogenous leptin has limited effect, suggesting leptin resistance. The discovery identified adipose tissue as an endocrine organ and led to the recognition of adipokines. It also led to the discovery of monogenic obesity caused by leptin gene mutations and provided a treatment avenue for such cases and lipodystrophy. Major efforts include clinical trials of leptin therapy in lipodystrophy, showing reductions in hemoglobin A1c, fasting blood glucose, triglycerides, liver size, and other metabolic parameters. Leptin therapy also reduces steatosis and NASH severity, mechanisms include reduced de novo lipogenesis. Leptin lowers A1c in patients with insulin receptor mutations and improves survival and quality of life in lipodystrophy patients. The FDA approved leptin for generalized lipodystrophy in February 2014. Current studies focus on a novel leptin receptor agonist antibody.

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