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 that is encoded by the obese (ob) gene. Ob/ob mice make a defective leptin product and are extremely obese and hyperphagic. Since leptin administration causes a dramatic reduction in weight and food intake in these mice, it was hoped that leptin could be used to treat obesity in humans. As leptin is produced and secreted by fat cells, leptin levels are proportional to fat tissue mass and are high in obese humans. Exogenous leptin has limited effect in inducing weight loss, suggesting that obese humans have leptin resistance. Nevertheless, the discovery of leptin was pivotal for a number of reasons. It identified adipose tissue as an endocrine organ and was the first of the adiopocyte-derived hormones, later termed adipokines, to be recognized. It led to the discovery of a monogenic form of obesity in rodents and humans in which mutations in the leptin gene cause congenital leptin deficiency. Finally, it presented a form of treatment for patients with leptin gene mutations and patients with lipodystrophy. Our major effort has been in a clinical trial of leptin therapy in lipodystrophy. Leptin levels are low in these patients and leptin replacement therapy results in a reduction in hemoglobin A1c, fasting blood glucose, triglyceride values, liver size, and liver function test abnormalities. Furthermore, in those patients who have normal reproductive organs, leptin therapy results in a robust increase in gonadotropin secretion following GNRH administration;this is associated with the beginning of menses in these otherwise amenorrheic patients. Thus, leptin therapy appears to have a major beneficial effect on the metabolic and endocrine abnormalities seen in these patients. In lipodystrophic patients, nonalcoholic steatohepatitis (NASH) is a common finding. Our studies have shown that leptin therapy not only reduces steatosis, but also decreases the severity of the NASH score, which largely measures the degree of oxidative stress. We continue the follow-up of these patients and our involvement in a CRADA with Amylin Pharmaceuticals. On the basis of our studies, the company is presenting a new drug application (NDA)to the FDA to license recombinant leptin. If approved, it will be the first novel therapy for extreme insulin resistance since the discovery of insulin over 85 years ago.

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Brown, Rebecca J; Chan, Jean L; Jaffe, Elaine S et al. (2016) Lymphoma in acquired generalized lipodystrophy. Leuk Lymphoma 57:45-50
Cochran, Elaine; Brown, Rebecca J; Gorden, Phillip (2016) COMMENTARY. Endocr Pract :
Kassai, Andrea; Muniyappa, Ranganath; Levenson, Amy E et al. (2016) Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy. J Clin Endocrinol Metab 101:1790-7
Levenson, Amy E; Haas, Mary E; Miao, Ji et al. (2016) Effect of Leptin Replacement on PCSK9 in ob/ob Mice and Female Lipodystrophic Patients. Endocrinology 157:1421-9
Chan, Jean L; Koda, Joy; Heilig, Joseph S et al. (2016) Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. Clin Endocrinol (Oxf) 85:137-49
Diker-Cohen, Talia; Cochran, Elaine; Gorden, Phillip et al. (2015) Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab 100:1802-10
Brown, Rebecca J; Meehan, Cristina Adelia; Gorden, Phillip (2015) Leptin Does Not Mediate Hypertension Associated With Human Obesity. Cell 162:465-6
Muniyappa, Ranganath; Brown, Rebecca J; Mari, Andrea et al. (2014) Effects of leptin replacement therapy on pancreatic *-cell function in patients with lipodystrophy. Diabetes Care 37:1101-7
Joseph, Jalaja; Shamburek, Robert D; Cochran, Elaine K et al. (2014) Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and Triglycerides. J Clin Endocrinol Metab :jc20141878
Christensen, John D; Lungu, Andreea O; Cochran, Elaine et al. (2014) Bone mineral content in patients with congenital generalized lipodystrophy is unaffected by metreleptin replacement therapy. J Clin Endocrinol Metab 99:E1493-500

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