Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes

Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is ch aracterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe Lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hep atic steatosis. We have also produced transgenic "skinny" mice that have he patic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stor es, and are hypophagic and show increased insulin sensitivity. To explore t he pathophysiological and therapeutic roles of leptin in lipoatrophic diabe tes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mic e (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly e levated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showe d improved hepatic steatosis, Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects we re stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve thei r insulin resistance, diabetes, or hepatic steatosis, demonstrating that th e beneficial effects of leptin were not due to the decreased food intake. C ontinuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steato sis and the disorder of glucose and lipid metabolism in A-ZTP/F-1 mice. The se data demonstrate that leptin can improve the insulin resistance and diab etes of a mouse model of severe lipoatrophic diabetes, suggesting that lept in may be therapeutically useful in the long-term treatment of lipoatrophic diabetes.