Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive di sorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to h yperinsulinaemia, hyperglycaemia and enlarged fatty liver(1). We have devel oped a mouse model that mimics these features of CGL(2): the syndrome occur s in transgenic mice expressing a truncated version of a nuclear protein kn own as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under t he control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in messenger RNAs encoding several fat-specific proteins, including leptin(2), a fat-derived hormone that regulates food i ntake and energy metabolism(3). Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of l ow doses of recombinant leptin, an effect that is not mimicked by chronic f ood restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intak e, and that leptin deficiency accounts for the insulin resistance found in CGL.