Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy.
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver. We have developed a mouse model that mimics these features of CGL: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under the 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, a fat-derived hormone that regulates food intake and energy metabolism. Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.
Shimomura
I
I
Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235-9046, USA.
Hammer
R E
RE
Ikemoto
S
S
Brown
M S
MS
Goldstein
J L
JL
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000209:etiology*; D004195:Disease Models, Animal; D005260:Female; D005508:Food Deprivation; D006801:Humans; D007333:Insulin Resistance; D020738:Leptin; D008060:Lipodystrophy / Q000150:complications / Q000151:congenital / Q000188:drug therapy / Q000209:etiology*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000502:physiology* / Q000627:therapeutic use; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D020738:Leptin; D009687:Nuclear Proteins; D011506:Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors