2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13-15 September 2000, Toronto, Canada

LESSON FROM LIPODYSTROPHIC MICE -A VICIOUS CYCLE IN METABOLISM

Antiviral Therapy 2000; 5(Suppl. 5):3 (abstract no. O2)

I Shimomura
Department of Molecular Genetics, University of Texas, Southwestern Medical Center at Dallas, Dallas, Tex., USA

Generalized lipodystrophy (GL) is a disorder characterized by a paucity of adipose (fat) tissue which is accompanied by a severe resistance to insulin, leading to hyperinsulinemia, hyperglycemia, and enlarged fatty liver. We have developed a mouse model that mimics these features of generalized lipodystrophy: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-lc (sterol-regulatory-element-binding protein-1c) under the control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in mRNAs encoding several fat-specific proteins, including leptin, a fat-derived hormone that regulates food intake and energy metabolism. We revealed that insulin resistance in the lipodystrophic mice can be overcome by a continuous systemic infusion of recombinant leptin, an effect that is not mimicked by chronic food restriction. These results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake. As humans with generalized lipodystrophy have extremely low levels of plasma leptin, clinical trials of leptin treatment in these patients are warranted. In lipodystrophic mice, leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance. In this condition, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. We found that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component in the insulin signalling in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcriptional factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophy.

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O2

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