Effect of Leptin on Fatless Mice

  • I. Shimomura
Conference paper
Part of the Research and Perspectives in Endocrine Interactions book series (RPEI)


Generalized lipodystrophy (GL) is a disorder characterized by a paucity of adipose (fat) tissue that is accompanied by a severe resistance to insulin, leading to hyperinsulinemia, hyperglycemia, and enlarged fatty liver. Our laboratory 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-1c (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 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 signaling 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.

The results obtained from mice were successfully applied to human disease. Leptin administration was reported to improve insulin resistance syndrome, including diabetes, hyperlipidemia and fatty liver in patients with generalized lipodystrophy.


Insulin Resistance Gluconeogenic Enzyme Congenital Generalize Lipodystrophy Chronic Food Restriction Generalize Lipodystrophy 
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Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • I. Shimomura
    • 1
    • 2
  1. 1.Department of Frontier Bioscience Graduate School of Frontier BioscienceOsaka UniversitySuitaJapan
  2. 2.Department of Medicine and Pathophysiology Graduate School of MedicineOsaka UniversitySuitaJapan

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