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

Abstract

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 liver1. We have developed a mouse model that mimics these features of CGL2: 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 leptin2, a fat-derived hormone that regulates food intake and energy metabolism3. 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.

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Figure 1: Metabolic parameters in wild-type (WT), transgenic aP2-nSREBP-1c436 (Tg), and ob/ob mice after continuous subcutaneous infusion of recombinant leptin (5 µg per day for 12 days).
Figure 2: Representative histological sections of liver (haematoxylin and eosin stain) from transgenic aP2–nSREBP-1c346 mice.
Figure 3: Metabolic parameters in wild-type (WT) and transgenic aP2-nSREBP-1c436 (Tg) mice after 12 days of food restriction.
Figure 4: Amounts of mRNAs in white fat and brown fat of wild-type (WT) and transgenic aP2–nSREBP-1c (Tg) mice treated with leptin.

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Acknowledgements

This work was supported by grants from the NIH, the Moss Heart Foundation, and the Perot Family foundation. I.S. held a research fellowship from the Manpei Suzuki Diabetes Foundation of Tokyo; S. Ikemoto holds a research fellowship from the National Institute of Health and Nutrition of Japan. We thank J. D. McGarry and R. Unger for their suggestions; R. Gibson, B. Hinnant, A. Cox and M. Villarreal for help with the animal studies; S. Clark and R. Craddock for technical assistance; and members of J. A. Richardson's laboratory for histology.

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Correspondence to Michael S. Brown or Joseph L. Goldstein.

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Shimomura, I., Hammer, R., Ikemoto, S. et al. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76 (1999). https://doi.org/10.1038/43448

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