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The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity

Abstract

Adiponectin is an adipocyte-derived hormone. Recent genome-wide scans have mapped a susceptibility locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where the gene encoding adiponectin is located. Here we show that decreased expression of adiponectin correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin decreases insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. This effect results from increased expression of molecules involved in both fatty-acid combustion and energy dissipation in muscle. Moreover, insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. We conclude that decreased adiponectin is implicated in the development of insulin resistance in mouse models of both obesity and lipoatrophy. These data also indicate that the replenishment of adiponectin might provide a novel treatment modality for insulin resistance and type 2 diabetes.

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Figure 1: Expression of adiponectin mRNA is associated with insulin sensitivity.
Figure 2: Replenishment of adiponectin ameliorates insulin resistance in lipoatrophic mice.
Figure 3: Adiponectin increases fatty-acid combustion and energy dissipation in lipoatrophic mice treated as indicated (described in Fig. 2).
Figure 4: Adiponectin reverses insulin resistance in murine models of type 2 diabetes.

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Acknowledgements

We thank I. Shimomura for helpful suggestions; T. Hashimoto for the generous gift of a DNA probe for ACO; K. Motojima for kindly providing CD36, UCP2 and PPAR-α cDNA probes; and S. Uchida, K. Kirii, S. Sakata and T. Nagano for technical assistance. This work was supported by a grant from the Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (to T.Y.); a Grant-in-Aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology (to T.K.); and a Grant-in-Aid for Creative Scientific Research 10NP0201 from Japan Society for the Promotion of Science (to T.K.); and by Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare (to T.K.).

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Correspondence to T. Kadowaki.

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Yamauchi, T., Kamon, J., Waki, H. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7, 941–946 (2001). https://doi.org/10.1038/90984

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