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Diet-induced insulin resistance in mice lacking adiponectin/ACRP30

Abstract

Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-α (TNF-α) mRNA in adipose tissue and high plasma TNF-α concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-α mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-α decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-α levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.

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Figure 1: Targeted disruption of the mouse adiponectin gene.
Figure 2: Characterization of KO mice in basal state.
Figure 3: Severe insulin resistance in adiponectin KO mice under HF/HS diet.
Figure 4: Adenovirus-mediated production of adiponectin ameliorates diet-induced insulin resistance in mice.
Figure 5: Adiponectin increased FATP1 mRNA, activated IRS-1-associated PI3-kinase and enhanced glucose uptake in C2C12 myocytes.
Figure 6: Adipo-muscular axis; reciprocal effects of adiponectin and TNF-α.

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Acknowledgements

We thank S. Tanaka and Y. Matsukawa for technical assistance. This study was supported in part by the 'Research for the Future' program from the Japan Society for the Promotion of Science (JSPS-RFTF97L00801) and grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (12307022, 12557090 and 12671084).

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Correspondence to Iichiro Shimomura.

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Maeda, N., Shimomura, I., Kishida, K. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8, 731–737 (2002). https://doi.org/10.1038/nm724

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