Diet-induced insulin resistance in mice lacking adiponectin/ACRP30

N Maeda, I Shimomura, K Kishida, H Nishizawa… - Nature medicine, 2002 - nature.com
N Maeda, I Shimomura, K Kishida, H Nishizawa, M Matsuda, H Nagaretani, N Furuyama…
Nature medicine, 2002nature.com
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) …
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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