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Cell Metab. 2011 Apr 6;13(4):401-412. doi: 10.1016/j.cmet.2011.02.010.

Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway.

Author information

1
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
2
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (TSBMI), University of Tokyo, Tokyo 113-8655, Japan. Electronic address: ueki-tky@umin.ac.jp.
3
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (TSBMI), University of Tokyo, Tokyo 113-8655, Japan; Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo 162-8636, Japan.
4
Department of Systems BioMedicine, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
5
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
6
Research Institute, International Medical Center of Japan, Tokyo 162-0052, Japan.
7
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; Translational Systems Biology and Medicine Initiative (TSBMI), University of Tokyo, Tokyo 113-8655, Japan. Electronic address: kadowaki-3im@h.u-tokyo.ac.jp.

Abstract

Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.

PMID:
21459325
DOI:
10.1016/j.cmet.2011.02.010
[Indexed for MEDLINE]
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