title: Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway.
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.
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Motoharu
authors: M
authors: Awazawa
authors: 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.
authors: Kohjiro
authors: K
authors: Ueki
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Kazunori
authors: K
authors: Inabe
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Toshimasa
authors: T
authors: Yamauchi
authors: 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.
authors: Naoto
authors: N
authors: Kubota
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Kazuma
authors: K
authors: Kaneko
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Masatoshi
authors: M
authors: Kobayashi
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Aya
authors: A
authors: Iwane
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Takayoshi
authors: T
authors: Sasako
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Yukiko
authors: Y
authors: Okazaki
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Mitsuru
authors: M
authors: Ohsugi
authors: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors: Iseki
authors: I
authors: Takamoto
authors: Department of Systems BioMedicine, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors: Satoshi
authors: S
authors: Yamashita
authors: Department of Systems BioMedicine, National Research Institute of Child Health and Development, Tokyo 157-8535, Japan.
authors: Hiroshi
authors: H
authors: Asahara
authors: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors: Shizuo
authors: S
authors: Akira
authors: Research Institute, International Medical Center of Japan, Tokyo 162-0052, Japan.
authors: Masato
authors: M
authors: Kasuga
authors: 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.
authors: Takashi
authors: T
authors: Kadowaki
mesh_terms: D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D054419:Receptors, Adiponectin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D052242:Adiponectin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D054419:Receptors, Adiponectin; D050796:STAT3 Transcription Factor; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse