Cited by 277Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismPeroxisome Proliferator-Activated Receptors

Adiponectin Enhances Insulin Sensitivity by Increasing Hepatic IRS-2 Expression via a Macrophage-Derived IL-6-Dependent Pathway

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Awazawa, Motoharu, Ueki, Kohjiro, Inabe, Kazunori, Yamauchi, Toshimasa, Kubota, Naoto, Kaneko, Kazuma, Kobayashi, Masatoshi, Iwane, Aya +9 more·2011·Cell Metabolism

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.

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Crossref · 10.1016/j.cmet.2011.02.010

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  • In peripheral tissues, adiponectin promotes liver insulin sensitivity via several independent mechanisms: an AMPK-dependent mechanism involving increased ACC phosphorylation, an AMPK-independent mechanism involving reduction in liver ceramide levels, and an IL-6-dependent mechanism involving upregulation of IRS-2 through STAT3 activation.

    “In the peripheral tissues, adiponectin promotes liver insulin sensitivity via several independent mechanisms: an AMPK‐dependent mechanism involving increased ACC phosphorylation, an AMPK‐independent mechanism that involves a reduction in liver ceramide levels 57, and an IL‐6‐dependent mechanism that involves the upregulation of insulin receptor substrate 2 (IRS‐2) through the activation of STAT3 5”

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Authors
Awazawa, M., Ueki, K., Inabe, K., Yamauchi, T., Kubota, N., Kaneko, K., Kobayashi, M., Iwane, A., Sasako, T., Okazaki, Y., Ohsugi, M., Takamoto, I., Yamashita, S., Asahara, H., Akira, S., Kasuga, M., & Kadowaki, T.
Affiliations
  • The University of Tokyo (JP)
  • National Institute of Health and Nutrition (JP)
  • National Research Institute for Child Health and Development (JP)
  • Immunology Frontier Research Center, The University of Osaka (JP)
Corresponding author
  • Ueki, Kohjiro
  • Kadowaki, Takashi
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2011-04
Volume
13
Issue
4
Pages
401-412
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2043958887
Cited by
277
References
53
Citations by year
2026: 7 · 2025: 9 · 2024: 10 · 2023: 16 · 2022: 12 · 2021: 20 · 2020: 23 · 2019: 18 · 2018: 25 · 2017: 18 · 2016: 25 · 2015: 17 · 2014: 22 · 2013: 29 · 2012: 16
FWCI
18.22
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology
  • Ministry of Health, Labour and Welfare
  • Takeda Science Foundation
  • Ministry of Health and Welfare
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
adiponectin, insulin sensitivity, insulin resistance, insulin receptor substrate 2, hepatic insulin signaling, macrophages, interleukin-6, STAT3, NF-κB, adiponectin receptors, AdipoR1, AdipoR2
MeSH terms
Animals, Disease Models, Animal, Insulin Resistance, Liver, Macrophages, Mice, Obese, Promoter Regions, Genetic, Signal Transduction, Interleukin-6, NF-kappa B, STAT3 Transcription Factor, Mice, Adiponectin, Receptors, Adiponectin, Insulin Receptor Substrate Proteins

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