Adiponectin Enhances Insulin Sensitivity by Increasing Hepatic IRS-2 Expression via a Macrophage-Derived IL-6-Dependent Pathway
Open accessAbstract
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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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”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [58]
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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
- ORCID
- 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
- bronze
- doi.org
- Licence
- 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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