Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo
Open accessAbstract
Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia. However, the mechanisms behind these effects are unclear. Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation. The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307. Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis. Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues. These results establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity.
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AMPK is responsive to imbalanced redox status.
“Recent lines of evidence have demonstrated AMPK responsiveness to imbalanced redox status, thus bringing new insights into the networks of redox-stimulated signals upstream of AMPK (Table 1) [42,43,44,45,46,47,48,49,50,51].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [50]
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- Authors
- Wu, Y., Song, P., Zhang, W., Liu, J., Dai, X., Liu, Z., Lu, Q., Ouyang, C., Xie, Z., Zhao, Z., Zhuo, X., Viollet, B., Foretz, M., Wu, J., Yuan, Z., & Zou, M.-H.
- Affiliations
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- University of Oklahoma Health Sciences Center (US)
- Hubei University of Science and Technology (CN)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Yuan, Zuyi
- Zou, Ming-Hui
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-03-23
- Volume
- 21
- Issue
- 4
- Pages
- 373-382
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4390501
- OpenAlex
- W2071163278
- Cited by
- 169
- References
- 71
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 17 · 2020: 20 · 2019: 13 · 2018: 16 · 2017: 21 · 2016: 15 · 2015: 7
- FWCI
- 8.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG047776, R01AG047776)
- National Heart, Lung, and Blood Institute (HL128014, HL-105157, R01HL105157, HL 079584, R01HL079584, HL110488, HL-080499, HL096032, HL074399, R01HL074399, R01HL080499, HL-089920, R01HL110488, R01HL128014, R01HL089920, R01HL096032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- AMPKα2, nicotine, insulin resistance, adipocytes, MKP-1, p38 MAPK, c-Jun N-terminal kinase, IRS-1 serine phosphorylation, Akt, lipolysis, free fatty acids, cigarette smoking, weight loss, proteasomal degradation
- MeSH terms
- Animals, Hypolipidemic Agents, Body Composition, Body Weight, Enzyme Activation, Homeostasis, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Nicotine, Phosphorylation, Pyrazines, Serine, Smoking, Adipocytes, Mice, Knockout, Adiposity, Mice, Rats, Dual Specificity Phosphatase 1, AMP-Activated Protein Kinases, Insulin Receptor Substrate Proteins, HEK293 Cells
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