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Insulin resistance causes inflammation in adipose tissue
Mitsugu Shimobayashi, … , Ralph Peterli, Michael N. Hall
Mitsugu Shimobayashi, … , Ralph Peterli, Michael N. Hall
Published March 12, 2018
Citation Information: J Clin Invest. 2018;128(4):1538-1550. https://doi.org/10.1172/JCI96139.
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Research Article Inflammation Metabolism

Insulin resistance causes inflammation in adipose tissue

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Abstract

Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.

Authors

Mitsugu Shimobayashi, Verena Albert, Bettina Woelnerhanssen, Irina C. Frei, Diana Weissenberger, Anne Christin Meyer-Gerspach, Nicolas Clement, Suzette Moes, Marco Colombi, Jerome A. Meier, Marta M. Swierczynska, Paul Jenö, Christoph Beglinger, Ralph Peterli, Michael N. Hall

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Figure 1

Quantitative proteome analysis reveals insulin/mTORC2 signaling functions in adipose tissue inflammation.

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Quantitative proteome analysis reveals insulin/mTORC2 signaling function...
(A) ITT for AdRiKO and control mice fed a HFD for 10 weeks. Mice were fasted for 5 hours prior to the ITT. Data are presented as the mean ± SEM. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA. n = 10 (control) and n = 5 (AdRiKO). (B) Immunoblots of eWAT from HFD-fed AdRiKO and control mice. eWAT samples were collected from ad libitum–fed mice. The same lysates were used for proteome analysis. (C) Regulated proteome with 3 biological replicates. See also Supplemental Table 1. (D) GO term analysis of the regulated proteome. Data are presented as the mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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