Abstract
Chronic inflammation is now recognized as a key step in the pathogenesis of obesity-induced insulin resistance and type 2 diabetes mellitus. This low-grade inflammation is mediated by the inflammatory (classical) activation of recruited and resident macrophages that populate metabolic tissues, including adipose tissue and liver. These findings have led to the concept that infiltration by and activation of macrophages in adipose tissue are causally linked to obesity-induced insulin resistance. Studies have shown, however, that alternatively activated macrophages taking residence in adipose tissue and liver perform beneficial functions in obesity-induced metabolic disease. Alternatively activated macrophages reduce insulin resistance in obese mice by attenuating tissue inflammation and increasing oxidative metabolism in liver and skeletal muscle. The discovery that distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance suggests that pathways controlling macrophage activation can potentially be targeted to treat these comorbidities of obesity. Thus, this Review focuses on the stimuli and mechanisms that control classical and alternative activation of tissue macrophages, and how these macrophage activation programs modulate insulin action in peripheral tissues. The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism.
Key Points
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Chronic, low-grade inflammation provides a molecular pathway that links obesity to insulin resistance
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Distinct subsets of macrophages are involved in the promotion or attenuation of insulin resistance
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Classically activated macrophages potentiate insulin resistance
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Alternatively activated macrophages confer protection against obesity and insulin resistance
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Obesity induces a switch in macrophage activation, leading to increased insulin resistance
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Peroxisome proliferator-activated receptors γ and δ regulate alternative activation of macrophages
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Acknowledgements
We thank A Loh for critical reading of the manuscript. This work was supported by grants made available to A Chawla from NIH (DK062386 and HL076746), Takeda Pharmaceuticals of North America, and the American Diabetes Association. Support was provided to JI Odegaard by Stanford Medical Scientist Training Program and the AHA.
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Odegaard, J., Chawla, A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Rev Endocrinol 4, 619–626 (2008). https://doi.org/10.1038/ncpendmet0976
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DOI: https://doi.org/10.1038/ncpendmet0976
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