Obesity induces a phenotypic switch in adipose tissue macrophage polarization
Carey N. Lumeng, … , Jennifer L. Bodzin, Alan R. Saltiel
Carey N. Lumeng, … , Jennifer L. Bodzin, Alan R. Saltiel
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):175-184. https://doi.org/10.1172/JCI29881.
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Research Article

Obesity induces a phenotypic switch in adipose tissue macrophage polarization

Abstract

Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80+CD11c+ population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or “alternatively activated” macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-α and iNOS that are characteristic of M1 or “classically activated” macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2–KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-α–induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.

Authors

Carey N. Lumeng, Jennifer L. Bodzin, Alan R. Saltiel

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Figure 8

Proposed model for ATM polarization and its function in adipose tissue with progressive obesity.

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Proposed model for ATM polarization and its function in adipose tissue w...
In lean, insulin-sensitive states, ATMs are polarized toward an M2 state with IL-10 and arginase expression. Early during HFD treatment, adipocytes undergo hypertrophy, releasing chemokines that induce recruitment of M1-polarized ATMs with low IL-10 expression and increased iNOS and TNF-α production. In these early stages of mild obesity with retained insulin sensitivity, M2-polarized resident ATMs are able to partially protect adipocytes from these inflammatory factors and may block M1 polarization. With increased adiposity, recruited CCR2+ ATMs form crownlike structures (CLS) and overwhelm the protective effects of M2 macrophages, leading to a dominant role for TNF-α and iNOS. These factors generate insulin resistance in adipocytes, activate JNK and NF-κB, alter adipokine secretion, and lead to excess circulating levels of free fatty acids due to adipocyte lipolysis and impaired lipogenesis.