Myeloid HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase Determines Adipose Tissue Inflammation, Insulin Resistance And Hepatic Steatosis In Diet-Induced Obese Mice.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell-specific reduction of HMG-CoA reductase (Hmgcr(m-/m-)), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr(m-/m-) mice than in control Hmgcr(fl/fl) mice in the setting of obesity. To test this hypothesis, we fed Hmgcr(m-/m-) and Hmgcr(fl/fl) mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell-specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell-specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.