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 3- hydroxy-3-methylglutaryl-coenzyme A 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 control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m-/m- and Hmgcr^fl/fl mice with 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 numbers of ATMs. The ATMs were reduced by decreased recruitment of macrophages due to their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in the 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.