Myeloid-specific Acat1 ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity.

Macrophages are phagocytes that play important roles in health and diseases. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) converts cellular cholesterol to cholesteryl esters and is expressed in many cell types. Unlike global Acat1 knockout (KO), myeloid-specific Acat1 KO ( Acat1(-)) does not cause overt abnormalities in mice. Here, we performed analyses in age- and sex-matched Acat1(-)(M/)(-)(M) and wild-type mice on chow or Western diet and discovered that Acat1(-)(M/)(-)(M) mice exhibit resistance to Western diet-induced obesity. On both chow and Western diets, Acat1(-)(M/)(-)(M) mice display decreased adipocyte size and increased insulin sensitivity. When fed with Western diet, Acat1(-)(M/)(-)(M) mice contain fewer infiltrating macrophages in white adipose tissue (WAT), with significantly diminished inflammatory phenotype. Without Acat1, the Ly6C(hi) monocytes express reduced levels of integrin-β(1), which plays a key role in the interaction between monocytes and the inflamed endothelium. Adoptive transfer experiment showed that the appearance of leukocytes from Acat1(-)(M/)(-)(M) mice to the inflamed WAT of wild-type mice is significantly diminished. Under Western diet, Acat1(-)(M/)(-)(M) causes suppression of multiple proinflammatory genes in WAT. Cell culture experiments show that in RAW 264.7 macrophages, inhibiting ACAT1 with a small-molecule ACAT1-specific inhibitor reduces inflammatory responses to lipopolysaccharide. We conclude that under Western diet, blocking ACAT1 in macrophages attenuates inflammation in WAT. Other results show that Acat1(-)(M/)(-)(M) does not compromise antiviral immune response. Our work reveals that blocking ACAT1 suppresses diet-induced obesity in part by slowing down monocyte infiltration to WAT as well as by reducing the inflammatory responses of adipose tissue macrophages.