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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<jats:sup>\u2212<\/jats:sup>) does not cause overt abnormalities in mice. Here, we performed analyses in age- and sex-matched Acat1<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>and wild-type mice on chow or Western diet and discovered that Acat1<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>mice exhibit resistance to Western diet-induced obesity. On both chow and Western diets, Acat1<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>mice display decreased adipocyte size and increased insulin sensitivity. When fed with Western diet, Acat1<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>mice contain fewer infiltrating macrophages in white adipose tissue (WAT), with significantly diminished inflammatory phenotype. Without Acat1, the Ly6C<jats:sup>hi<\/jats:sup>monocytes express reduced levels of integrin-\u03b2<jats:sub>1<\/jats:sub>, 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<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>mice to the inflamed WAT of wild-type mice is significantly diminished. Under Western diet, Acat1<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>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<jats:sup>\u2212<\/jats:sup><jats:sup>M\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><jats:sup>M<\/jats:sup>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.<\/jats:p>","DOI":"10.1152\/ajpendo.00174.2017","type":"journal-article","created":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T22:19:37Z","timestamp":1520979577000},"page":"E340-E356","source":"Crossref","is-referenced-by-count":29,"title":["Myeloid-specific<i>Acat1<\/i>ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity"],"prefix":"10.1152","volume":"315","author":[{"given":"Li-Hao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaina M.","family":"Melton","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Sohn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DaeYoung","family":"Jung","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Yi","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HyeKyung","family":"Ha","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall H.","family":"Friedline","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Kim","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Usherwood","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine C. 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