Liver-specific loss of the transcriptional coregulator ARGLU1 protects against diet-induced obesity in mice through decreased lipid absorption.

New medications that decrease food intake show promise in addressing the global obesity epidemic; however, additional therapies are needed for patients who are intolerant or unresponsive to these drugs. ARGLU1 is a transcriptional coregulator of several nuclear receptors. Herein, we detail the discovery that mice lacking ARGLU1 in hepatocytes (LKO) are resistant to diet-induced obesity, with no difference in food intake, locomotion, or energy expenditure compared to wildtype mice. LKO mice have lower plasma and liver cholesterol levels, attributed to impaired lipid absorption secondary to changes in bile acid composition. The decrease in CYP8B1 in LKO mice corresponded to fewer 12α-hydroxylated bile acids, increasing the relative hydrophobicity of bile, which decreased lipid (triglyceride and cholesterol) absorption. LKO mice further showed preferential use of fatty acids as their fuel source, thereby establishing a mechanistic basis for resistance of LKO mice to diet-induced obesity and identifying a new molecular target for obesity.