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

SUMMARY 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. Interestingly, LKO mice exhibited decreased CYP8B1, corresponding to fewer 12α-hydroxylated bile acids, increasing the relative hydrophobicity of bile which decreases lipid emulsification. Notably, LKO mice have lower plasma and liver cholesterol levels, attributed to impaired lipid absorption. Furthermore, LKO mice showed preferential use of fatty acids as their fuel source. Herein, we establish a mechanistic basis for resistance of ARGLU1 LKO mice to diet-induced obesity, identifying a potential new molecular target for obesity.