Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis

Objective: The adipose tissue–liver axis is a major regulator of the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Retinoic acid signaling plays an important role in development and metabolism. However, little is known about the role of adipose retinoic acid signaling in the development of obesity-associated NAFLD. In this work, the aim was to investigate whether and how retinoic acid receptor alpha (RARα) regulated the development of obesity and NAFLD. Methods: RARα expression in adipose tissue of db/db or ob/ob mice was determined. Rarα^fl/fl mice and adipocyte-specific Rarα^−/− (Rarα^Adi−/−) mice were fed a chow diet for 1 year or high-fat diet (HFD) for 20 weeks. Primary adipocytes and primary hepatocytes were co-cultured. Metabolic regulation and inflammatory response were characterized. Results: RARα expression was reduced in adipose tissue of db/db or ob/ob mice. Rarα^Adi−/− mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RARα induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co-culture studies, loss of RARα in adipocytes induced inflammatory and lipogenic programs in hepatocytes. Conclusions: The data demonstrate that RARα in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.