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

ObjectiveThe 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 (RAR alpha) regulated the development of obesity and NAFLD.MethodsRAR alpha expression in adipose tissue of db/db or ob/ob mice was determined. Rar alpha fl/fl mice and adipocyte-specific Rar alpha-/- (Rar alpha 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.ResultsRAR alpha expression was reduced in adipose tissue of db/db or ob/ob mice. Rar alpha Adi-/- mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RAR alpha induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co-culture studies, loss of RAR alpha in adipocytes induced inflammatory and lipogenic programs in hepatocytes.ConclusionsThe data demonstrate that RAR alpha in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.