Given the increasing prevalence of
obesity and the
metabolic syndrome, identification of intrinsic molecular programs responsible for ensuring fuel homeostasis and preventing
metabolic disease is needed. We investigated whether the
orphan nuclear receptor estrogen-related receptor α (ERRα), a major regulator of energy metabolism, plays a role in
lipid homeostasis and the development of
nonalcoholic fatty liver disease (
NAFLD) in response to chronic high-fat diet (HFD) consumption and long-term fasting. Systemic ablation of ERRα in mice demonstrated clear beneficial effects for loss of ERRα function in protection from HFD-provoked
body weight gain manifested not only from a reduction in white adipose tissue stores but also from an impediment in intrahepatic
lipid accumulation. The prevention of HFD-induced
NAFLD in ERRα-null mice was underscored by transcriptional repression of de novo lipogenesis, which was upregulated in wild-type mice, a known contributing factor to
lipid-stimulated hepatic steatosis. Surprisingly, given these findings, ERRα deficiency had no significant impact on the degree of fasting-induced
NAFLD, involving the mobilization of adipocyte
triglyceride (TG) stores into the liver. However, the presence of ERRα was essential for acute refeeding-mediated reversal of fasting-induced hepatic TG accretion, underpinned by impaired downregulation of adipose TG lipolysis and reduced hepatic mitochondrial oxidative activity. Taken together, the regulation of
lipid handling by ERRα depended on the nutritional state, suggesting that negative modulation of ERRα activity could be envisaged to prevent
lipid-induced
NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease.