Estrogen Receptor Alpha Is Required to Protect Daily Metabolic Rhythms From Disruption by High-Fat Feeding in Female Mice

The circadian system is a critical regulator of obesity in male mice, but its role in females is poorly understood. In our previous studies we found that estrogen regulates daily rhythms in female mice to confer resistance to diet-induced obesity, but the mechanism is unknown. Estrogen signals via the classical estrogen receptor alpha (ERα) to regulate metabolism and obesity. Therefore, in this study we tested the hypothesis that estrogen regulates daily metabolic rhythms in females via ERα. To do so, we studied daily rhythms in female global ERα knockout (ERα KO) with the circadian reporter, PERIOD2::LUCIFERASE, mice fed high-fat diet for 6 weeks. ERα KO female mice became obese and hyperglycemic when fed high-fat diet, while wild-type females were resistant to diet-induced obesity. Chronic high-fat diet feeding also reduced the amplitude of the daily rhythm of eating behavior in ERα KO, but not wild-type, female mice. In wild-type females, the amplitude of the locomotor activity rhythm increased during high-fat feeding. In contrast, high-fat feeding decreased the amplitude of the activity rhythm in ERα KO females. The temporal relationship between central and peripheral circadian tissue clocks was disrupted by high-fat feeding in ERα KO females since the phase of the liver PERIOD2::LUCIFERASE rhythm was advanced 4 hours by high-fat feeding in ERα KO mice compared to wild-type females. Taken together these results show that estrogen signals via ERα to protect daily metabolic rhythms from disruption by high-fat feeding in female mice.