The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism

Mutations of clock genes can lead to diabetes and obesity. REV-ERB alpha, a nuclear receptor involved in the circadian clockwork, has been shown to control lipid metabolism. To gain insight into the role of REV-ERB alpha in energy homeostasis in vivo, we explored daily metabolism of carbohydrates and lipids in chow-fed, unfed, or high-fat-fed Rev-erb alpha(-/-) mice and their wild-type littermates. Chow-fed Rev-erb alpha(-/-) mice displayed increased adiposity (2.5-fold) and mild hyperglycemia (similar to 10%) without insulin resistance. Indirect calorimetry indicates that chow-fed Rev-erb alpha(-/-) mice utilize more fatty acids during daytime. A 24-h nonfeeding period in Rev-erb alpha(-/-) animals favors further fatty acid mobilization at the expense of glycogen utilization and gluconeogenesis, without triggering hypoglycemia and hypothermia. High-fat feeding in Rev-erb alpha(-/-) mice amplified metabolic disturbances, including expression of lipogenic factors. Lipoprotein lipase (Lpl) gene, critical in lipid utilization/storage, is triggered in liver at night and constitutively up-regulated (similar to 2-fold) in muscle and adipose tissue of Rev-erb alpha(-/-) mice. We show that CLOCK, up-regulated (2-fold) at night in Rev-erb alpha(-/-) mice, can transactivate Lpl. Thus, overexpression of Lpl facilitates muscle fatty acid utilization and contributes to fat overload. This study demonstrates the importance of clock-driven Lpl expression in energy balance and highlights circadian disruption as a potential cause for the metabolic syndrome.-Delezie, J., Dumont, S., Dardente, H., Oudart, H., Grechez-Cassiau, A., Klosen, P., Teboul, M., Delaunay, F., Pevet, P., Challet, E. The nuclear receptor REV-ERB alpha is required for the daily balance of carbohydrate and lipid metabolism. FASEBJ. 26, 3321-3335 (2012). www.fasebj.org