The Hepatic Circadian Clock Fine-Tunes The Lipogenic Response To Feeding Through Ror Alpha/Gamma

Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors ROR alpha and ROR gamma, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. ROR alpha/gamma controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of ROR alpha/gamma causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders.