The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

Y Zhang, R Papazyan, M Damle, B Fang… - Genes & …, 2017 - genesdev.cshlp.org
Y Zhang, R Papazyan, M Damle, B Fang, J Jager, D Feng, LC Peed, D Guan, Z Sun…
Genes & Development, 2017genesdev.cshlp.org
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 RORα and RORγ, 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. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced …
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 RORα and RORγ, 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. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ 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.
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