The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ
- Yuxiang Zhang1,2,3,
- Romeo Papazyan1,2,
- Manashree Damle1,2,
- Bin Fang1,2,
- Jennifer Jager1,2,
- Dan Feng1,2,
- Lindsey C. Peed1,2,
- Dongyin Guan1,2,
- Zheng Sun1,2,4,5 and
- Mitchell A. Lazar1,2
- 1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 2The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 3Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 4Department of Molecular and Cellular Biology, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas 77030, USA;
- 5Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
- Corresponding author: lazar{at}mail.med.upenn.edu
Abstract
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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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.302323.117.
- Received May 21, 2017.
- Accepted June 29, 2017.
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