Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice
Marine Adlanmerini, … , Matthew R. Hayes, Mitchell A. Lazar
Marine Adlanmerini, … , Matthew R. Hayes, Mitchell A. Lazar
Published October 6, 2020
Citation Information: J Clin Invest. 2021;131(1):e140424. https://doi.org/10.1172/JCI140424.
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Research Article Endocrinology Metabolism

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

Abstract

Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control food intake and energy expenditure. Here we report that, in contrast with females, male mice lacking circadian nuclear receptors REV-ERBα and –β in the tuberal hypothalamus (HDKO mice) gained excessive weight on an obesogenic high-fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB–dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HDKO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.

Authors

Marine Adlanmerini, Hoang C.B. Nguyen, Brianna M. Krusen, Clare W. Teng, Caroline E. Geisler, Lindsey C. Peed, Bryce J. Carpenter, Matthew R. Hayes, Mitchell A. Lazar

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Figure 5

REV-ERBα directly regulates ARC transcriptome on HFD.

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REV-ERBα directly regulates ARC transcriptome on HFD. (A) HA-REV-ERBα ci...
(A) HA-REV-ERBα cistrome specific to the ARC on HFD. ChIP-seq analysis of HA immunoprecipitation in the ARC from HA-REV-ERBα mice on HFD at ZT4 (reads per million mapped reads [RPM] > 1, >7-fold over input, FDR < 0.0001). Ten independent hypothalamic nuclei punches were pooled together (n = 1). (B) Motif analysis of ARC-specific cistrome of HA-REV-ERBα on HFD with default HOMER parameters. (C) Scatterplot analysis of the HFD-HDKO–specific ARC transcriptome at ZT4. The direct regulome was identified by the integration of the HA-REV-ERBα cistrome in the ARC on HFD (TPM > 0.1, FDR < 0.05 for differentially expressed genes; RPM > 1, >7-fold over input for peaks within 100 kb). (D) Genome browser view of HA-REV-ERBα ChIP-seq peaks in the ARC. (E) Fabp7 staining by RNAscope in the ARC from control and HDKO mice on HFD. Representative pictures at ZT4 and quantification at ZT4 and ZT16 are presented. Scale bars: 50 μm. 3V, third ventricle. Results were compared by 2-way ANOVA (interaction P = 0.1705) and Holm-Šidák multiple-comparison test. *P < 0.05, **P < 0.01.