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 4

Food consumption is regulated by REV-ERB–dependent leptin signaling in the ARC on HFD.

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Food consumption is regulated by REV-ERB–dependent leptin signaling in t...
(A) Heatmap of the genes differentially expressed in HDKO mice in the ARC only on HFD. Gene expression analysis at ZT4 from HDKO mice and their control littermates on NCD and HFD in the ARC (TPM > 0.1, FDR < 0.05). Two to 4 independent hypothalamic nuclei punches were pooled together per biological replicate (n = 4–5). (B) Pathway analysis of genes differentially expressed in HDKO mice on HFD in the ARC (Enrichr q value < 0.05). (C) Box-and-whisker plot showing minimum, maximum, median, first quartile, and third quartile from quantification of enrichment of the REV-ERB motif in the transcriptome from HDKO mice and their control littermates on NCD or HFD in the ARC. P values were calculated with the Mann-Whitney test. (D) Enrichr transcription factor analysis on the genes downregulated in HDKO mice on HFD in the ARC. (E) Box-and-whisker plot showing minimum, maximum, median, first quartile and third quartile from quantification of enrichment of the STAT3 motif in the transcriptome from HDKO mice and their control littermates on NCD or HFD in the ARC. P values were calculated with the Mann-Whitney test. (F) Leptin circulating levels at ZT4 in control and HDKO mice on HFD (n = 8–10, mean ± SEM). Results were compared by Mann-Whitney test. *P < 0.05, **P < 0.01.