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.
View: Text | PDF
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

×

Figure 6

Hypothalamic REV-ERBs regulate diurnal leptin sensitivity on HFD.

Options: View larger image (or click on image) Download as PowerPoint
Hypothalamic REV-ERBs regulate diurnal leptin sensitivity on HFD. (A) He...
(A) Heatmap of the genes differentially expressed in HDKO mice in the ARC in basal condition (fasted) and exacerbated during refeeding and leptin treatments. Gene expression analysis at ZT4 from HDKO mice and their control littermates after 24 hours of fasting and refeeding with HFD after injection of PBS or leptin (TPM > 0.1, FDR < 0.05). Two independent hypothalamic nuclei punches were pooled together per biological replicate (n = 3–4). (B) Volcano plot of the genes differentially expressed in HDKO mice identified in panel A, highlighting genes involved in circadian regulation (in green) or leptin signaling (in red). (C) Heatmap of the genes differentially expressed in HDKO mice in response to leptin. Gene expression analysis at ZT4 from HDKO mice and their control littermates after 24 hours of fasting and refeeding with HFD after injection of PBS or leptin (TPM > 0.1, FDR < 0.05). Two independent hypothalamic nuclei punches were pooled together per biological replicate (n = 3–4). (D) GSEA of leptin signaling during refeeding in response to leptin in the ARC from HDKO mice and their control littermates. (E) Percentage of p-STAT3–positive cells in the ARC after 24 hours of fasting, and PBS or leptin injection at ZT1 in HDKO mice and their control littermates on HFD (n = 2–4, mean ± SEM). Results were compared by 2-way ANOVA (interaction P = 0.1187) and Holm-Šidák multiple-comparison test. (F and G) Rebound feeding on HFD at ZT1 (F) and ZT13 (G) after 24 hours of fasting and injection of PBS or leptin in HDKO mice and their control littermates (n = 4-6, mean ± SEM). A representative experiment is shown at ZT1 (of 2 separate experiments with similar results). Results were compared by 2-way ANOVA and Holm-Šidák multiple-comparison test. **P < 0.01.