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 3

Hypothalamic REV-ERBs regulate diurnal eating behaviors on HFD.

Options: View larger image (or click on image) Download as PowerPoint
Hypothalamic REV-ERBs regulate diurnal eating behaviors on HFD. (A and B...
(A and B) Food consumption in HDKO mice and their control littermates on HFD. (A) Twenty-four-hour food consumption calculated from 8 days of records are presented (n = 8–10, mean ± SEM). (B) Light phase and dark phase food consumption calculated from 48 hours of records are presented (n = 6–7, mean ± SEM). Results were compared by Mann-Whitney test. (C and D) Rebound feeding at ZT1–ZT4 after 24 hours of fasting in HDKO mice and their control littermates on NCD (C) and HFD (D) (n = 3–5, mean ± SEM). Results were compared by Mann-Whitney test. Three-hour time course of rebound feeding on HFD is also displayed (n = 3, mean ± SEM). A representative experiment is shown (of 2 separate experiments with similar results). Results were compared by repeated measures 2-way ANOVA and Holm-Šidák multiple-comparison test. *P < 0.05, **P < 0.01.