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

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

doi:10.1172/JCI140424

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

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

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English
Article number	e140424
Journal	Journal of Clinical Investigation
Volume	131
Issue number	1
DOIs	https://doi.org/10.1172/JCI140424
State	Published - Jan 4 2021

Bibliographical note

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

Funding

We gratefully acknowledge L. Woodie for critically reading the manuscript. We thank L. Cheng from the Penn Molecular Pathology and Imaging Core for help with histology, as well as the Gene Expression and Functional Genomics Core of the Penn Diabetes Research Center (DK19525). This work was supported by NIH R01DK45586, the JPB Foundation, and the Cox Institute for Medical Research (to MAL). MA was supported by an American Diabetes Association Training grant (1-18-PDF-126). MRH was supported by NIH grant R01DKDK021397. Conflict of interest: MAL is an advisory board member for Eli Lilly and Pfizer Inc., consultant to Novartis, and receives research support from Pfizer. MRH has received research support from investigator-initiated sponsored proposals from Eli Lilly & Co. and Boehringer-Ingelheim. Copyright: © 2021, American Society for Clinical Investigation. Submitted: May 19, 2020; Accepted: September 29, 2020; Published: January 4, 2021. Reference information: J Clin Invest. 2021;131(1):e140424. https://doi.org/10.1172/JCI140424.

Funders	Funder number
Cox Institute for Medical Research
Eli Lilly & Co. and Boehringer-Ingelheim
National Institutes of Health (NIH)	R01DK45586
National Institutes of Health (NIH)
American Diabetes Association Inc	1-18-PDF-126, R01DKDK021397
American Diabetes Association Inc
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK019525
National Institute of Diabetes and Digestive and Kidney Diseases
JPB Foundation

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General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "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.",

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

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AU - Adlanmerini, Marine

AU - Nguyen, Hoang C.B.

AU - Krusen, Brianna M.

AU - Teng, Clare W.

AU - Geisler, Caroline E.

AU - Peed, Lindsey C.

AU - Carpenter, Bryce J.

AU - Hayes, Matthew R.

AU - Lazar, Mitchell A.

PY - 2021/1/4

Y1 - 2021/1/4

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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