Adipocyte NR1D1 dictates adipose tissue expansion during obesity

Ann Louise Hunter; Charlotte Pelekanou; Nichola Barron; Rebecca Northeast; Magdalena Grudzien; Antony Adamson; Polly Downton; Thomas Cornfield; Peter Cunningham; Jean-Noël Billaud; Leanne Hodson; Andrew S. I. Loudon; Richard Unwin; Mudassar Iqbal; David Ray; David Bechtold

doi:10.7554/eLife.63324

Adipocyte NR1D1 dictates adipose tissue expansion during obesity

Ann Louise Hunter, Charlotte Pelekanou, Nichola Barron, Rebecca Northeast, Magdalena Grudzien, Antony Adamson, Polly Downton, Thomas Cornfield, Peter Cunningham, Jean-Noël Billaud, Leanne Hodson, Andrew S. I. Loudon, Richard Unwin, Mudassar Iqbal, David Ray, David Bechtold

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

Abstract

The circadian clock component NR1D1 (REVERB) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional pro1ling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT in2ammation and 1brosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.

Original language	English
Article number	e63324
Journal	eLife
Volume	10
Early online date	5 Aug 2021
DOIs	https://doi.org/10.7554/eLife.63324
Publication status	Published - 12 Aug 2021

Keywords

Adipocytes/metabolism
Adipose Tissue/metabolism
Animals
Energy Metabolism
Gene Deletion
Lipid Metabolism
Male
Mice
Nuclear Receptor Subfamily 1, Group D, Member 1/genetics
Obesity/genetics

UN SDGs

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

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10.7554/eLife.63324

Cite this

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title = "Adipocyte NR1D1 dictates adipose tissue expansion during obesity",

abstract = "The circadian clock component NR1D1 (REVERB) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional pro1ling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT in2ammation and 1brosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.",

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author = "Hunter, {Ann Louise} and Charlotte Pelekanou and Nichola Barron and Rebecca Northeast and Magdalena Grudzien and Antony Adamson and Polly Downton and Thomas Cornfield and Peter Cunningham and Jean-No{\"e}l Billaud and Leanne Hodson and Loudon, {Andrew S. I.} and Richard Unwin and Mudassar Iqbal and David Ray and David Bechtold",

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T1 - Adipocyte NR1D1 dictates adipose tissue expansion during obesity

AU - Hunter, Ann Louise

AU - Pelekanou, Charlotte

AU - Barron, Nichola

AU - Northeast, Rebecca

AU - Grudzien, Magdalena

AU - Adamson, Antony

AU - Downton, Polly

AU - Cornfield, Thomas

AU - Cunningham, Peter

AU - Billaud, Jean-Noël

AU - Hodson, Leanne

AU - Loudon, Andrew S. I.

AU - Unwin, Richard

AU - Iqbal, Mudassar

AU - Ray, David

AU - Bechtold, David

PY - 2021/8/12

Y1 - 2021/8/12

N2 - The circadian clock component NR1D1 (REVERB) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional pro1ling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT in2ammation and 1brosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.

AB - The circadian clock component NR1D1 (REVERB) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional pro1ling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT in2ammation and 1brosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.

KW - Adipocytes/metabolism

KW - Adipose Tissue/metabolism

KW - Animals

KW - Energy Metabolism

KW - Gene Deletion

KW - Lipid Metabolism

KW - Male

KW - Mice

KW - Nuclear Receptor Subfamily 1, Group D, Member 1/genetics

KW - Obesity/genetics

U2 - 10.7554/eLife.63324

DO - 10.7554/eLife.63324

M3 - Article

C2 - 34350828

VL - 10

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e63324

ER -

Adipocyte NR1D1 dictates adipose tissue expansion during obesity

Abstract

Keywords

UN SDGs

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