Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism

Esther Paulo; Yun Zhang; Ruchi Masand; Tony L. Huynh; Youngho Seo; Danielle L. Swaney; Margaret Soucheray; Erica Stevenson; David Jimenez-Morales; Nevan J. Krogan; Biao Wang

Cell Reports (Sep 2021)

Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism

Esther Paulo,
Yun Zhang,
Ruchi Masand,
Tony L. Huynh,
Youngho Seo,
Danielle L. Swaney,
Margaret Soucheray,
Erica Stevenson,
David Jimenez-Morales,
Nevan J. Krogan,
Biao Wang

Affiliations

Esther Paulo: Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
Yun Zhang: Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
Ruchi Masand: Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
Tony L. Huynh: Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA
Youngho Seo: Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA
Danielle L. Swaney: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA
Margaret Soucheray: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA
Erica Stevenson: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA
David Jimenez-Morales: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA
Nevan J. Krogan: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA
Biao Wang: Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author

Journal volume & issue: Vol. 36, no. 12
p. 109742

Abstract

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Summary: Cold-induced thermogenesis in endotherms demands adaptive thermogenesis fueled by mitochondrial respiration and Ucp1-mediated uncoupling in multilocular brown adipocytes (BAs). However, dietary regulation of thermogenesis in BAs isn’t fully understood. Here, we describe that the deficiency of Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) in BAs reduces mtDNA-encoded ETC gene expression, causes ETC proteome imbalance, and abolishes the mitochondria-fueled thermogenesis. BA-specific Lrpprc knockout mice are cold resistant in a 4°C cold-tolerance test in the presence of food, which is accompanied by the activation of transcription factor 4 (ATF4) and proteome turnover in BAs. ATF4 activation genetically by BA-specific ATF4 overexpression or physiologically by a low-protein diet feeding can improve cold tolerance in wild-type and Ucp1 knockout mice. Furthermore, ATF4 activation in BAs improves systemic metabolism in obesogenic environment regardless of Ucp1’s action. Therefore, our study reveals a diet-dependent but Ucp1-independent thermogenic mechanism in BAs that is relevant to systemic thermoregulation and energy homeostasis.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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