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
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.
