Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-09-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721011955 |
| _version_ | 1818738248206254080 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Esther Paulo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T01:05:55Z |
| format | Article |
| id | doaj.art-015a097e0be34c6e8fa4b0b95cd1c48c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-18T01:05:55Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-015a097e0be34c6e8fa4b0b95cd1c48c2022-12-21T21:26:13ZengElsevierCell Reports2211-12472021-09-013612109742Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolismEsther Paulo0Yun Zhang1Ruchi Masand2Tony L. Huynh3Youngho Seo4Danielle L. Swaney5Margaret Soucheray6Erica Stevenson7David Jimenez-Morales8Nevan J. Krogan9Biao Wang10Cardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USACardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USACardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USADepartment 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, USACardiovascular Research Institute, Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721011955brown adipocytethermogenesisATF4 |
| spellingShingle | 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 Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism Cell Reports brown adipocyte thermogenesis ATF4 |
| title | Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism |
| title_full | Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism |
| title_fullStr | Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism |
| title_full_unstemmed | Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism |
| title_short | Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism |
| title_sort | brown adipocyte atf4 activation improves thermoregulation and systemic metabolism |
| topic | brown adipocyte thermogenesis ATF4 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721011955 |
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