1. Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism
- Author
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Paulo, Esther, Zhang, Yun, Masand, Ruchi, Huynh, Tony L, Seo, Youngho, Swaney, Danielle L, Soucheray, Margaret, Stevenson, Erica, Jimenez-Morales, David, Krogan, Nevan J, and Wang, Biao
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Obesity ,Nutrition ,Activating Transcription Factor 4 ,Adipose Tissue ,Brown ,Animals ,Body Weight ,Cold Temperature ,Diet ,Energy Metabolism ,Female ,Iodide Peroxidase ,Liver ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mitochondria ,Neoplasm Proteins ,Thermogenesis ,Uncoupling Protein 1 ,Iodothyronine Deiodinase Type II ,ATF4 ,brown adipocyte ,thermogenesis ,Medical Physiology ,Biological sciences - Abstract
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
- 2021