한빛사 논문
울산대학교 의과대학, 서울아산병원
Gil Myoung Kang1,10, Se Hee Min2,10, Chan Hee Lee1,10, Ji Ye Kim1, Hyo Sun Lim3, Min Jeong Choi4, Saet-Byel Jung4, Jae Woo Park3, Seongjun Kim3, Chae Beom Park3, Hong Dugu3, Jong Han Choi2, Won Hee Jang3, Se Eun Park3, Young Min Cho5, Jae Geun Kim6, Kyung-Gon Kim1, Cheol Soo Choi7, Young-Bum Kim8, Changhan Lee9,*, Minho Shong4,10,*, Min-Seon Kim2,11,*
1Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Korea
2Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul 05505, Korea
3Department of Biomedical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center and University of Ulsan College of Medicine, Seoul 05505, Korea
4Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon 35015, Korea
5Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
6Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Korea
7Lee Gil Ya Cancer and Diabetes Institute, Korea Mouse Metabolic Phenotyping Center, Gachon University, Inchon 21999, Korea
8Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
9Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
10Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Korea
10These authors contributed equally
11Lead Contact
*Corresponding author
Abstract
Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPRmt) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPRmt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.
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