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Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice.
Ko, Myoung Seok; Yun, Ji Young; Baek, In-Jeoung; Jang, Jung Eun; Hwang, Jung Jin; Lee, Seung Eun; Heo, Seung-Ho; Bader, David A; Lee, Chul-Ho; Han, Jaeseok; Moon, Jong-Seok; Lee, Jae Man; Hong, Eun-Gyoung; Lee, In-Kyu; Kim, Seong Who; Park, Joong Yeol; Hartig, Sean M; Kang, Un Jung; Moore, David D; Koh, Eun Hee; Lee, Ki-Up.
Afiliación
  • Ko MS; Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Yun JY; Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Baek IJ; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Jang JE; Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Hwang JJ; Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Lee SE; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Heo SH; Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Bader DA; Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Lee CH; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Han J; Convergence Medicine Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Moon JS; Molecular and Cellular Biology and Medicine, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas, USA.
  • Lee JM; Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
  • Hong EG; Soonchunhyang Institute of Med-bio Science (SIMS), Soonchunhyang University, Korea.
  • Lee IK; Soonchunhyang Institute of Med-bio Science (SIMS), Soonchunhyang University, Korea.
  • Kim SW; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea.
  • Park JY; Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea.
  • Hartig SM; Department of Internal Medicine and Biochemistry, Kyungpook National University School of Medicine, Daegu, Korea.
  • Kang UJ; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea.
  • Moore DD; Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Koh EH; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • Lee KU; Molecular and Cellular Biology and Medicine, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas, USA.
Autophagy ; 17(5): 1205-1221, 2021 05.
Article en En | MEDLINE | ID: mdl-32400277
Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.Abbreviations: ACTB: actin, beta; BAPs: brown adipocyte precursors; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; ChIP: chromatin immunoprecipitation; EE: energy expenditure; HFD: high-fat diet; IL1B: interleukin 1 beta; ITT: insulin tolerance test; KO: knockout; LPS: lipopolysaccharide; NLRP3: NLR family, pyrin domain containing 3; PINK1: PTEN induced putative kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RD: regular diet; ROS: reactive oxygen species; RT: room temperature; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Tejido Adiposo Pardo / Inflamasomas / Mitofagia / Proteína con Dominio Pirina 3 de la Familia NLR Límite: Animals Idioma: En Revista: Autophagy Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Tejido Adiposo Pardo / Inflamasomas / Mitofagia / Proteína con Dominio Pirina 3 de la Familia NLR Límite: Animals Idioma: En Revista: Autophagy Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos