한빛사 논문
Myoung Seok Koa*, Ji Young Yuna,b*, In-Jeoung Baeka, Jung Eun Janga,b, Jung Jin Hwangc , Seung Eun Leea,b, Seung-Ho Heod, David A. Badere, Chul-Ho Leef, Jaeseok Hang, Jong-Seok Moong, Jae Man Leeh, Eun- Gyoung Hongi, In-Kyu Leej, Seong Who Kimk, Joong Yeol Parka,b, Sean M. Hartige, Un Jung Kangl, David D. Moorem, Eun Hee Koha,b,#, and Ki-up Leea,b,#
aBiomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
bDepartment of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
cInstitute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
dConvergence Medicine Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea;
eMolecular and Cellular Biology and Medicine, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas, USA;
fLaboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;
gSoonchunhyang Institute of Med-bio Science (SIMS), Soonchunhyang University, Korea;
hDepartment of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea;
iDivision of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea;
jDepartment of Internal Medicine and Biochemistry, Kyungpook National University School of Medicine, Daegu, Korea;
kDepartment of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea;
lDepartment of Neurology, Neuroscience and Physiology, Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders, NYU Langone Health, New York, USA;
mDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
*These authors contributed equally to this work.
#Corresponding author
Abstract
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.
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