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TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response

Authors
 Jinyoung Kim  ;  Seong Hun Kim  ;  Hyereen Kang  ;  Soyeon Lee  ;  Shi-Young Park  ;  Yoonil Cho  ;  Yu-Mi Lim  ;  Ji Woong Ahn  ;  Young-Hwan Kim  ;  Seungsoo Chung  ;  Cheol Soo Choi  ;  Yeon Jin Jang  ;  Hye Soon Park  ;  Yoonseok Heo  ;  Kook Hwan Kim  ;  Myung-Shik Lee 
Citation
 NATURE METABOLISM, Vol.3(3) : 410-427, 2021-03 
Journal Title
NATURE METABOLISM
ISSN
 2522-5812 
Issue Date
2021-03
MeSH
Adipose Tissue / metabolism ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism* ; Growth Differentiation Factor 15 / metabolism* ; Humans ; Insulin Resistance* ; Lysosomes / metabolism* ; Macrophages / metabolism ; Mice ; Mice, Transgenic ; Obesity / metabolism ; Obesity / prevention & control* ; Stress, Physiological*
Abstract
TFEB, a key regulator of lysosomal biogenesis and autophagy, is induced not only by nutritional deficiency but also by organelle stress. Here, we find that Tfeb and its downstream genes are upregulated together with lipofuscin accumulation in adipose tissue macrophages (ATMs) of obese mice or humans, suggestive of obesity-associated lysosomal dysfunction/stress in ATMs. Macrophage-specific TFEB-overexpressing mice display complete abrogation of diet-induced obesity, adipose tissue inflammation and insulin resistance, which is independent of autophagy, but dependent on TFEB-induced GDF15 expression. Palmitic acid induces Gdf15 expression through lysosomal Ca2+-mediated TFEB nuclear translocation in response to lysosomal stress. In contrast, mice fed a high-fat diet with macrophage-specific Tfeb deletion show aggravated adipose tissue inflammation and insulin resistance, accompanied by reduced GDF15 level. Finally, we observe activation of TFEB-GDF15 in ATMs of obese humans as a consequence of lysosomal stress. These findings highlight the importance of the TFEB-GDF15 axis as a lysosomal stress response in obesity or metabolic syndrome and as a promising therapeutic target for treatment of these conditions.
Full Text
https://www.nature.com/articles/s42255-021-00368-w
DOI
10.1038/s42255-021-00368-w
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hyereen(강혜린)
Kim, Jinyoung(김진영) ORCID logo https://orcid.org/0000-0002-3810-8549
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
Chung, Seung Soo(정승수) ORCID logo https://orcid.org/0000-0002-3119-9628
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184271
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