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

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Abstract
Kim et al. reveal that TFEB expression is protective in the setting of diet-induced obesity by activating the expression of GDF15 in adipose tissue macrophages in mice and humans.

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.
Author(s)
강혜린김국환김성훈김영환김진영박시영박혜순안지웅이명식이소연임유미장연진정성수조윤일최철수허윤석
Issued Date
2021
Type
Article
Keyword
Adipose Tissue - metabolismAnimalsBasic Helix-Loop-Helix Leucine Zipper Transcription Factors - geneticsBasic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolismGrowth Differentiation Factor 15 - metabolismHumansInsulin ResistanceLysosomes - metabolismMacrophages - metabolismMiceTransgenicObesity - metabolismObesity - prevention & controlPhysiological
DOI
10.1038/s42255-021-00368-w
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7879
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2504777335&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,TFEB-GDF15%20axis%20protects%20against%20obesity%20and%20insulin%20resistance%20as%20a%20lysosomal%20stress%20response&offset=0&pcAvailability=true
Publisher
NATURE METABOLISM
Location
영국
Language
영어
ISSN
2522-5812
Citation Volume
3
Citation Number
3
Citation Start Page
410
Citation End Page
215
Appears in Collections:
Medicine > Medicine
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