1. TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response.
- Author
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Kim J, Kim SH, Kang H, Lee S, Park SY, Cho Y, Lim YM, Ahn JW, Kim YH, Chung S, Choi CS, Jang YJ, Park HS, Heo Y, Kim KH, and Lee MS
- Subjects
- Adipose Tissue metabolism, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Humans, Macrophages metabolism, Mice, Mice, Transgenic, Obesity metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Growth Differentiation Factor 15 metabolism, Insulin Resistance, Lysosomes 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 Ca
2+ -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.- Published
- 2021
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