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Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement

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Han, Hye-Sook; Ahn, Eunyong; Park, Eun Seo; Huh, Tom; Choi, Seri; Kwon, Yongmin; Choi, Byeong Hun; Lee, Jueun; Choi, Yoon Ha; Jeong, Yujin L.; Lee, Gwang Bin; Kim, Minji; Seong, Je Kyung; Shin, Hyun Mu; Kim, Hang-Rae; Moon, Myeong Hee; Kim, Jong Kyoung; Hwang, Geum-Sook; Koo, Seung-Hoi

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Nature Aging, Vol.3 No.8, pp.982-+
Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo. Adipose tissue has an important role in metabolic homeostasis and undergoes age-related changes contributing to metabolic decline, via mechanisms that remain incompletely explored. Here the authors show that Crtc2 deficiency in adipocytes protects against age-related hyperactivation of the BCAA-mTORC1 axis and metabolic alterations.
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Research Area Function, Immune modulation by metabolites, T-cell anergy, differentiation of memory CD8+ T cells, metabolism


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