Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy

Author:

Yamamuro TadashiORCID,Kawabata Tsuyoshi,Fukuhara AtsunoriORCID,Saita Shotaro,Nakamura ShuheiORCID,Takeshita Hikari,Fujiwara Mari,Enokidani Yusuke,Yoshida Gota,Tabata KeisukeORCID,Hamasaki Maho,Kuma Akiko,Yamamoto Koichi,Shimomura Iichiro,Yoshimori Tamotsu

Abstract

AbstractThe systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.

Funder

Japan Agency for Medical Research and Development

MEXT | Japan Society for the Promotion of Science

Takeda Science Foundation

Human Frontier Science Program

A3 Foresight Program

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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