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

Tadashi Yamamuro, Tsuyoshi Kawabata, Atsunori Fukuhara, Shotaro Saita, Shuhei Nakamura, Hikari Takeshita, Mari Fujiwara, Yusuke Enokidani, Gota Yoshida, Keisuke Tabata, Maho Hamasaki, Akiko Kuma, Koichi Yamamoto, Iichiro Shimomura () and Tamotsu Yoshimori ()
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Tadashi Yamamuro: Osaka University
Tsuyoshi Kawabata: Osaka University
Atsunori Fukuhara: Osaka University
Shotaro Saita: Osaka University
Shuhei Nakamura: Osaka University
Hikari Takeshita: Osaka University
Mari Fujiwara: Osaka University
Yusuke Enokidani: Osaka University
Gota Yoshida: Osaka University
Keisuke Tabata: Osaka University
Maho Hamasaki: Osaka University
Akiko Kuma: Osaka University
Koichi Yamamoto: Osaka University
Iichiro Shimomura: Osaka University
Tamotsu Yoshimori: Osaka University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract The 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.

Date: 2020
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DOI: 10.1038/s41467-020-17985-w

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