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

Nat Commun. 2020 Aug 18;11(1):4150. doi: 10.1038/s41467-020-17985-w.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adipogenesis / genetics
  • Adipose Tissue / cytology
  • Adipose Tissue / metabolism
  • Adiposity / genetics
  • Aging / physiology*
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / genetics*
  • Autophagy / physiology
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Gene Knockout Techniques
  • Glucose / genetics
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipid Metabolism / genetics
  • Metabolic Diseases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubule-Associated Proteins / metabolism
  • Nuclear Receptor Coactivator 1 / metabolism
  • Nuclear Receptor Coactivator 2 / metabolism
  • PPAR gamma / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • GABARAP protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • Ncoa2 protein, mouse
  • Nuclear Receptor Coactivator 2
  • PPAR gamma
  • rubicon protein, mouse
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Glucose