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.
Highlights
The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases
We found that SRC-1 and TIF2 were dramatically decreased in aged adipose tissue, along with the reduction in adiponectin (Fig. 6e, f), suggesting that the reductions in SRC-1 and TIF2 could contribute to age-dependent adipocyte dysfunction
Using the iLIR database[54], we found that SRC-1 and TIF2 have evolutionarily conserved LC3-interacting region (LIR)/GABARAP-interacting motif (GIM)-like motifs (Fig. 7a), which are comparable to the ATG8-interacting motif in yeast ATG355, suggesting that their autophagic degradation is mediated by binding to LC3 and/or GABARAP
Summary
The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. The direct cause of adipocyte dysfunction in aged organisms, which in turn leads to age-associated metabolic disorders, remains unknown. We found that genetic ablation of Rubicon in adipocytes causes inadequate upregulation of autophagy, which in turn disrupts proper adipocyte functions, leading to fat atrophy, glucose intolerance, dyslipidaemia and hepatic fat accumulation. These changes arise from a reduction in adipogenic gene expressions, which can be restored by activation of PPARγ. We propose that age-dependent loss of adipose Rubicon results in excess autophagy, which decreases the levels of SRC-1 and TIF2, contributing to the development of age-associated metabolic disorders
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