Research Paper Volume 10, Issue 4 pp 764—774
Novel role of autophagy-associated Pik3c3 gene in gonadal white adipose tissue browning in aged C57/Bl6 male mice
- 1 Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- 2 Geriatric Research, Education and Clinical Care Center (GRECC), VA Ann Arbor Health System, Ann Arbor, MI 48105, USA
received: March 14, 2018 ; accepted: April 20, 2018 ; published: April 25, 2018 ;https://doi.org/10.18632/aging.101426
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Copyright: Ghosh et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Adipose tissue dysfunction is associated with inflammation, metabolic syndrome and other diseases in aging. Recent work has demonstrated that compromised autophagy activity in aging adipose tissue promotes ER stress responses, contributing to adipose tissue and systemic inflammation in aging. Phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3) is an 887 amino acid lipid kinase that regulates intracellular membrane trafficking and autophagy activity. To address the mechanistic link between autophagy and ER stress response in aging adipose tissue, we generated a line of adipose tissue-specific Pik3c3 knock out (~mutant mice) with the Fabp4 (Fatty acid binding protein 4) promoter driven Cre recombinase system. We found elevated ER stress response signaling with reduced autophagy activity without any significant change on adiposity or glucose tolerance in early life of Pik3c3 mutant mice. Interestingly, middle- and old-aged mutant mice exhibited improved glucose tolerance (GTT) and reduced adiposity compared to age and sex-matched littermates. In addition, adipose tissue-specific Pik3c3 mutants display reduced expression of adiposity-associated genes with the signature of adipose tissue browning phenotypes in old age. Overall, the results suggest that altered adipose tissue characteristics due to autophagy inhibition early in life has beneficial effects that promote adipose tissue browning and improves glucose tolerance in late-life.