Abstract
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.
Highlights
Chronic low-grade inflammation of white adipose tissue (WAT) is considered as one of the root causes of insulin resistance in aging, along with other age-associated diseases
Recent work from our group indicated that compromised autophagy is linked to elevated ER stress responses that contributed to the inflammation of WAT in aging [1]
Adipose tissue is at the crossroad of longevity and ageassociated diseases involving inflammation and metabolic dysfunction
Summary
Chronic low-grade inflammation of white adipose tissue (WAT) is considered as one of the root causes of insulin resistance in aging, along with other age-associated diseases. Recent work from our group indicated that compromised autophagy is linked to elevated ER stress responses that contributed to the inflammation of WAT in aging [1]. Results of differential expressions of autophagy genes in mice of varying ages suggested a plausible link between compromised WAT autophagy activity and inflammation in aging [1]. Macro-autophagy (hereafter autophagy) plays an essential role in cellular homeostasis and stress adaptation, deficiency of which promotes multiple chronic diseases in aging [3]. Cellular and tissue homeostasis is maintained with autophagy process by eliminating damaged organelles and misfolded proteins and dysregulation of which is implicated in developmental defects and multiple age-associated diseases [3, 5,6,7,8,9]
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