Research Article: Novel role of autophagy-associated Pik3c3 gene in gonadal white adipose tissue browning in aged C57/Bl6 male mice

Date Published: April 25, 2018

Publisher: Impact Journals

Author(s): Amiya Kumar Ghosh, Theresa Mau, Martin O’Brien, Raymond Yung.

http://doi.org/10.18632/aging.101426

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.

Partial Text

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]. Our previous works have examined the expressions of ER stress response genes in young and old animals in basal state or under the influence of chemical inducer/inhibitor of ER stress response [2]. 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].

Adipose tissue is at the crossroad of longevity and age-associated diseases involving inflammation and metabolic dysfunction. Longevity is extended with interventions that limit visceral fat development, such as: a) caloric restriction [20]. b) fat cell insulin receptor knock out (FIRKO), insulin receptor substrate (IRS-1) or S6 kinase 1 knockout mice models [21,22]. c) growth hormone receptor knock out (GHRKO) mice model [23]. d) rapamycin treatment [24,25], and by e) surgical removal of visceral fat [26,27]. To understand the molecular basis of adipose tissue inflammation, our work on gWAT across the lifespan have provided strong evidence of autophagy impairment [1] as a basis of elevated ER stress response which in turn promotes gWAT inflammation in aging mice. Recently, we have demonstrated that proficient autophagy activity and reduced senescence in gWAT were associated with improved glucose tolerance in aging Tlr4-knockout mice [28]. Much of the previous conclusions were derived by comparing expressions of ER stress response genes in young or old animals in basal state or under the influence of chemical inducers for ER stress response [29]. Similarly, differential expressions of autophagy genes in mice of varying ages suggested a causal association of autophagy activity with WAT inflammation in aging [1].

 

Source:

http://doi.org/10.18632/aging.101426

 

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