A crucial role for adipose tissue p53 in the regulation of insulin resistance

Abstract

Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

“…Indeed, eliminating senescent cells in mice with a progeroid syndrome delays some age‐associated disorders, while in wild‐type mice it reduces aging‐related diseases and extends lifespan (Baker et al, 2016, 2011 ). The list of age‐related diseases improved by delaying senescence or eliminating senescent cells is increasing and includes osteoporosis, type 2 diabetes, and atherosclerosis (Childs et al, 2016, 2017 ; Farr et al, 2017; Minamino et al, 2009). However, the role of cellular senescence in premature aging remains largely unclear.…”

Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect

“…Excessive calorie intake has been reported to induce cellular senescence-like changes such as expression of p53 and inflammation in the WAT (Minamino, 2009). Inhibition of p53 activity in the WAT markedly ameliorates the senescence-related changes and inflammation, and improves insulin resistance and glucose intolerance (Minamino, 2009).…”

“…Inhibition of p53 activity in the WAT markedly ameliorates the senescence-related changes and inflammation, and improves insulin resistance and glucose intolerance (Minamino, 2009). In the present study, p53 protein abundance and the downstream p21 protein levels in the epididymal adipose tissue were significantly reduced in Adipoq-RD and Adipoq-HFD mice, compared with WT-RD and WT-HFD mice (p53; p = 0.0004, p < 0.0001, p21; p < 0.0001, p = 0.0004); there was no difference between WT-RD and WT-HFD mice ( Fig.…”

“…Excess calorie intake in mice, either genetically-induced or resulting from dietary changes, leads to the accumulation of oxidative stress in the WAT and promotes senescence-like changes including increased expression of p53 and production of proinflammatory cytokines in the WAT (Minamino, 2009). Concomitantly, whole body insulin resistance and glucose intolerance occur in mice; these impairments are ameliorated by inhibition of p53 in the WAT (Minamino, 2009).…”

“…Concomitantly, whole body insulin resistance and glucose intolerance occur in mice; these impairments are ameliorated by inhibition of p53 in the WAT (Minamino, 2009). In the present study, to understand the molecular mechanisms underlying the effect of CR on insulin and glucose homeostasis, we first tested whether or not Adipoq overexpression ameliorates the senescence-like phenotypes in the WAT in parallel with insulin sensitization.…”