The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders

Abstract

Adipose tissue as the largest energy reservoir and endocrine organ is essential for maintenance of systemic glucose, lipid and energy homeostasis, but these metabolic functions decline with ageing and obesity. Adipose tissue senescence is one of the common features in obesity and ageing. Although cellular senescence is a defensive mechanism preventing tumorigenesis, its occurrence in adipose tissue causatively induces defective adipogenesis, inflammation, aberrant adipocytokines production and insulin resistance, leading to adipose tissue dysfunction. In addition to these paracrine effects, adipose tissue senescence also triggers systemic inflammation and senescence as well as insulin resistance in the distal metabolic organs, resulting in Type 2 diabetes and other premature physiological declines. Multiple cell types including mature adipocytes, immune cells, endothelial cells and progenitor cells gradually senesce at different levels in different fat depots with ageing and obesity, highlighting the heterogeneity and complexity of adipose tissue senescence. In this review, we discuss the causes and consequences of adipose tissue senescence, and the major cell types responsible for adipose tissue senescence in ageing and obesity. In addition, we summarize the pharmacological approaches and lifestyle intervention targeting adipose tissue senescence for the treatment of obesity- and ageing-related metabolic diseases.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…Obesity is a major predictor contributing to type 2 diabetes (T2D), CKD, CVD, and increased mortality [135,136]. Besides being risk factors for CKD, obesity and T2D also contribute to cellular senescence per se [137,138]. Furthermore, the adverse effects of an increased fat mass are at least partly related to the secretion of proteins from adipocytes into the circulation, that is, adipocytokines.…”

Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes

“…Emerging evidence from human and animal studies suggests that the INK4a/ARF locus controls the balance between adipocyte differentiation and senescence [ 49 , 50 , 51 , 52 , 53 ] ( Figure 2 ). Like aging, obesity can be seen as an accelerated form of AT senescence [ 63 ]. In both cases, cell senescence characterized by elevated p16INK4a/p53 expression appears to be a key mechanism for reduced regenerative potential of adipose progenitor cells and impaired adipocyte replacement.…”

“…In both cases, cell senescence characterized by elevated p16INK4a/p53 expression appears to be a key mechanism for reduced regenerative potential of adipose progenitor cells and impaired adipocyte replacement. However, unlike aging, MDM2 expression is paradoxically increased in obese AT, indicating that the pathways leading to p53 activation in aged and obese AT may be distinct [ 63 ]. In addition to defective adipogenesis, in both obesity and aging, the immune profile dramatically alters to inflammatory status and associates with number of senescent cells, aberrant adipocytokines production, leading to local (AT) and systemic insulin resistance and T2D [ 49 , 50 , 51 , 52 , 53 , 64 ].…”

“…Although metabolic insults (such as high glucose and saturated fatty acid) directly up-regulate p16INK4a/p53 expression, yet the underlying mechanisms are still unclear. In addition, it remains elusive whether the cell cycle changes are causative or resultant of AT dysfunction [ 63 ]. In short, the defective adipogenesis is mainly due to poor-differentiating ability of senescent progenitor cells and senescent microenvironment within AT in obesity and aging.…”

Clinical Science Editorial 2020 – a year gone by and the year ahead

“…I would like to personally thank our authors for choosing to publish their highest quality research in Clinical Science, contributing to the journal's success in delivering comprehensive studies using a multidisciplinary approach to unravel molecular mechanisms of human disease. I invite you to read a selection of the best papers published over the past 2 years [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23], indicating the broad spectrum of biomedical specialities featured in the Journal.…”