PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions.

Keywords: PPAR; adipose tissue; aging; caloric restriction; metabolism; obesity; pregnancy.

Figure 1

Overview of the effects of peroxisome proliferator-activated receptors (PPARs) activation in obesity, pregnancy, and aging. In obesity, PPARs activation decreases fibro-inflammation and ectopic fat accumulation in the adipose tissue (AT). In pregnancy, PPARs activation stimulates glucose uptake and fatty acid oxidation in the mother, while the placenta decreases insulin uptake to ameliorate abnormal fetal growth. In aging, this PPARs activation increases the glucose uptake and lipid metabolism in the subcutaneous white AT (scWAT). Moreover, both PPARs activation and caloric restriction (CR, dotted arrow) in aging promote browning in the AT, which improves the whole-body metabolism. The final effect of PPARs activation in all situations is the improvement of insulin resistance (IR). PPARs activation; . effects or PPARs activation; CR effect; inhibition; increase or decrease effect.