Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor isoforms with key roles in the regulation of lipid and glucose metabolism. Synthetic ligands for PPAR gamma (and PPAR alpha) have effects of promoting insulin sensitization in the context of obesity. Recent evidence suggests that activation of PPAR delta might produce similar effects. Both PPAR gamma and PPAR alpha have also been shown to produce selected anti-inflammatory effects and to reduce the progression of atherosclerosis in animals (alpha and gamma) or in humans (alpha). Mechanisms underlying insulin-sensitizing effects are complex. For PPAR gamma, direct effects on adipose tissue lipid metabolism with secondary benefits in liver and/or muscle (lipid levels and insulin signaling) have been implicated. For PPAR alpha, accelerated lipid catabolism may contribute to reduced muscle or liver 'steatosis'. Anti-inflammatory mechanisms as contributors to the beneficial metabolic effects of PPAR activation are also worth considering for the following reasons: (1) obesity and insulin resistance are associated with a proinflammatory milieu. (2) PPAR gamma has clear effects to oppose the effects of tumor necrosis factor-alpha (TNFalpha) in adipocytes. (3) effects of PPAR ligands on cytokine-mediated signaling (eg via NF-kappa B) may be expected to enhance insulin action. (4) Adipose production of several molecules that are implicated as markers or mediators of inflammation is reduced. (5) In humans, treatment with either PPAR alpha or PPAR gamma agonists has been shown to reduce circulating levels of proteins that serve as markers of inflammation. (6) Adiponectin, a fat-derived circulating factor that has been implicated as having anti-inflammatory activity, is induced by PPAR gamma agonism.