PPAR-gamma: a thrifty transcription factor

Abstract

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a prototypical metabolic nuclear receptor that acts as a lipid sensor, integrating the homeostatic control of energy, lipid, and glucose metabolism. This perspective will highlight three lines of evidence which place PPAR-gamma as a key player in a feed-forward pathway favoring differentiation and energy storage by adipocytes.

Figure 1. Hypothesis summarizing the relationship between PPAR-γ activity, adipogenesis and glucose homeostasis.

This scheme is based on both genetic (Pro115Gln, Pro12Ala, Pro467 Leu) and pharmacological evidence (agonists, modulators or partial agonists, and antagonists). Only human mutations are shown for simplicity, but studies in mouse mutants support the human data. Higher PPAR-γ activity translates into insulin sensitization, but is associated with increased fat mass accretion. This underscores the importance of PPAR-γ modulation - or even antagonism - as the preferred strategy to combat the metabolic syndrome.

Figure 2. Physiological effects of PPAR-γ activation.

PPAR-γ induces adipocyte differentiation and genes involved in fat deposition. Plasma-derived fatty acids are directed to adipose tissue at the expense of skeletal muscle, which increases glucose uptake and utilization in the muscle. Direct effects of PPAR-γ activation have also been observed in liver, including decreased gluconeogenesis and increased fat uptake and storage. Additionally, PPAR-γ activation results in increased cholesterol efflux in macrophages via upregulation of ABCA1, but also increased uptake of proatherogenic oxidized LDL particles via upregulation of CD36.