PPARg, a Versatile Metabolic Regulator
Laurent Gelman, and Johan Auwerx.
Institut Pasteur, 59019 Lille, France.
The peroxisome proliferator activated receptors (PPAR), a, b, and g, with each a specific tissue distribution, compose a subfamily of the nuclear hormone receptor gene family. Activated PPARs heterodimerize with RXR and alter the transcription of target genes after binding to specific response elements or PPREs, consisting of a direct repeat spaced by 1 nucleotide. PPARg is highly expressed in adipose tissue and triggers adipocyte differentiation in vitro by inducing the expression of several genes critical for lipid storage and adipogenesis. The important role of PPARg in adipogenesis is supported by the recent identification of two mutations in the human PPARg gene. In fact, a common Pro12Ala mutation in the PPARg2-specific B exon, that renders PPARg less active, is associated with a decrease in BMI, whereas a constitutively active PPARg, secondary to a rare Pro115Gln mutation, is associated with obesity. Prostaglandin J2 derivatives and thiazolidinedione antidiabetic agents are ligands of PPARg. It is currently tought that the effects of activation of the PPARg/RXR heterodimer on glucose homeostasis are due to the effect of these nuclear receptors on the production of adipocyte-derived signalling molecules, which affect muscle glucose metabolism.
Potential signalling molecules derived from adipocytes, and modified by PPARg/RXR activation include TNFa and leptin, which both interfere with glucose homeostasis. In addition to its effects on the these proteins, PPARg/RXR also profoundly affects fatty acid metabolism. Activation of PPARg will selectively induce the expression of several genes involved in fatty acid uptake, such as lipoprotein lipase, fatty acid transport protein and acyl-CoA synthetase, in adipose tissue without changing their expression in muscle tissue. This coordinate regulation of fatty acid partitioning by PPARg results in an adipocyte "FFA steal", causing a relative depletion of fatty acids in the muscle. Based on the well established interference of muscle fatty acid and glucose metabolism it is hypothesized that reversal of muscle fatty acid accumulation will contribute to the improvement in whole body glucose homeostasis. In addition to adipose tissue, PPARg is highly expressed in colon epithelium and in macrophages. PPARg activation in C57BL/6J-APCMin /+ mice, a well established animal model for colorectal cancer, results in increased tumor multiplicity and size, suggesting a potential role of this receptor in the development of colon cancer. Moreover, recently we demonstrated the presence of PPARg in human monocytes. PPARg expression is strongly induced during differentiation of monocytes to macrophages as well as by exposure of macrophages to oxidized-LDL, suggesting that PPARg also in the macrophage could control lipid accumulation and be involved in foam cell formation. PPARg is hence a key control molecule with effects on adipocyte, macrophage, and colon (patho)physiology.