The PPARs were first identified as an activity that mediated the dramatic proliferation of rat hepatic peroxisomes in response to fibrates, industrial plasticizers, and herbicides.379 Two physiologically interesting results arise from treatment with these xenobiotic compounds in rodents. The peroxisomal response results in reduction of serum triglyceride levels by virtue of 3 and a oxidation of long chain fatty acids within the peroxisomal and mitochondrial compartments, and prolonged treatment of rodents with these compounds directly correlated with hepa-tocarcinogenicity.380-383 Subsequent cloning efforts produced three PPAR cDNAs, designated a, 3/8 (NUC-1, FAAR), and y, which exhibit similar DNA-binding specificities but distinct expression patterns and ligand-binding profiles.158,384,385 Activity of PPARa promotes fatty acid catabolism by activating expression of genes required for fatty acid uptake and long chain fatty acid 3 and a oxidation, presumably in response to dietary, circulating, or intracellular concentrations of fatty acids. Although potent synthetic ligands for PPARa activation have been produced, the identity of endogenous lig-ands remains obscure: PPARa can be activated by a number of diverse long chain polyunsatu-rated fatty acids, such as linoleate, arachidonate, and the prostaglandin metabolite leukotriene B4, at high concentrations.386,387 Targeted disruption of this receptor in the mouse suggests that its function is not essential for survival as null homozygotes are phenotypically normal. However, these animals are insensitive to the actions of peroxisome proliferators and, when challenged with fasting or high-fat diets, experience perturbations in lipid and glucose homeosta-sis.388,389 These observations suggest that PPARa not only functions as a xenobiotic receptor but also may play a significant role in lipid home-ostasis in response to unknown physiological lig-ands.
While PPARa contributes to systemic fatty acid disposal through oxidation, PPARy regulates and promotes lipid storage by its activities in adipocytes and macrophages. The y isoform was initially thought to be an adipose-specific NR, whose activation by the prostaglandin metabolite 15-deoxy-A12,14-prostaglandin J2 (or synthetic thiazolidinedione) resulted in differentiation of multiple cell types to an adipocyte phenotype.390-395 The adipogenic process minimally requires insulin and glucocorticoid signaling, as well as the activities of multiple basic helix-loop-helix-leucine zipper transcription factors of the CAAT/enhancer binding protein and sterol regulatory element binding protein class.396 In addition to its established role in adi-pogenesis, however, PPARy performs unique roles in macrophage function, intestinal mucosal proliferation/differentiation, and placentogene-sis.239,397-399 Activation of PPARy in these tissues may not induce the same program of target genes observed in adipocyte differentiation, suggesting the existence of cell-specific, differential gene targets. One possible explanation for this cell specificity is the identification of tissue specific coactivators as candidates for this activity have been identified.87 Analysis of PPARy function by gene knockout in mice reveals part of the essential function of PPARy: disruption of both PPARy alleles results in embryonic lethality at E10 due to lack of placentogen-esis and mycardial thinning, similar to RXRa-deficient embryos.399 Furthermore, rescue of this early lethality by tetraploid rescue reveals the requirement of PPARy for adipogenesis since these animals fail to form fat pads. While these studies demonstrate the requirement for PPARy in adipogenesis (i.e., absence of fat pads), it remains unclear what other systems or tissues are affected by loss of PPARy function.
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS AND OBESITY: INSULIN SIGNALING
The observations that the thiazolidinedione class of Type 2 diabetic non-insulin-dependent diabetes mellitus insulin sensitizers act as direct PPARy ligands implicates PPARy as a NR involved in glucose as well as lipid homeostasis.400 Although adipose tissue and obesity contribute to insulin resistance, the molecular details concerning this relationship remain unclear.401 Several possibilities for the involvement of PPARy activity in insulin and glucose resistance have been suggested, such as regulation of adipocyte size, glucose transporters, and circulating leptin and free fatty acid levels.402-405 Since PPARy activity may directly or indirectly contribute to regulation of several of these parameters, it is likely that this receptor will continue to be targeted in the pharmacological intervention of Type 2 diabetes and obesity.406 Additionally, several studies have implicated PPARy as a regulator of macrophage foam cell generation, a process directly correlated to the incidence of atherosclerosis, linking PPARy activity to yet another disease state associated with lipid dysregulation.
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