PPAR-γ: A Master Metabolic Nuclear Receptor

Abstract

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of metabolic nuclear receptors called PPARs, which regulate all facets of the fatty acid metabolism including transport, synthesis, storage, mobilization, activation and oxidation of fatty acids. Hence, this receptor could be a drug target for metabolic syndrome-related noncommunicable diseases (NCD) like obesity, diabetes, cardiovascular disease and cancers. The PPAR-γ gene has different size and transcriptional variants in different species. The major transcriptional variants (PPAR-γ1 and PPAR-γ2) encode proteins with 475/477 and 505 amino acids, respectively. Transcriptional regulation of PPAR-γ is mainly due to combinatorial activity of several transcription factors, chromatin remodelers and non-coding RNA at its promoters and enhancers during energy-surplus state. The miR-130a/b could be a major miRNA regulating PPAR-γ transcripts at post-transcriptional levels. Its protein has a large ligand-binding pocket to bind a wide range of endogenous and exogenous natural (e.g., dietary lipids) and synthetic ligands (TZDs). Along with its obligate partner RXR, and other co-activators, it exerts its action by DNA binding at DR1 and DR2 repeats and also by chromatin remodeling at the promoters and enhancers of its target genes. It has important physiological roles in adipocyte differentiation, inflammation, insulin sensitivity and reproduction. By enhancing the transcription of genes related to lipid uptake, triglyceride synthesis and glucose metabolism, PPAR-γ sequesters the plasma-free fatty acids into adipose tissue and, thereby, it plays a greater role of promoting systemic insulin sensitivity. Hence, it is a key target for anti-diabetic drugs like TZDs. Due to many side effects for classical PPAR-γ-targeting drugs like TZDs, selective PPAR-γ modulators are gaining a great lot of attention. Future studies need to be carried out to understand its transcriptional and post-transcriptional regulation in non-adipose tissues adopting advanced "omics" approaches. Such studies will be helpful in designing selective PPAR-γ modulators with limited side effects.