Isoforms

            1.  there are two different isoforms of PPARg (generated by alternate promoter sites)

                        a)  mouse have two PPARg isoforms (Zhu, Qi et al. 1995)

                        b)  human has two PPARg isoforms (Fajas, Auboeuf et al. 1997)

            ** actually three

                        a)  all

                                    1)  share the six 3’ coding region, but differ in their 5’ region

                        b)  PPARg1 – predominant – eight exons, including two g1 specific exons in the 5’UTR, A1 and A2, and the other six coding regions common to all of them.

                                    1)  1.9kb (Kliewer, Forman et al. 1994)

                        c)  PPARg2 - ~15% - seven exons, exon B (the 5’UTR) (found between the second g1 specific exon and the first common exon (Gearing, Crickmore et al. 1994)-19,24,25)

                                    1)  the AF1 domain of this subtype is about 5-10 fold more active than the one in PPARg1 ­(Werman, Hollenberg et al. 1997)

                                    2)  2.1kb (Kliewer, Forman et al. 1994)

                                    3)  adipocyte specific

                                    4)  extra 30 aa residues in the amino terminus contribute to a 5-10 fold greater constitutive transcription activation function than that of PPARg1 (Werman, Hollenberg et al. 1997)

                        d)  PPARg3 – same protein as PPARg1, but has an alternative promoter located in the region flanking exon A2 in 5’ (Gearing, Crickmore et al. 1994)-26

            2.  expression of subtypes

                        a)  PPARg1 is expressed in hepatocytes and macrophages (Zhu, Alvares et al. 1993; Greene, Blumberg et al. 1995)

                        b)  PPARg2 is unique to adipocytes

                                    1)  in the virgin mammary gland, PPARg2 mRNA is 10X that of PPARg1 (Gimble, Pighetti et al. 1998)

            3.  functional differences between the isoforms

                        a)  ligand binding

                                    1)  similar binding to rosiglitazone and 15dPGJ2 in GST-PPAR expression construct tests (Mueller, Drori et al. 2002)

                        b)  adipogenesis

                                    1)  PPARg2 is better able to induce adipogenesis under stringent conditions (Mueller, Drori et al. 2002)

                        c)  coactivator interaction

                                    1)  PPARg2 is better at interacting with PGC1a, TRAP220, and TRAP170 in vitro (Mueller, Drori et al. 2002)