PPARG (peroxisome proliferator activated receptor gamma) forms an obligate, evolutionarily conserved heterodimer with RXRA (retinoid X receptor alpha). The heterodimer was initially named ARF6 and isolated from HIB-1B cell line, derived from a brown adipose tissue tumor of a transgenic mouse, as a transcription factor complex bound to an adipocyte-specific enhancer of the Fabp4 (aP2) gene, and involved in stimulation of Fabp4 gene transcription. In this study, it could not be determined whether the PPARG isoform bound to RXRA was PPARG1 (PPARgamma1) or PPARG2 (PPARgamma2), although PPARG2 was much more abundant in HIB-1B cells (Tontonoz et al. 1994).

The dimerization of PPARG and RXRA involves several heterodimer interfaces, of which the interface in the ligand binding domain (LBD) was studied in most detail (Chandra et al. 2008). Analysis of the crystal structure of a heterodimer composed of recombinant ligand binding domains (LBDs) of PPARG and RXRA, where RXRA LBD was bound to the ligand 9-cis-retinoic acid and PPARG LBD was bound to one of the synthetic agonists, either rosiglitazone or GI262570, in the presence of the coactivator NCOA1 (SRC1), showed that the heterodimer was asymmetric (Gampe et al. 2000).

Three splicing isoforms have been reported for both mouse and human RXRA, named RXRA1 (RXRalpha1), RXRA2 (RXRalpha2), and RXRA3 (RXRalpha3), where RXRA1 is the canonical and most thoroughly studied isoform. All three isoforms are able to form a complex with PPARG and activate transcription of reporter gene constructs in a ligand-dependent manner. However, due to differential expression in different tissues, it is uncertain whether complexes of PPARG and RXRA2 or RXRA3 are physiologically relevant. Neither RXRA2 nor RXRA3 were detected in adipocytes (Kojo et al. 2004). Therefore, only the canonical RXRA (corresponding to RXRA1) is shown in this pathway.

Based on mouse studies, PHLDA1 (TDAG51) inhibits formation of heterodimers of PPARG and RXRA by competing with RXRA for binding to PPARG. Consequently, PHLDA1 inhibits transcription of PPARG target genes such as aP2 (FABP4) (Kim et al. 2021). Mouse Phlda1 is only expressed at early stages of adipogenic lineage, and its levels rapidly decrease at the onset of adipogenic differentiation (Burton et al. 2004). Phlda1 knockout mice develop mature-onset obesity, hepatic steatosis, and insulin resistance (Basseri et al. 2013). Phlda1 knockdown increases the level of nuclear Pparg and Pparg activity, and alleviates neuronal apoptosis induced by mitochondrial dysfunction and endoplasmic reticulum stress (Liu et al. 2023).