Other natural ligands of PPARG were reported to be 9S-HODE - (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (Nagy et al 1998: an order of a magnitude lower affinity for mouse PPARG than 15d-PGJ2; Itoh et al. 2008: crystal structure of the ligand-binding domain – LBD – of human PPARG associated with 9S-HODE suggest that two molecules of 9S-HODE might bind to the LBD of PPARG; Umeno et al. 2020: contradicts other studies implying that 9S-HODE acts as an antagonist of PPARG) and 13S-HODE - (9Z,11E,13S)-13-hydroxyoctadeca-9,11-dienoic acid (Nagy et al. 1998: an order of magnitude lower affinity for mouse PPARG than 15d-PGJ2 and lower affinity than 9S-HODE; Zuo et al. 2006: 13S-HODE, produced from linoleic acid by human 15-lipoxygenase-1, binds to and activates transcriptional activity of human PPARG; Itoh et al. 2008: crystal structure of the LBD of human PPARG associated with 13S-HODE suggests that 13S-HODE is a weaker ligand than 9S-HODE; Umeno et al. 2020: 13S-HODE activates Pparg in mouse adipocyte line 3T3-L1). A study using mouse Pparg1 and Pparg2 showed that 15d-PGJ2 binds to both Pparg isoforms with equal affinity (Mueller et al. 2002).

Other possible natural ligands of PPARG include abietic acid (Takahashi et al. 2003), 4-hydroxydocosahexaenoic acid (4-HDHA) (Itoh et al. 2008), 5-hydroxyeicosapentaenoic acid (5-HEPA) (Itoh et al. 2008), docosahexaenoic acid (DHA) (Itoh et al. 2008), 4-oxodocosahexaenoic acid (4-oxoDHA) (Itoh et al. 2008), and 6-oxooctadecatrienoic acid (6-oxoOTE) (Itoh et al. 2008). Oxo fatty acids, 4-oxoDHA and 6-oxoOTE, form a covalent bond with the LBD of human PPARG and are more potent in activating PPARG (Itoh et al. 2008).

It is uncertain whether any of these natural ligands serve as physiological ligands. A study of mouse pre-adipocyte cell line 3T3-L1 suggested that an endogenous, physiological ligand, likely different from 15d-PGJ2, appeared early in adipogenesis in response to increase in cAMP, accumulated in the medium, and dissipated in later stages of adipogenesis (Tzameli et al. 2004). The synthesis of endogenous ligand, which is maximal in the first four days of adipogenic differentiation of 3T3-L1 cells, is dependent on the activity of lipoxygenases (Madsen et al. 2003).

In an early study, it was shown that ligands of PPARG do not access PPARG through passive diffusion but are delivered by scavenger receptors such as CD36 (Nagy et al. 1998). A detailed study of ligand delivery to PPARs showed that FABP4 delivers both the natural ligand 15d-PGJ2 and synthetic ligands to PPARG through channeling, which involved direct contact between PPARG and FABP4 (Tan et al. 2002: mouse Fabp4 and Pparg were used). Binding of certain ligands triggers nuclear translocation of FABP4, enabling it to interact with PPARG (Gillilan et al. 2007: mouse Fabp4 was used).

While ligands bind to the LBD located in the C-terminus of PPARG, ligand binding is regulated by intramolecular communication between the amino-terminal A/B domain of PPARG with its LBD; MAPK-mediated phosphorylation of S112 in the A/B domain of PPARG negatively regulates ligand binding (Shao et al. 1998).

It is important to note that plasticizers, such as phtalates, which are used to increase the flexibility of polyvinyl chloride (PVC) products, once inside the body, produce metabolites that were reported to act as PPARG agonists, which can have adverse effect on human and animal health (Useini et al. 2023).