Moreover, due to the promiscuous nature of RXR heterodimer activation, PPAR signaling pathways may be initiated through the use of RXR agonists. Thus, RXR agonists could benefit any disease in which PPAR activation has proven effective. This promiscuity also creates unique challenges and opportunities. Since these signaling cascades may be differentially activated based on the binding specificity and affinity of various ligands to the receptor, RXR activation may not mimic the spectrum of changes that occur when PPAR-specific agonists are used to activate the heterodimer complex. Currently, it is not known which heterodimeric partner RXR exerts its beneficial effects through. Thus, a level of precision concerning RXR signaling is missing. Given the similarity of actions between PPAR and RXR activation, RXR activation may be exerting its effects by concurrently activating multiple PPAR pathways. Also, studies have shown that PPAR and RXR agonists, when used together to simultaneously activate the heterodimer complex, have synergistic effects allowing for maximal stimulation and expanding possible treatment paradigms (Papi et al., 2009; Yamanaka et al., 2012).
