Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists

Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription1–6. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARγ and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARγ is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of non-insulin-dependent diabetes mellitus (NIDDM) and obesity, RXR agonists function as insulin sensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. This antidiabetic activity can be further enhanced by combination treatment with PPARγ agonists, such as thiazolidinediones. These data suggest that the RXR:PPARγ heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARγ dimer with rexinoids may provide a new and effective treatment for NIDDM.