SENSITIZATION OF DIABETIC AND OBESE MICE TO INSULIN BY RETINOID-X-RECEPTOR AGONISTS

Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxis ome 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 transcription(1-6). We investi gated whether RXR-selective agonists replicate the activity of ligands for several of these receptors! We demonstrate here that RXR-selectiv e ligands (referred to as rexinoids) function as RXR heterodimer-selec tive agonists, activating RXR: PPAR gamma and RXR:LXR dimers but not R XR:RAR or RXR:TR heterodimers. Because PPAR gamma is a target for anti diabetic agents, we investigated whether RXR ligands could alter insul in and glucose signalling. In mouse models of noninsulin-dependent dia betes mellitus (NIDDM) and obesity, RXR agonists function as insulin s ensitizers and can decrease hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia, This antidiabetic activity can be further enhanced by combination treatment with PPAR gamma agonists, such as thiazolidin ediones. These data suggest that the RXR:PPAR gamma heterodimer is a s ingle-function complex serving as a molecular target for treatment of insulin resistance, Activation of the RXR:PPAR gamma dimer with rexino ids may provide a new and effective treatment for NIDDM.