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Title:
Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists | Nature
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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.
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nature portfolio permissions reprints privacy policy cardiovascular research retinoid research advertising social media subscribe nature insulin-dependent diabetes mellitus nature 355 nature 358 nature 383 nature 345 nature 371 nature 372 nature 336 nature 386 nature single-function complex serving springerlink instant access rxr-selective agonists replicate permissions metabolic disorders induced rxr heterodimer-selective agonists personal data high affinity ligand retinoic acid receptors 9-cis retinoic acid promotes adipocyte differentiation ppar gamma diabetes gene encodes data protection data suggest leptin receptor gene insulin resistance privacy unique response pathways cognate response elements explore content subscription content uclear receptor lxrα european economic area regulate transcription1–6 institutional subscriptions read mouse obese gene alternative oxygen acceptor health science center human nutritional relevance suggested nutritional guidelines saad naunyn-schmiedeberg'
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- We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors?
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