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Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists
R Mukherjee1, P J Davies, D L Crombie
1Department of Cardiovascular Research, Ligand Pharmaceuticals, San Diego, California 92121, USA.
Abstract:
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 transcription. 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: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling. In mouse models of noninsulin-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 PPARgamma agonists, such as thiazolidinediones. These data suggest that the RXR:PPARgamma heterodimer is a single-function complex serving as a molecular target for treatment of insulin resistance. Activation of the RXR:PPARgamma dimer with rexinoids may provide a new and effective treatment for NIDDM.
Insights
RXR-selective agonists, or rexinoids, activate specific receptor dimers, showing promise for treating type 2 diabetes by improving insulin sensitivity and reducing hyperglycemia.
Area of Science:
- Molecular Endocrinology
- Nuclear Receptor Signaling
- Metabolic Disease Research
Background:
- Nuclear receptors like Retinoic Acid Receptor (RAR), Thyroid Hormone Receptor (TR), Peroxisome Proliferator-Activated Receptors (PPARs), and Liver X Receptor (LXR) regulate transcription via heterodimers with Retinoid X Receptor (RXR).
- RXR forms crucial heterodimers with various nuclear receptors, influencing diverse cellular processes.
Purpose of the Study:
- To investigate if RXR-selective agonists (rexinoids) can mimic the activity of ligands targeting RAR, TR, PPARs, and LXR.
- To determine the therapeutic potential of rexinoids in treating metabolic disorders, specifically non-insulin-dependent diabetes mellitus (NIDDM).
Main Methods:
- Utilized RXR-selective ligands (rexinoids) to activate specific RXR heterodimers.
- Tested rexinoid activity on RXR:PPARgamma and RXR:LXR dimers, as well as RXR:RAR and RXR:TR dimers.
- Evaluated the effects of RXR agonists on insulin and glucose signaling in mouse models of NIDDM and obesity.
Main Results:
- Rexinoids selectively activated RXR:PPARgamma and RXR:LXR heterodimers, but not RXR:RAR or RXR:TR dimers.
- In mouse models, RXR agonists demonstrated insulin-sensitizing effects, reducing hyperglycemia, hypertriglyceridemia, and hyperinsulinemia.
- Combination therapy with PPARgamma agonists enhanced the antidiabetic activity of RXR agonists.
Conclusions:
- The RXR:PPARgamma heterodimer acts as a single-function complex and a viable molecular target for treating insulin resistance.
- Activation of the RXR:PPARgamma dimer using rexinoids offers a potential new therapeutic strategy for managing NIDDM.