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.

We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPAR␥2 and hPPAR␥1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPAR␥ activators. Human PPAR␥ binds to DNA as a heterodimer with the retinoid X receptor (RXR). This heterodimer was activated by both RXR agonists and antagonists and the addition of PPAR␥ ligands with retinoids resulted in greater than additive activation. Such heterodimer-selective modulators may have a role in the treatment of PPAR␥/RXR-modulated diseases like diabetes. Northern blot analysis indicated the presence of PPAR␥ in skeletal muscle, and a sensitive RNase protection assay confirmed the presence of only PPAR␥1 in muscle that was not solely due to fat contamination. However, both PPAR␥1 and PPAR␥2 RNA were detected in fat, and the ratio of PPAR␥1 to PPAR␥2 RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPAR␥1 to PPAR␥2 raised the possibility that isoform expression may be modulated in disease states like non-insulin-dependent diabetes mellitus. Interestingly, a third protected band was detected with fat RNA indicating the possible existence of a third human PPAR␥ isoform.

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(a) skeletal muscle PPARgamma1 expression does not differ between normal and diabetic subjects, and is not induced by short-term hyperinsulinemia; (b) skeletal muscle PPARgamma1 expression was higher in subjects whose percent body fat exceeded 25%, and this may be a compensatory phenomenon in an attempt to maintain normal insulin sensitivity.

Abstract-Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are members of the intracellular receptor superfamily. PPARs bind to peroxisome proliferator-response elements (PPREs) as heterodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPAR␣ activators and are used in the treatment of hyperlipidemia. We show that the RXR ligand LGD1069 (Targretin ™ ), like gemfibrozil, can activate the PPAR␣/RXR signal-transduction pathway, including transactivation of the bifunctional enzyme or acyl-CoA oxidase response elements in a cotransfection assay. The activation also occurs in vivo, whereby in rats treated with LGD1069 or gemfibrozil, bifunctional enzyme and acyl-CoA oxidase RNA are induced and the combination of LGD1069 and gemfibrozil leads to a greater induction. Importantly, in hypertriglyceridemic db/db mice treated with RXR or PPAR␣ agonists, triglyceride levels are lowered, and the combination again has significantly greater efficacy. RXR agonists also raise HDL cholesterol levels without changing apoA-I RNA expression. This observation suggests the use of RXR-selective agonists, "rexinoids," either alone or in combination with a fibrate as a new therapeutic approach to treating patients with high triglyceride and low HDL cholesterol levels. 10 -12 In fibrate-treated animals, there is a rapid increase in the expression of genes that encode enzymes for the ␤-oxidation of fatty acids such as AOX and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (bifunctional enzyme).13 PPREs have been identified in the promoters of these genes, suggesting that activation of the peroxisomal fatty acid ␤-oxidation pathway contributes to the lipid lowering observed with fibrates.We have recently shown that the RXR/PPAR␥ heterodimer is activated by RXR agonists. 4 This finding emphasizes the permissive nature of the RXR/PPAR heterodimer, whereby either partner can bind ligand and activate gene expression. RXR agonists have similar effects as thiazolidinediones; they induce adipocyte differentiation, 14 lower elevated glucose and insulin levels, and improve insulin resistance in ob/ob and db/db mice. 15 We refer to these RXRselective ligands as "rexinoids" because their pharmacology is clearly distinct from "retinoids," which are retinoic acid receptor activators that mimic the action of retinoic acid. 16 We hypothesized that rexinoids would mimic the effects of fibrates via activation of the RXR side of the RXR/PPAR␣ heterodimer. Here we demonstrate for the first time that rexinoids elicit similar responses as PPAR␣ activators in vivo. In particular, expression of the bifunctional enzyme and AOX gene is induced in rat livers by gemfibrozil or an RXRselective agonist LGD1069 (Targretin ™ ) treatment. 17 The combination of LGD1069 and gemfibrozil gives a much stronger induction. Further, in db/db mice, RXR activators like LGD1069 17 and LG100268 18 lower triglyceride levels. HDL-C levels are also raised in rexinoid-treated...