Therapeutic Potential of Retinoid X Receptor Modulators for the Treatment of the Metabolic Syndrome

Abstract

The increasing prevalence of obesity is a fundamental contributor to the growing prevalence of the metabolic syndrome. Rexinoids, a class of compounds that selectively bind and activate RXR, are being studied as a potential option for the treatment of metabolic syndrome. These compounds have glucose-lowering, insulin-sensitizing, and antiobesity effects in animal models of insulin resistance and type 2 diabetes. However, undesirable side effects such as hypertriglyceridemia and suppression of the thyroid hormone axis also occur. This review examines and compares the effects of four RXR-selective ligands: LGD1069, LG100268, AGN194204, and LG101506, a selective RXR modulator. Similar to selective modulators of other nuclear receptors such as the estrogen receptor (SERMs), LG101506 binding to RXR selectively maintains the desirable characteristic effects of rexinoids while minimizing the undesirable effects. These recent findings suggest that, with continued research efforts, RXR-specific ligands with improved pharmacological profiles may eventually be available as additional treatment options for the current epidemic of obesity, insulin resistance, type 2 diabetes, and all of the associated metabolic sequelae.

Retinoid receptor-specific agonists regulate bovine in vitro early embryonic development, differentiation and expression of genes related to cell cycle arrest and apoptosis

“…However, because its highly specific binding to RXR, LG100268 has been reported to execute an apoptotic program in rats without undesirable toxicity [43]. On the other hand, RXR agonists binding may lead to heterodimerization with peroxisome proliferator-activated receptors (PPARs), affecting glucose and insulin metabolism [44]. These are effects that could limit the interpretation of our results.…”

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

“…However, effects of rexinoids on TG in rodents are highly dependent on the strain of mice used (48). In A/J mice, we surprisingly observed a significant decrease in plasma TG levels between the untreated control group and the mice fed with rexinoids (P < 0.05, Table 2C).…”

ENDOCRINE SIDE-EFFECTS OF ANTI-CANCER DRUGS: The impact of retinoids on the thyroid axis

“…Rexinoids have many other effects. Among these, they exert beneficial glucose-lowering and insulin-sensitizing effects as well as antiobesity actions in animal models of insulinresistance and diabetes, and bexarotene improves cholesterol homeostasis and inhibits the development of atherosclerosis in a mouse model of mixed dyslipidemia (17,18). They also increase both hepatic liver oxidative metabolism through the increase in cytochrome P450, particularly the isoenzymes CYP4A, CYP2B1/2, and CYP3A levels, and the glycuronyltransferase activity (19).…”