Retinoids and Retinoid Receptors in the Control of Energy Balance: Novel Pharmacological Strategies in Obesity and Diabetes

F.      Villarroya; R.      Iglesias; M.      Giralt

Abstract

Obesity and type II diabetes are closely related metabolic diseases with an increasing incidence worldwide. No clear-cut pharmacological treatment for these complex metabolic disturbances is available despite current efforts. New directions and perspectives for the pharmacological or nutritional treatment of these diseases should be defined. In recent years, a growing body of evidence shows that retinoids and retinoic acid receptors are involved in the control of biological aspects (e.g. adiposity and energy expenditure mechanisms), which offers great potential for research on the treatment of obesity and type II diabetes. All-trans retinoic acid is known to inhibit adipocyte differentiation, whereas, molecules activating the retinoid Xreceptor (rexinoids) promote the differentiation of adipocytes. Treatment with rexinoids ameliorates glycemic control in rodent models of type II diabetes and obesity, although other findings indicate similar positive effects by inhibiting the receptor. Moreover, natural products of dietary origin, such as phytanic acid can activate RXR and thus, trigger adipose cell differentiation. Finally, the activation of retinoic acid receptors or retinoid X receptors has been reported to induce the gene expression of uncoupling proteins, which are mitochondrial proteins involved in the regulation of energy expenditure and fatty acid metabolism. Further research is required to exploit the capacities of the retinoid-dependent pathways of regulation of adiposity, insulin sensitivity and energy expenditure for drug development in metabolic disturbances.

Keywords: retinoic acid, retinoic acid receptor, rexinoid, adipose tissue, uncoupling protein, obesity, diabetes

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