Role of G protein-coupled receptor kinase 2 (GRK2) in insulin resistance and obesity

Abstract

Resumen del trabajo presentado al XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Barcelona del 5 al 8 de septiembre de 2011.Prevalence of obesity has reached epidemic scope in industrialized countries and it currently stands as a risk factor for the development of common metabolic disorders as insulin resistance and T2D. Nowadays, GRK2 has been recognized as an integrative node regulating a variety of transduction pathways including the insulin signaling cascade. We have recently reported that GRK2 plays a relevant physiological role in the modulation of insulin responses in vivo. In cultured adipocytes and myocytes, increased GRK2 levels inhibit insulin-stimulated glucose uptake and signaling by a mechanism involving the formation of dynamic GRK2/IRS1 complexes. This work also uncovers a role for GRK2 in the regulation of adiposity since GRK2+/- mice were resistant to diet and age-induced obesity (Garcia-Guerra et al., 2010). We further evaluated the potential contribution of brown fat to the leaner phenotype of GRK2+/- mice. Our results indicate that GRK2 modulate white and brown fat lipid metabolism. GRK2+/- adult mice exhibited increased energy expenditure and a lower RER, consistently with a less deteriorated BAT morphology. Indeed, decreased GRK2 protein levels were associated with higher core body temperature and a better thermogenic capacity. In addition, we detect a negative effect of GRK2 in the metabolism and differentiation of cultured brown adipocytic cells, further supporting the hypothesis that the lean phenotype of GRK2 +/- mice clearly involves a role for this kinase in BAT function. In summary, our data identify GRK2 as an important negative regulator of insulin effects and point at GRK2 inhibition as a potential tool for the enhancement of brown fat activity, which may have important therapeutic implications for the treatment of obesity and associated metabolic disorders.Peer Reviewe