β-Adrenergic control of stearoyl-CoA desaturase 1 repression in relation to sympathoadrenal regulation of thermogenesis

Abstract

Mice lacking b-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether b-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking b-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking b-adrenoceptors is not a direct effect of blunted b-adrenergic signalling, and that b-adrenergic control of SCD1 repression is unlikely to be a primary effector mechanism in sympathoadrenal regulation of thermogenesis. Whether approaches that target both SCD1 and molecular effectors of thermogenesis under b-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management. Keywords: thermogenesis; type 2 diabetes; sympathetic nervous system; catecholaminesThe sympathoadrenal system, through the release of norepinephrine from sympathetic nerves innervating peripheral tissues and through circulatory epinephrine released by adrenal medulla, plays an important role in the regulation of mammalian heat production. 1,2 Whereas in large mammals, the sites and molecular mechanisms underlying adrenergic control of heat production are poorly understood, studies in small rodents have implicated an elevation in sympathetic nervous system (SNS) activity in brown adipose tissue (BAT) -via b-adrenoceptor activation of its uncoupling protein (UCP1) -as a common mechanism for the stimulation of thermogenesis in response to both dietary and cold stimuli. 3,4 This contention is supported by the demonstrations that both SNS activity and UCP1 are elevated in BAT from rats and mice exhibiting adaptive increases in thermogenesis in response to cold or to overfeeding, and conversely they are both diminished in BAT from animals showing adaptive suppression of thermogenesis in response to fasting or severe food restriction. A major role for the SNS-BAT-UCP1 axis in thermoregulatory thermogenesis is further supported by the demonstration that mice lacking badrenoceptors (i.e. b-less mice) and mice deficient in UCP1 show impaired thermogenesis and poor tolerance to cold exposure. [5][6][7] However, the findings that only the b-less mice, but not the UCP1-deficient mice, are highly susceptible to develop obesity have also underscored the existence, even in small rodents, of mechanisms other than the SNS-BAT-UCP1 ...