Subfornical organ insulin receptors tonically modulate cardiovascular and metabolic function

Abstract

Insulin acts within the central nervous system through the insulin receptor to influence both metabolic and cardiovascular physiology. While a major focus has been placed on hypothalamic regions, participation of extrahypothalamic insulin receptors in cardiometabolic regulation remains largely unknown. We hypothesized that insulin receptors in the subfornical organ (SFO), a forebrain circumventricular region devoid of a blood-brain barrier, are involved in metabolic and cardiovascular regulation. Immunohistochemistry in mice revealed widespread insulin receptor-positive cells throughout the rostral to caudal extent of the SFO. SFO-targeted adenoviral delivery of Cre-recombinase in insulin receptorlox/lox mice resulted in sufficient ablation of insulin receptors in the SFO. Interestingly, when mice were maintained on a normal chow diet, deletion of SFO insulin receptors resulted in greater weight gain and adiposity, relative to controls, independently of changes in food intake. In line with this, ablation of insulin receptors in the SFO was associated with marked hepatic steatosis and hypertriglyceridemia. Selective removal of SFO insulin receptors also resulted in a lower mean arterial blood pressure, which was primarily due to a reduction in diastolic blood pressure, whereas systolic blood pressure remained unchanged. Cre-mediated targeting of SFO insulin receptors did not influence heart rate. These data demonstrate multidirectional roles for insulin receptor signaling in the SFO, with ablation of SFO insulin receptors resulting in an overall deleterious metabolic state while at the same time maintaining blood pressure at low levels. These novel findings further suggest that alterations in insulin receptor signaling in the SFO could contribute to metabolic syndrome phenotypes.