Abstract

Objective The hypothalamic neuropeptide orexin influences (feeding) behaviour as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats.

Research Design and Methods We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two step hyperinsulinemic-euglycemic clamps, immunohistochemistry and RT-PCR studies.

Results Hypothalamic disinhibition of neuronal activity by GABA-receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons, but not melanocortin concentrating hormone-containing neurons, were activated. The increased BIC-induced EGP was largely prevented by i.c.v. pretreatment with the orexin-1 receptor antagonist. I.c.v. administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of i.c.v. orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at 2x or 6x basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes.

Conclusions Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis.