Upregulation of orexin receptor in paraventricular nucleus promotes sympathetic outflow in obese Zucker rats

Sympathetic vasomotor tone is elevated in obesity-related hypertension. Orexin importantly regulates energy metabolism and autonomic function. We hypothesized that alteration of orexin receptor in the paraventricular nucleus (PVN) of the hypothalamus leads to elevated sympathetic vasomotor tone in obesity. We used in vivo measurement of sympathetic vasomotor tone and microinjection into brain nucleus, whole-cell patch clamp recording in brain slices, and immunocytochemical staining in obese Zucker rats (OZRs) and lean Zucker rats (LZRs). Microinjection of orexin 1 receptor (OX1R) antagonist SB334867 into the PVN reduced basal arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in anesthetized OZRs but not in LZRs. Microinjection of orexin A into the PVN produced greater increases in ABP and RSNA in OZRs than in LZRs. Western blot analysis revealed that OX1R expression levels in the PVN were significantly increased in OZRs compared with LZRs. OX1R immunoreactivity was positive in retrogradely labeled PVN-spinal neurons. The basal firing rate of labeled PVN-spinal neurons was higher in OZRs than in LZRs. SB334867 decreased the basal firing activity of PVN-spinal neurons in OZRs but had no effect in LZRs. Orexin A induced a greater increase in the firing rate of PVN-spinal neurons in OZRs than in LZRs. In addition, orexin A induced larger currents in PVN-spinal neurons in OZRs than in LZRs. These data suggest that upregulation of OX1R in the PVN promotes hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in obesity. [Display omitted] •Orexin 1 receptor (OX1R) is upregulated in the hypothalamus in obesity.•Hypothalamic OX1R contributes to elevated sympathetic vasomotor tone in obesity.•Blocking OX1R reduces sympathetic vasomotor tone in obese Zucker rats.•OX1R is a potential target to treat obesity-related hypertension.