Activation of corticotropin-releasing factor receptors in the rostral ventrolateral medulla is required for glucose-induced sympathoexcitation

Abstract

Energy expenditure is determined by metabolic rate and diet-induced thermogenesis. Normally, energy expenditure increases due to neural mechanisms that sense plasma levels of ingested nutrients/hormones and reflexively increase sympathetic nerve activity (SNA). Here, we investigated neural mechanisms of glucose-driven sympathetic activation by determining contributions of neuronal activity in the hypothalamic paraventricular nucleus (PVN) and activation of corticotropin-releasing factor (CRF) receptors in the rostral ventrolateral medulla (RVLM). Glucose was infused intravenously (150 mg/kg, 10 min) in male rats to raise plasma glucose concentration to a physiological postprandial level. In conscious rats, glucose infusion activated CRF-containing PVN neurons and TH-containing RVLM neurons, as indexed by c-Fos immunofluorescence. In ␣-chloralose/urethane-anesthetized rats, glucose infusion increased lumbar and splanchnic SNA, which was nearly prevented by prior RVLM injection of the CRF receptor antagonist astressin (10 pmol/50 nl). This cannot be attributed to a nonspecific effect, as sciatic afferent stimulation increased SNA and ABP equivalently in astressin-and aCSF-injected rats. Glucose-stimulated sympathoexcitation was largely reversed during inhibition of PVN neuronal activity with the GABA-A receptor agonist muscimol (100 pmol/50 nl). The effects of astressin to prevent glucose-stimulated sympathetic activation appear to be specific to interruption of PVN drive to RVLM because RVLM injection of astressin prior to glucose infusion effectively prevented SNA from rising and prevented any fall of SNA in response to acute PVN inhibition with muscimol. These findings suggest that activation of SNA, and thus energy expenditure, by glucose is initiated by activation of CRF receptors in RVLM by descending inputs from PVN. corticotropin releasing factor; sympathetic nerve activity; rostral ventrolateral medulla DECREASING THE RISK of obesity-related metabolic (e.g., type 2 diabetes) and cardiovascular diseases (hypertension, atherosclerosis, and stroke) is often achieved by weight loss. Normal body weight is maintained by a balance between food intake and energy expenditure, and even small perturbations in this balance can produce large changes in body composition over time. Therefore, it is imperative to understand the neural circuits and synaptic mechanisms that control energy expenditure. Daily energy expenditure is determined by three major components: resting metabolic rate, exercise-induced increases in metabolic rate, and diet-induced thermogenesis (37). Among sedentary individuals, resting metabolic rate is the major determinant of daily energy expenditure and is maintained by a combination of sympathetic nerve activity (SNA), cortisol levels, and thyroid hormones (41, 42). Many features of the neural circuitry that drive energy expenditure, especially through activation of SNA, remain incompletely understood. Food intake stimulates energy expenditure through neural mechanisms that sense the elevation of ...

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Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors

“…Stress-induced increases in SNA are also thought to involve CRF-containing neurons in the PVN that innervate and activate neurons in the RVLM to increase SNA. Furthermore, direct injections of CRF into the RVLM results in increases in lumbar SNA [86] and BP [87]. Together, the peripheral increase in catecholamine release from the adrenal gland and the increase in SNA result in an increase in BP and hypertension.…”

“…Stress activates the hypothalamic-pituitaryadrenal (HPA) axis, and corticotrophin-releasing factor (CRF)-containing neurons in the PVN stimulate adrenocorticotrophic hormone (ACTH) release from the anterior pituitary and an increase in glucocorticoid and catecholamine release from the adrenal gland [85,86]. Stress-induced increases in SNA are also thought to involve CRF-containing neurons in the PVN that innervate and activate neurons in the RVLM to increase SNA.…”

Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress

“…In other experiments, the effect of MIF transduction on the expression of mRNA for several stress-related neurotransmitters within the PVN was determined. Specifically, corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) expression was measured since these are key mediators of HPA axis activation and can also contribute to central mechanisms of sympathoexcitation (2,33,55). Dopamine-␤-hydroxylase (D␤H) expression was measured as a marker of catecholaminergic activity, as catecholaminergic neurotransmission within the PVN contributes to the HPA axis response to acute stress (21) and influences blood pressure regulation (64).…”