Biphasic effects of orexin-A on autonomic nerve activity and lipolysis.
ABSTRACT Previously, we showed that orexin-A, a 33-aa peptide, influences renal sympathetic nerve activity. Because the autonomic nervous system plays an important role in the regulation of lipid metabolism, we investigated the in vivo effects of orexin-A on the sympathetic nerve activity innervating white adipose tissue (WAT-SNA) and lipolysis. We found that intracerebroventricular (icv) administration of orexin-A at doses of 1 microg/rat and 10 ng/rat elevated and suppressed WAT-SNA, respectively. The effect of the high dose of orexin-A (1 microg/rat) was eliminated by pretreatment with diphenhydramine hydrochloride, a histamine H(1) receptor antagonist. In contrast, the effect of the low dose of orexin-A (10 ng/rat) was suppressed by thioperamide maleate salt, a histamine H(3) receptor antagonist. Moreover, icv administration of 1 microg/rat and 10 ng/rat of orexin-A increased and decreased the levels of plasma free fatty acids (FFAs), respectively. The effect of 1 microg/rat of orexin-A on plasma FFA was eliminated by propranolol hydrochloride, a beta-adrenergic receptor blocker, and also by diphenhydramine. The effect of orexin-A at dose of 10 ng/rat disappeared by pretreatment with atropine sulfate, a muscarinic receptor blocker, and thioperamide maleate salt. Our results suggest that high doses of orexin-A may regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nervous system, which is driven by histamine neurons through the H(1) receptor, and that the beta(3)-receptor may be involved in this enhanced lipolytic response. Low doses of orexin-A, on the other hand, may lower lipolysis by suppressing sympathetic nerve activity via the H(3)-receptor, and the muscarinic receptor may be related to this response.
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ABSTRACT: The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the important role for hypothalamic leptin receptors as a striking example. The hypothalamic biological clock uses its projections to the preautonomic hypothalamic neurons to control the daily rhythms in plasma glucose concentration, glucose uptake, and insulin sensitivity. Euglycemic, hyperinsulinemic clamp experiments combined with either sympathetic-, parasympathetic-, or sham-denervations of the autonomic input to the liver have further delineated the hypothalamic pathways that mediate the control of the circadian timing system over glucose metabolism. In addition, these experiments clearly showed both that next to the biological clock peripheral hormones may "use" the preautonomic neurons in the hypothalamus to affect hepatic glucose metabolism, and that similar pathways may be involved in the control of lipid metabolism in liver and white adipose tissue.Annals of the New York Academy of Sciences 11/2010; 1212:114-29. · 3.15 Impact Factor