Central Lipoprivation-Induced Suppression of Luteinizing Hormone Pulses Is Mediated by Paraventricular Catecholaminergic Inputs in Female Rats

Abstract

The present study aims to clarify the role of fatty acids in regulating pulsatile LH secretion in rats. To produce an acute central lipoprivic condition, mercaptoacetate (MA), an inhibitor of fatty acids oxidation, was administered into the fourth cerebroventricle (4V) in ad libitum fed ovariectomized (OVX) rats (0.4, 2, and 10 micromol/rat) with or without an estradiol (E2) implant producing diestrus plasma E2 levels. Pulsatile LH secretion was suppressed by 4V MA administration in a dose-dependent manner in both OVX and OVX plus E2 rats. Mean LH levels and LH pulse frequency and amplitude were significantly reduced by the highest dose of MA in OVX rats, and by the middle and highest dose of MA in E2-treated rats, suggesting that estrogen enhanced LH suppression. Blood glucose levels increased immediately after the highest dose of MA in both groups. Fourth ventricular injection of trimetazidine (2 and 3 micromol/rat), another inhibitor of fatty acids oxidation, also inhibited pulsatile LH release, resulting in significant and dose-dependent suppression of LH pulse frequency and an increase in blood glucose levels in OVX plus E2 rats. In contrast, peripheral injection of the highest 4V dose of MA (10 micromol/rat) did not alter LH release or blood glucose levels. Microdialysis of the hypothalamic paraventricular nucleus (PVN) revealed that norepinephrine release in the region was increased by 4V MA administration. Preinjection of alpha-methyl-p-tyrosine, a catecholamine synthesis inhibitor, into the PVN completely blocked the lipoprivic inhibition of LH and the counter-regulatory increase in blood glucose levels in OVX plus E2 rats. Together, these studies indicate that fatty acid availability may be sensed by a central detector, located in the lower brainstem to maintain reproduction, and that noradrenergic inputs to the PVN mediate this lipoprivic-induced suppression of LH release.

Central Injection of Ketone Body Suppresses Luteinizing Hormone Release via the Catecholaminergic Pathway in Female Rats

“…57: [379][380][381][382][383][384] 2011) eproductive functions are known to be impaired under malnutrition in both sexes in several mammalian species [1][2][3][4][5]. Fasting, glucoprivation or lipoprivation has been well established to inhibit gonadal functions through suppressing pulsatile luteinizing hormone (LH) secretion in rats [6][7][8][9][10][11][12]. Malnutrition is often accompanied by a high level of circulating ketone bodies, which are by-products of enhanced fatty acid mobilization.…”

“…Numerous studies have indicated that the brain energy sensor resides within the hypothalamus and brainstem [18][19][20][21][22][23]. Previous studies have raised the possibility that brainstem energy sensors sense glucose and fatty acid availability to regulate gonadotropin secretion because administration of 2-deoxyglucose (2DG), a competitive inhibitor of glucose oxidation, or mercaptoacetate (MA), an inhibitor of fatty acid oxidation, into the fourth cerebroventricle (4V) suppresses LH pulses in rats [12,24,25]. Likewise, blockade of hindbrain monocarboxylate transporter 1 (MCT1), a ketone body transporter located in ependymocytes around the 4V, results in normalization of diabetic hyperphagia in rats [26].…”

“…To this end, the effect of 3HB injection into the 4V on pulsatile LH secretion was examined in female rats to investigate whether ketone bodies sensed by the hindbrain energy sensor act as a negative signal. We also examined whether noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) are associated with 3HB-induced pulsatile LH suppression because our previous studies showed that glucoprivic suppression of pulsatile LH suppression was mediated by noradrenergic inputs to the PVN [11] and that lipoprivation also suppressed pulsatile LH secretion via the PVN noradrenergic pathway [12,25]. …”

“…Intracellular calcium levels in the hindbrain ependymocytes respond to the change in extracellular glucose levels [23]. Hindbrain ependymocytes also might sense fatty acids because 4V MA administration inhibits pulsatile LH secretion [12]. Monocarboxylate transporter 1, a ketone body transporter, is expressed in ependymocytes around the 4V [26] as well as the lateral ventricle and third ventricle [32,33], and blockade of hindbrain MCT1 reverses diabetic hyperphagia in rats [26].…”

“…Thus, ketone bodies may be associated with the inhibition of glucose metabolism in ependymocytes to sense the level of energy substrates. Further studies are required to address these points.Previous studies suggested that LH pulse suppression caused by malnutrition, such as fasting [9], glucoprivation [11] or lipoprivation [12,25], is mediated by noradrenergic neurons projecting to the PVN. Local PVN injection of α1-or α2-adrenergic receptor agonists suppressed pulsatile LH release in female rats [10].…”