Hindbrain A2 noradrenergic neuron adenosine 5′‐monophosphate‐activated protein kinase activation, upstream kinase/phosphorylase protein expression, and receptivity to hormone and fuel reporters of short‐term food deprivation are regulated by estradiol

Abstract

Estradiol (E) mitigates acute and post-acute adverse effects of 12 hr-food deprivation (FD) on energy balance. Hindbrain 5′-monophosphate-activated protein kinase (AMPK) regulates hyperphagic and hypothalamic metabolic neuropeptide and norepinephrine responses to FD in an E-dependent manner. Energy state information from AMPK-expressing hindbrain A2 noradrenergic neurons shapes neural responses to metabolic imbalance. Here, we investigated the hypothesis that FD causes divergent changes in A2 AMPK activity in E versus oil (O)-implanted ovariectomized female rats, alongside dissimilar adjustments in circulating metabolic fuel [glucose, free fatty acids (FFA)] and energy deficit-sensitive hormone [corticosterone, glucagon, leptin] levels. FD decreased blood glucose in oil (O)-, but not E-implanted ovariectomized female rats, and elevated or reduced glucagon levels in O and E, respectively. FD decreased circulating leptin in O and E, but increased corticosterone and FFA concentrations in E only. Western blot analysis of laser-microdissected A2 neurons showed that glucocorticoid receptor type II and very long-chain acyl-CoA synthetase 3 protein profiles were amplified in FD/E versus FD/O. A2 total AMPK protein was elevated without change in activity in FD/O, while FD/E exhibited increased AMPK activation along with decreased upstream phosphatase expression. The catecholamine biosynthetic enzyme, dopamine-β-hydroxylase (DβH), was increased in FD/O, but not FD/E A2 cells. Data show discordance between A2 AMPK activation and glycemic responses to FD as sensor activity was refractory to glucose decrements in FD/O, but augmented in FD/E despite stabilized glucose and elevated FFA levels. E-dependent amplification of AMPK activity may reflect adaptive conversion to fatty acid oxidation and/or glucocorticoid stimulation. FD augmentation of A2 DβH protein profiles in FD/O but not FD/E animals suggests that FD may correspondingly regulate NE synthesis versus metabolism/release in the absence versus presence of E. Mechanisms underlying translation of E-contingent A2 neuron responses to FD into regulatory signaling remain to be determined.

Rebound Feeding in the Wake of Short-Term Suspension of Food Intake Differs in the Presence of Estrous Cycle Peak versus Nadir Levels of Estradiol

“…Current data show that FD-12 increased A2 pAMPK in E-300, but not E-30 animals, confirming previous reports that A2 pAMPK expression is refractory to FD-12 in the presence of nadir E levels [ 19 ]. Results moreover indicate that FD-12 augmentation of pAMPK protein was abolished by Cc.…”

“…Our previous studies showed that serum levels of the energy deficit-sensitive hormones leptin and insulin were correspondingly decreased or unaffected by FD-12 duration in OVX rats replaced with baseline E levels [ 19 ]. It is well documented that both hormones impose critical physiological restraint on food intake [ 20 21 22 ].…”

Norepinephrine regulation of ventromedial hypothalamic nucleus metabolic transmitter biomarker and astrocyte enzyme and receptor expression: Impact of 5′ AMP-activated protein kinase

“…Blood glucose levels were determined using an ACCU-CHECK Aviva plus glucometer (Roche Diagnostic Corporation, Indianapolis, IN) [Kale et al, 2006]. Plasma free fatty acid concentrations using Free Fatty Acid Quantitation Kit reagents (MAK044; Sigma Aldrich, St. Louis, Mo) [Briski et al, 2017]. Plasma corticosterone (ADI-900-097; Enzo Life Sciences, Inc., Farmingdale, NY) and glucagon (EZGLU-30K, EMD Millipore, Billerica, MA) concentrations were determined using commercial ELISA kit reagents, as described [Alhamami et al, 2018].…”

Hindbrain 5′-Adenosine Monophosphate-activated Protein Kinase Mediates Short-term Food Deprivation Inhibition of the Gonadotropin-releasing Hormone–Luteinizing Hormone Axis: Role of Nitric Oxide

“…Indeed, short-term suspension of food intake, planned or unplanned, is an unavoidable and unpredictable metabolic stressor inherent to modern life. Interrupted feeding over several hours elicits estradiol (E)-dependent patterns of hyperphagia and adjustments in circulating substrate fuel and energy deficit-sensitive hormone levels in ovariectomized (OVX) female rats [Ibrahim and Briski, 2015; Alenazi et al, 2016; Briski et al, 2016]. The ultra-sensitive energy sensor adenosine 5′-monophosphate-activated protein kinase (AMPK) acts within the caudal dorsomedial hindbrain to control feeding and forebrain AMPK and metabolic neuropeptide responses to short-term food deprivation (FD) [Alenazi et al, 2016].…”