Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat

Abstract

This study addressed the hypothesis that dorsomedial hindbrain adenosine 5’-monophosphate-activated protein kinase (AMPK) imposes inherent control over hypothalamic AMPK, neuropeptide, and norepinephrine (NE) activity and governs feeding in an estradiol-dependent manner. Groups of estradiol (E)- or oil (O)-implanted ovariectomized rats were injected with the AMPK inhibitor Compound C (Cc) or vehicle into the caudal fourth ventricle (CV4) prior to micropunch-dissection of individual hypothalamic metabolic loci or assessment of food intake. Cc decreased hindbrain dorsal vagal complex phosphoAMPK (pAMPK) profiles in both E and O; tissue ATP levels were reduced by this treatment in O only. In E/Cc, pAMPK expression was diminished in the lateral hypothalamic area (LHA) and ventromedial (VMH) and paraventricular (PVH) nuclei; only PVH pAMPK was suppressed by this treatment in O/Cc. Cc decreased PVH corticotropin-releasing hormone and arcuate (ARH) proopiomelanocortin (POMC) and neuropeptide Y in O, but suppressed only POMC in E. O/Cc exhibited both augmented (PVH, VMH) and decreased (LHA, ARH) hypothalamic NE content, whereas Cc treatment of E elevated preoptic and dorsomedial hypothalamic nucleus NE. Cc completely or incompletely repressed feeding in E versus O, respectively. Results implicate dorsomedial hindbrain AMPK in physiological stimulus-induced feeding in females. Excepting POMC, hypothalamic neuropeptide targets of input from that sensor may differ in presence vs. absence of estrogen. Estradiol likely determines hypothalamic targets of altered NE signaling due to hindbrain AMPK activation. Divergent changes in NE content of hypothalamic loci in O/Cc uniquely demonstrate sensor-induced bimodal catecholamine signaling to those sites.

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

“…Previous studies show that caudal hindbrain AMPK crucially shapes hypothalamic AMPK and metabolic neurotransmitter responses to FD in female rats and that this sensor is the primary if not exclusive source of impetus to refeed in FD/E animals (Alenazi et al, ). AMPK‐expressing A2 noradrenergic neurons are an important E‐sensitive (Ibrahim et al, ) sensory element of the brain metabolic regulatory network (Gujar et al, ).…”

“…On the other hand, we cannot disregard the prospect that, notwithstanding a lack of change in DβH protein expression, FD may regulate A2 norepinephrine transmission through control of norepinephrine metabolism and release within projection sites. Indeed, FD elicits adjustments in tissue norepinephrine content in different forebrain structures in O vs. E animals, responses that are attenuated by the AMPK inhibitor Cc (Alenazi et al, ). We speculate that E may determine downstream targets of norepinephrine noradrenergic signals of hindbrain sensor status through actions at noradrenergic axon terminals to “silence” or “unsilence” AMPK‐sensitive norepinephrine release within distinct forebrain loci.…”

“…This compound's metabolic stress also exerts E‐dependent effects during later resumption of circadian‐induced food intake, e.g., increased consumption vs. weight gain in the presence vs. absence of E. These results signify that E mitigates acute and postacute adverse effects of disrupted fuel acquisition on systemic energy balance. cDVC AMPK impacts E influence; E‐ vs. oil (O)‐implanted ovariectomized (OVX) female rats exposed to FD display divergent patterns of cDVC AMPK activation (Ibrahim and Briski, ) as well as disparate adjustments in feeding and hypothalamic AMPK phosphorylation, metabolic neurotransmitter expression, and norepinephrine activity after intra‐CV4 delivery of the AMPK inhibitor compound C (Alenazi et al, ). Compound C treatment of FD/E but not FD/O animals normalizes food intake to full‐fed ad libitum levels, implying that, in the presence of E, primary if not exclusive impetus to refeed emanates from this sensor.…”

Perinatal free‐choice of a high‐calorie low‐protein diet affects leptin signaling through IRS1 and AMPK dephosphorylation in the hypothalami of female rat offspring in adulthood

“…These results can be explained by a strong sexual dimorphism in hypothalamic AMPK activity that is likely associated with a putative response of sex hormones to maternal energy imbalance. In this sense, estradiol regulates energy expenditure, metabolic neuropeptides and food intake via hypothalamic AMPK . Future studies should address whether sex hormones compromise long‐term metabolic programming in the context of impaired maternal nutrient exposure.…”

“…In this sense, estradiol regulates energy expenditure, metabolic neuropeptides and food intake via hypothalamic AMPK. 76,77 Future studies should address whether sex hormones compromise long-term metabolic programming in the context of impaired maternal nutrient exposure.…”