Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8840791 | Neuroscience | 2018 | 12 Pages |
Abstract
The hypothalamic energy sensor adenosine 5â²-monophosphate-activated protein kinase (AMPK), an important regulator of counter-regulatory responses to hypoglycemia, responds to pharmacological manipulation of hindbrain AMPK activity. Dorsomedial hindbrain A2 noradrenergic neurons express hypoglycemia-sensitive metabolo-sensory biomarkers, including AMPK. Here, adult male rats were pretreated by intra-caudal fourth ventricular administration of the selective neurotoxin 6-hydroxydopamine (6-OHDA) to determine if catecholamine signaling from the aforesaid site governs hypothalamic AMPK activation during insulin-induced hypoglycemia (IIH). Micropunched arcuate (ARH), ventromedial (VMH), paraventricular (PVH), dorsomedial (DMH) nuclei and lateral hypothalamic area (LHA) tissues were obtained at the neutral protamine Hagedorn insulin-induced hypoglycemic nadir, coincident with A2 AMPK activation, for Western blot analysis of AMPK, phospho-AMPK (pAMPK), and relevant metabolic neuropeptides. ARH, VMH, LHA, and DMH norepinephrine levels were altered according to insulin dose; 6-OHDA-mediated reversal of these responses was site-specific. IIH elevated LHA and reduced VMH pAMPK protein, profiles that were respectively unchanged or increased by 6-OHDA. PVH and ARH pAMPK was resistant to IIH, but augmented in ARH of neurotoxin- plus insulin-treated rats. ARH neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) proteins were correspondingly increased or refractory to IIH; 6-OHDA pretreatment normalized NPY and elevated POMC expression after insulin injection. Results demonstrate site-specific bi-directional adjustments in hypothalamic AMPK reactivity to hypoglycemia. Intensification of ARH/VMH pAMPK by 6-OHDA implies dorsomedial hindbrain improvement of energy balance in those sites during IIH. Neurotoxin-mediated augmentation versus suppression of basal catabolic (ARH POMC/VMH steroidogenic factor-1) or IIH-associated anabolic (ARH NPY) neuropeptide profiles, respectively, may involve local AMPK-dependent against independent mechanisms.
Keywords
pro-opiomelanocortinNeutral protamine Hagedorn insulinSF-1NPHVMHIIHPVHCV4AMPKLHAARH6-Hydroxydopamine6-OHDANPYPOMCpAMPKadenosine 5′-monophosphate-activated protein kinaseEDTAEthylenediaminetetraacetic acidOrexin-ASteroidogenic factor-1lateral hypothalamic areanorepinephrineVentromedial hypothalamic nucleusarcuate hypothalamic nucleusparaventricular hypothalamic nucleusInsulin-induced hypoglycemiaWestern blottingcatecholamineNeuropeptide Y
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Authors
Hussain N. Alhamami, Md. Main Uddin, A.S.M. Hasan Mahmood, Karen P. Briski,