title: Hindbrain medulla catecholamine cell group involvement in lactate-sensitive hypoglycemia-associated patterns of hypothalamic norepinephrine and epinephrine activity.
abstract: Cell-type compartmentation of glucose metabolism in the brain involves trafficking of the oxidizable glycolytic end product, l-lactate, by astrocytes to fuel neuronal mitochondrial aerobic respiration. Lactate availability within the hindbrain medulla is a monitored function that regulates systemic glucostasis as insulin-induced hypoglycemia (IIH) is exacerbated by lactate repletion of that brain region. A2 noradrenergic neurons are a plausible source of lactoprivic input to the neural gluco-regulatory circuit as caudal fourth ventricular (CV4) lactate infusion normalizes IIH-associated activation, e.g. phosphorylation of the high-sensitivity energy sensor, adenosine 5'-monophosphate-activated protein kinase (AMPK), in these cells. Here, we investigated the hypothesis that A2 neurons are unique among medullary catecholamine cells in directly screening lactate-derived energy. Adult male rats were injected with insulin or vehicle following initiation of continuous l-lactate infusion into the CV4. Two hours after injections, A1, C1, A2, and C2 neurons were collected by laser-microdissection for Western blot analysis of AMPKα1/2 and phosphoAMPKα1/2 proteins. Results show that AMPK is expressed in each cell group, but only a subset, e.g. A1, C1, and A2 neurons, exhibit increased sensor activity in response to IIH. Moreover, hindbrain lactate repletion reversed hypoglycemic augmentation of pAMPKα1/2 content in A2 and C1 but not A1 cells, and normalized hypothalamic norepinephrine and epinephrine content in a site-specific manner. The present evidence for discriminative reactivity of AMPK-expressing medullary catecholamine neurons to the screened energy substrate lactate implies that that lactoprivation is selectively signaled to the hypothalamus by A2 noradrenergic and C1 adrenergic cells.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, United States.
authors.forename: P K
authors.initials: PK
authors.lastname: Shrestha
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, United States.
authors.forename: P
authors.initials: P
authors.lastname: Tamrakar
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, United States.
authors.forename: B A
authors.initials: BA
authors.lastname: Ibrahim
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, United States. Electronic address: briski@ulm.edu.
authors.forename: K P
authors.initials: KP
authors.lastname: Briski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D059331:Adrenergic Neurons / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D003345:Corticosterone / Q000097:blood; D004837:Epinephrine / Q000032:analysis / Q000378:metabolism*; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007773:Lactates; D055372:AMP-Activated Protein Kinases; D003345:Corticosterone; D009638:Norepinephrine; D004837:Epinephrine
keywords: A2 noradrenergic neurons; C1 adrenergic neurons; Western blotting; insulin-induced hypoglycemia; laser-catapult microdissection; pAMPK