title: Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia.
abstract: Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, Louisiana.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Gujar
authors.forename: Baher A
authors.initials: BA
authors.lastname: Ibrahim
authors.forename: Pratistha
authors.initials: P
authors.lastname: Tamrakar
authors.forename: Ajeesh Koshy
authors.initials: AK
authors.lastname: Cherian
authors.forename: Karen P
authors.initials: KP
authors.lastname: Briski
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D059331:Adrenergic Neurons / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004734:Energy Metabolism; D004789:Enzyme Activation; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D007003:Hypoglycemia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D007031:Hypothalamus / Q000201:enzymology* / Q000503:physiopathology; D057967:Infusions, Intraventricular; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D000068797:Orexins; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012249:Rhombencephalon / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction
chemical_list: D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D012333:RNA, Messenger; D019344:Lactic Acid; D011333:Pro-Opiomelanocortin; D055372:AMP-Activated Protein Kinases
keywords: 6-hydroxydopamine; A2 noradrenergic neurons; AMPK; Western blot analysis; insulin-induced hypoglycemia; lactate; laser-catapult microdissection; neuropeptide Y; orexin-A; oxytocin; proopiomelanocortin; qPCR; α-cyano-4-hydroxycinnamate