Hindbrain lactate regulates preoptic gonadotropin-releasing hormone (GnRH) neuron GnRH-I protein but not AMPK responses to hypoglycemia in the steroid-primed ovariectomized female rat.
Steroid positive-feedback activation of the gonadotropin-releasing hormone (GnRH)-pituitary luteinizing hormone (LH) neuroendocrine axis propagates the pre ovulatory LH surge, a crucial component of female reproduction. Our work shows that this key event is restrained by inhibitory metabolic input from hindbrain A2 noradrenergic neurons. GnRH neurons express the ultra-sensitive energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK); here, we investigated the hypothesis that GnRH nerve cell AMPK and peptide neurotransmitter responses to insulin-induced hypoglycemia are controlled by hindbrain lack of the oxidizable glycolytic end-product L-lactate. Data show that hypoglycemic inhibition of LH release in steroid-primed ovariectomized female rats was reversed by coincident caudal hindbrain lactate infusion. Western blot analyses of laser-microdissected A2 neurons demonstrate hypoglycemic augmentation [Fos, estrogen receptor-beta (ER-β), phosphoAMPK (pAMPK)] and inhibition (dopamine-beta-hydroxylase, GLUT3, MCT2) of protein expression in these cells, responses that were normalized by insulin plus lactate treatment. Hypoglycemia diminished rostral preoptic GnRH nerve cell GnRH-I protein and pAMPK content; the former, but not the latter response was reversed by lactate. Results implicate caudal hindbrain lactoprivic signaling in hypoglycemia-induced suppression of the LH surge, demonstrating that lactate repletion of that site reverses decrements in A2 catecholamine biosynthetic enzyme and GnRH neuropeptide precursor protein expression. Lack of effect of lactate on hypoglycemic patterns of GnRH AMPK activity suggests that this sensor is uninvolved in metabolic-inhibition of positive-feedback-stimulated hypophysiotropic signaling to pituitary gonadotropes.
Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
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Shrestha
Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States. Electronic address: briski@ulm.edu.
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Briski
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D059331:Adrenergic Neurons / Q000187:drug effects*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007003:Hypoglycemia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007328:Insulin / Q000633:toxicity; D019344:Lactic Acid / Q000008:administration & dosage*; D007986:Luteinizing Hormone / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010052:Ovariectomy; D011301:Preoptic Area / Q000166:cytology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012249:Rhombencephalon / Q000187:drug effects*
D001786:Blood Glucose; D007328:Insulin; D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; C074283:estradiol 3-benzoate; D007987:Gonadotropin-Releasing Hormone; D019344:Lactic Acid; D004958:Estradiol; D007986:Luteinizing Hormone; D055372:AMP-Activated Protein Kinases
A2 noradrenergic neurons; Western blot; gonadotropin-releasing hormone; laser-microdissection; luteinizing hormone surge; phosphoAMPK