title: Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats.
abstract: Melatonin can contribute to glucose homeostasis either by decreasing gluconeogenesis or by counteracting insulin resistance in distinct models of obesity. However, the precise mechanism through which melatonin controls glucose homeostasis is not completely understood. Male Wistar rats were administered an intracerebroventricular (icv) injection of melatonin and one of following: an icv injection of a phosphatidylinositol 3-kinase (PI3K) inhibitor, an icv injection of a melatonin receptor (MT) antagonist, or an intraperitoneal (ip) injection of a muscarinic receptor antagonist. Anesthetized rats were subjected to pyruvate tolerance test to estimate in vivo glucose clearance after pyruvate load and in situ liver perfusion to assess hepatic gluconeogenesis. The hypothalamus was removed to determine Akt phosphorylation. Melatonin injections in the central nervous system suppressed hepatic gluconeogenesis and increased hypothalamic Akt phosphorylation. These effects of melatonin were suppressed either by icv injections of PI3K inhibitors and MT antagonists and by ip injection of a muscarinic receptor antagonist. We conclude that melatonin activates hypothalamus-liver communication that may contribute to circadian adjustments of gluconeogenesis. These data further suggest a physiopathological relationship between the circadian disruptions in metabolism and reduced levels of melatonin found in type 2 diabetes patients.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.
authors.forename: Juliana A
authors.initials: JA
authors.lastname: Faria
authors.forename: Andrezza
authors.initials: A
authors.lastname: Kinote
authors.forename: Letícia M
authors.initials: LM
authors.lastname: Ignacio-Souza
authors.forename: Thiago M
authors.initials: TM
authors.lastname: de Araújo
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Razolli
authors.forename: Diego L
authors.initials: DL
authors.lastname: Doneda
authors.forename: Lívia B
authors.initials: LB
authors.lastname: Paschoal
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.forename: Gisele L
authors.initials: GL
authors.lastname: Bertolini
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Anhê
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D005943:Gluconeogenesis / Q000187:drug effects*; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044122:Receptor, Melatonin, MT1 / Q000187:drug effects*; D044123:Receptor, Melatonin, MT2 / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects
chemical_list: D000975:Antioxidants; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D011976:Receptors, Muscarinic; D019289:Pyruvic Acid; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D008550:Melatonin
keywords: gluconeogenesis; liver; melatonin; melatonin receptors