title: Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone levels.
abstract: Fructose consumption causes insulin resistance and favors hepatic gluconeogenesis through mechanisms that are not completely understood. Recent studies demonstrated that the activation of hypothalamic 5'-AMP-activated protein kinase (AMPK) controls dynamic fluctuations in hepatic glucose production. Thus, the present study was designed to investigate whether hypothalamic AMPK activation by fructose would mediate increased gluconeogenesis. Both ip and intracerebroventricular (icv) fructose treatment stimulated hypothalamic AMPK and acetyl-CoA carboxylase phosphorylation, in parallel with increased hepatic phosphoenolpyruvate carboxy kinase (PEPCK) and gluconeogenesis. An increase in AMPK phosphorylation by icv fructose was observed in the lateral hypothalamus as well as in the paraventricular nucleus and the arcuate nucleus. These effects were mimicked by icv 5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside treatment. Hypothalamic AMPK inhibition with icv injection of compound C or with injection of a small interfering RNA targeted to AMPKα2 in the mediobasal hypothalamus (MBH) suppressed the hepatic effects of ip fructose. We also found that fructose increased corticosterone levels through a mechanism that is dependent on hypothalamic AMPK activation. Concomitantly, fructose-stimulated gluconeogenesis, hepatic PEPCK expression, and glucocorticoid receptor binding to the PEPCK gene were suppressed by pharmacological glucocorticoid receptor blockage. Altogether the data presented herein support the hypothesis that fructose-induced hypothalamic AMPK activation stimulates hepatic gluconeogenesis by increasing corticosterone levels.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Alexander Fleming Street, #101, 13084-971Campinas SP, Brazil.
authors.forename: Andrezza
authors.initials: A
authors.lastname: Kinote
authors.forename: Juliana A
authors.initials: JA
authors.lastname: Faria
authors.forename: Erika A
authors.initials: EA
authors.lastname: Roman
authors.forename: Carina
authors.initials: C
authors.lastname: Solon
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Razolli
authors.forename: Letícia M
authors.initials: LM
authors.lastname: Ignacio-Souza
authors.forename: Carolina S
authors.initials: CS
authors.lastname: Sollon
authors.forename: Lucas F
authors.initials: LF
authors.lastname: Nascimento
authors.forename: Thiago M
authors.initials: TM
authors.lastname: de Araújo
authors.forename: Ana Paula L
authors.initials: AP
authors.lastname: Barbosa
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.forename: Licio 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: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D003345:Corticosterone / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005632:Fructose / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005632:Fructose; D055372:AMP-Activated Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D003345:Corticosterone