Ativação da AMPK hipotalâmica induzida por frutose aumenta a gliconeogênese hepática e a expressão de PEPCK no fígado de ratos = Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone lev

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(1)ANDREZZA PINHEIRO BEZERRA DE MENEZES KINOTE. ATIVAÇÃO DA AMPK HIPOTALÂMICA INDUZIDA POR FRUTOSE AUMENTA A GLICONEOGÊNESE HEPÁTICA E A EXPRESSÃO DE PEPCK NO FÍGADO DE RATOS. FRUCTOSE-INDUCED HYPOTHALAMIC AMPK ACTIVATION STIMULATES HEPATIC PEPCK AND GLUCONEOGENESIS DUE TO INCREASED CORTICOSTERONE LEVELS OF RATS. CAMPINAS. 2014. i.

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(3) UNIVERSIDADE ESTADUAL DE CAMPINAS Faculdade de Ciências Médicas. ANDREZZA PINHEIRO BEZERRA DE MENEZES KINOTE. ATIVAÇÃO DA AMPK HIPOTALÂMICA INDUZIDA POR FRUTOSE AUMENTA A GLICONEOGÊNESE HEPÁTICA E A EXPRESSÃO DE PEPCK NO FÍGADO DE RATOS FRUCTOSE-INDUCED HYPOTHALAMIC AMPK ACTIVATION STIMULATES HEPATIC PEPCK AND GLUCONEOGENESIS DUE TO INCREASED CORTICOSTERONE LEVELS OF RATS ORIENTAÇÃO: Prof. Dr. Gabriel Forato Anhê. Tese de Doutorado apresentada à Pós-Graduação da Faculdade de Ciências Médicas da Universidade Estadual de Campinas - UNICAMP para obtenção de título de Doutora em Farmacologia Doctoral Thesis presented to the Pharmacology Program of the Faculty of Medical Sciences, University of Campinas - UNICAMP, for obtainment of the Ph.D. degree in Pharmacology. ESTE EXEMPLAR CORRESPONDE À VERSÃO FINAL DA TESE DEFENDIDA POR ANDREZZA PINHEIRO BEZERRA DE MENEZES KINOTE E ORIENTADA PELO PROF. DR. GABRIEL FORTAO ANHÊ.. ________________________________ Assinatura do Orientador iii.

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(201) . Fructose-Induced Hypothalamic AMPK Activation Stimulates Hepatic PEPCK and Gluconeogenesis due to Increased Corticosterone Levels . Andrezza Kinote, Juliana A. Faria, Erika A. Roman, Carina Solon, Daniela S. Razolli, Letícia M. Ignacio-Souza, Carolina S. Sollon, Lucas F. Nascimento, Thiago M. de Araújo, Ana Paula L. Barbosa, Camilo Lellis-Santos, Licio A. Velloso, Silvana Bordin, and Gabriel F. Anhê Departments of Pharmacology (A.K., J.A.F., C.S.S., T.M.d.A., A.P.L.B., G.F.A.), and Internal Medicine (E.A.R., C.S., D.S.R., L.M.I.-S., L.F.N., L.A.V.), Faculty of Medical Sciences, State University of Campinas, 13084-971 Campinas, SP, Brazil; and Department of Physiology and Biophysics (C.L.-S., S.B.), Institute of Biomedical Sciences, University of Sao Paulo, 05508-900 Sao Paulo SP, Brazil Fructose consumption causes insulin resistance and favors hepatic gluconeogenesis through mech- anisms 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 intracere- broventricular (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-[3-D-ribofuranoside treatment. Hypothalamic AMPK inhibition with icv injection of compound C or with injection of a small interfering RNA targeted to AMPKa2 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. . . F. nonobese humans, fructose consumption was described as reducing insulin sensitivity and increasing fasting hepatic glucose output (2). In rodents, fructose-enriched diets have been demonstrated to cause hepatic insulin resistance (3) and to increase gluconeogenesis (4). Gluconeogenesis is an important component of the increased rate of hepatic glucose production, acting together with peripheral insulin resistance to promote hyperglyce-. ructose is a naturally occurring monosaccharide and is rarely present in the human diet as a single nutrient. Human exposure to dietary fructose results mainly from the consumption of sucrose (fructose-glucose) and highfructose corn syrup. High-fructose corn syrup currently represents the most popular sweetener in the United States, and its consumption, along with the incidence of obesity and diabetes, is continuously increasing (1). In. 46 .