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The regulation of Clk2 and IKK epsilon in the hypothalamus of obese mice

Grant number: 12/10338-6
Support type:Regular Research Grants
Duration: August 01, 2012 - January 31, 2015
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Patrícia de Oliveira Prada
Grantee:Patrícia de Oliveira Prada
Home Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil


Hypothalamic insulin and leptin participate of energy balance control. The protein Cdc2-like kinase (Clk2) is regulated in the liver by refeeding and insulin. Previously was shown by our group that Clk2 is expressed in hypothalamic nuclei. Thus we will investigate the role of refeeding, insulin and leptin on Clk2 phosphorylation and if this alteration is dependent of PI3q/Akt pathway. In addition, we will investigate whether the reduction or overexpression of Clk2 by adenovirus alters adiposity, food intake, energy expenditure, respiratory exchange rate, locomotor activity, neuropeptides expression, glycemia, and hepatic glucose production. High fat diet is associated with insulin and leptin resistance in the hypothalamus. Thus, it will be investigated whether Clk2 expression/phosphorylation is altered in DIO mice. Obesity induces metabolic inflammation in the hypothalamus by IKKbeta/IkB/NFkB activation. Recently, it was shown that another isoform of IKK, IKKepsilon, was altered in hepatic and adipose tissues of obese mice. However, the role of IKKe in the hypothalamus was not explored. Since we previously showed that IKKe is expressed in the hypothalamus of obese mice, we will investigate the regulation of IKKµ in hypothalamic nuclei of DIO mice. Additionally, whether the inhibition of IKKµ, by pharmacological inhibitor or siRNA, alters body weight, food intake, energy expenditure, hypothalamic insulin and leptin signaling and neuropeptides expression. (AU)

Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
QUARESMA, P. G. F.; WEISSMANN, L.; ZANOTTO, T. M.; SANTOS, A. C.; DE MATOS, A. H. B.; FURIGO, I. C.; SIMABUCO, F. M.; DONATO, JR., J.; BITTENCOURT, J. C.; LOPES-CENDES, I.; PRADA, P. O. Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis. International Journal of Obesity, v. 41, n. 2, p. 268-278, FEB 2017. Web of Science Citations: 5.
QUARESMA, P. G. F.; REENCOBER, N.; ZANOTTO, T. M.; SANTOS, A. C.; WEISSMANN, L.; DE MATOS, A. H. B.; LOPES-CENDES, I.; FOLLI, F.; SAAD, M. J. A.; PRADA, P. O. Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway. International Journal of Obesity, v. 40, n. 1, p. 138-146, JAN 2016. Web of Science Citations: 11.
ZAMBOM DE SOUZA, ALESSANDRA ZANIN; ZAMBOM, ADRIANO ZANIN; ABBOUD, KAHLILE YOUSSEF; REIS, SABRINA KAREN; TANNIHAO, FABIANA; GUADAGNINI, DIOZE; SAAD, MARIO J. A.; PRADA, PATRICIA OLIVEIRA. Oral supplementation with L-glutamine alters gut microbiota of obese and overweight adults: A pilot study. NUTRITION, v. 31, n. 6, p. 884-889, JUN 2015. Web of Science Citations: 18.
CONDES AREIAS, MARIA FERNANDA; PRADA, PATRICIA OLIVEIRA. Mechanisms of insulin resistance in the amygdala: Influences on food intake. Behavioural Brain Research, v. 282, p. 209-217, APR 2015. Web of Science Citations: 22.
WEISSMANN, LAIS; QUARESMA, PAULA G. F.; SANTOS, ANDRESSA C.; DE MATOS, ALEXANDRE H. B.; PASCOAL, VINICIUS D'AVILA BITTENCOURT; ZANOTTO, TAMIRES M.; CASTRO, GISELE; GUADAGNINI, DIOZE; DA SILVA, JOELCIMAR MARTINS; VELLOSO, LICIO A.; BITTENCOURT, JACKSON C.; LOPES-CENDES, ISCIA; SAAD, MARIO J. A.; PRADA, PATRICIA O. IKK epsilon Is Key to Induction of Insulin Resistance in the Hypothalamus, and Its Inhibition Reverses Obesity. Diabetes, v. 63, n. 10, p. 3334-3345, OCT 2014. Web of Science Citations: 20.
PRADA, PATRICIA O.; SAAD, MARIO J. A. Tyrosine kinase inhibitors as novel drugs for the treatment of diabetes. EXPERT OPINION ON INVESTIGATIONAL DRUGS, v. 22, n. 6, p. 751-763, JUN 2013. Web of Science Citations: 1.

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