Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis

Autor(es):Mostrar menos -

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.

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Obesity; v. 41, n. 2, p. 268-278, FEB 2017.
• Citações Web of Science: 5

Resumo

OBJECTIVE: To investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance. SUBJECTS: Swiss mice on chow or high-fat diet (HFD) and db/db mice on chow diet were used to address the role of CLK2 in the hypothalamus. RESULTS: Hypothalamic CLK2(Thr343) phosphorylation, which induces CLK2 activity, is regulated in vivo by refeeding, insulin and leptin, in a PI3K (phosphoinositide 3-kinase)-dependent manner. The reduction of CLK2 expression in the hypothalamus, by chronic pharmacological inhibition with TG003 or by chronic knockdown with small interfering RNA was sufficient to abolish the anorexigenic effect of insulin and leptin, to increase body weight, fat mass, food intake and to decrease energy expenditure in mice on chow. In contrast, CLK2(Thr343) phosphorylation in the hypothalamus in response to insulin, leptin or refeeding was impaired in mice on HFD or in db/db mice. Chronic CLK2 inhibition in the hypothalamus was associated with a slight increase in the fasting blood glucose levels, reduction in PEPCK (phosphoenolpyruvate carboxykinase) expression in the liver and enhanced glucose production from pyruvate, suggesting a regulation of hepatic glucose production. Further, overexpressing CLK2 in the mediobasal hypothalami of mice on HFD or in db/db mice by adenovirus partially reversed the obese phenotype. CONCLUSIONS: Thus, our results suggest that protein CLK2 integrates some important hypothalamic pathways, and may be a promising molecule for new therapeutic approaches for obesity and diabetes. (AU)

• Processo FAPESP: 15/00343-0 - Efeito da obesidade na regulação da AMPK em amígdala: implicações no metabolismo energético
• Beneficiário: Patrícia de Oliveira Prada
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 12/10338-6 - Regulação das proteínas Clk2 e IKK epsilon em hipotálamo de camundongos obesos
• Beneficiário: Patrícia de Oliveira Prada
• Modalidade de apoio: Auxílio à Pesquisa - Regular