Artículos de revistas
Cdc2-like Kinase 2 In The Hypothalamus Is Necessary To Maintain Energy Homeostasis
Registro en:
International Journal Of Obesity. Nature Publishing Group, v. 41, p. 268 - 278, 2017.
0307-0565
1476-5497
WOS:000394143700010
10.1038/ijo.2016.174
Autor
Quaresma
P. G. F.; Weissmann
L.; Zanotto
T. M.; Santos
A. C.; de Matos
A. H. B.; Furigo
I. C.; Simabuco
F. M.; Donato
J.
Jr.; Bittencourt
J. C.; Lopes-Cendes
I.; Prada
P. O.
Institución
Resumen
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 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. 41 2 268 278 State University of Campinas (FUNCAMP) FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo), Sao Paulo, Brazil [2012/10338-6, 2015/00343-0, CEPID 2013/07607-8] CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) [481084/2013-4] INCT (Instituto Nacional Ciencia e Tecnologia de Obesidade e Diabetes) [573856/2008-7] Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)