title: Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis.
abstract: 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.
  
  
  
  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.
  
  
  
  Hypothalamic CLK2Thr343phosphorylation, 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, CLK2Thr343phosphorylation 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.
  
  
  
  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.
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.|Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: P G F
authors.initials: PG
authors.lastname: Quaresma
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.|Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Weissmann
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.|Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: T M
authors.initials: TM
authors.lastname: Zanotto
authors.affiliation: Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Santos
authors.affiliation: Department of Medical Genetics, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: A H B
authors.initials: AH
authors.lastname: de Matos
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: I C
authors.initials: IC
authors.lastname: Furigo
authors.affiliation: School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
authors.forename: F M
authors.initials: FM
authors.lastname: Simabuco
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: J
authors.initials: J
authors.lastname: Donato
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
authors.forename: J C
authors.initials: JC
authors.lastname: Bittencourt
authors.affiliation: Department of Medical Genetics, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: I
authors.initials: I
authors.lastname: Lopes-Cendes
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.|Department of Medical Clinics, Obesity and Comorbidities Research Center (OCRC), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.|School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
authors.forename: P O
authors.initials: PO
authors.lastname: Prada
mesh_terms: D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004435:Eating; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D042846:CDC2-CDC28 Kinases