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The specific deletion of CLK2 in GABA neurons: the impact on feeding behavior and energy metabolism in mice

Grant number: 18/20087-7
Support type:Regular Research Grants
Duration: April 01, 2019 - March 31, 2021
Field of knowledge:Biological Sciences - Physiology
Cooperation agreement: FACEPE
Principal Investigator:Patrícia de Oliveira Prada
Grantee:Patrícia de Oliveira Prada
Home Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil

Abstract

Obesity has been exponentially increasing in the last decades, making urgent to understand the underlying mechanisms contributing to its development, maintenance and associated comorbidities. The maintenance of energetic homeostasis is under the control of endocrine hormones and neural signals. The hormones, insulin and leptin, are the most investigated in central energy regulation, as well as food intake and behavior tests . Our research team, has recently demonstrated that Clk2 (Cdc-like kinase 2) is expressed in hypothalamic neurons and can be phosphorylated and activated in response to insulin and leptin. The pharmacological inhibition or the knockdown of hypothalamic Clk2 led to obesity due to hyperphagia and reduced energy expenditure. Conversely, the restoration of hypothalamic Clk2 expression by adenovirus, in obese animals, partially restored the energetic homeostasis. However, in our first study, we did not demonstrate the neuron where the Clk2 was expressed in the hypothalamus. Since depending on the neuron we would obtain different physiological responses, we choose to delete the Clk2 in GABA neurons because it is not known what type of neuron could express Clk2 and also, the importance of neurons expressing the neurotransmitters ³-aminobutyric acid (GABA) and glutamate for the regulation of energy homeostasis. Thus, the objectives of the present study are: 1) to create GABA neurons-specific Clk2 knockout mice (Clk2flox /flox.Vgat) and to monitor longitudinally, metabolic parameters such as body weight, body composition by microCT, food intake, oxygen consumption, respiratory quotient, fasting glycemia, insulinemia and leptinemia, serum cytokines, glucose, insulin and pyruvate tolerance in the animals fed with standard diet; 2) to investigate the action and hypothalamic signaling to leptin, as well as, the gene expression of NPY, AgRP and POMC in the hypothalamus and to analyze the behavior of Clk2flox/flox.Vgat and control mice, fed with standard diet, 3) to evaluate the eating behavior and exploratory activity in an elevated plus-maze test. (AU)

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