Specific deletion of Clk2 in GABA neurons: impact on mice energy metabolism

• Grant number: 18/18341-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2019
• End date: October 31, 2021
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Patrícia de Oliveira Prada
• Grantee: Sónia Maria Norberto Alves
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Obesity and its comorbidities, such as Type 2 Diabetes Mellitus, have increased exponentially, making it urgent to understand the mechanisms involved in the development of these diseases. The maintenance of energy homeostasis is performed by hormones such as leptin and insulin in addition to neural signs. Our group 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. Inhibition of hypothalamic Clk2 led to Obesity due to hyperphagia and lower energy expenditure. Conversely, overexpression of Clk2 by adenovirus in obese animals partly restored energy homeostasis. However, this first study did not investigate which neuron expresses Clk2, nor what role Clk2 plays in regulating behavior. Given the abundance of neurons expressing ³-aminobutyric acid (GABA) neurotransmitters and their potential for control of energy and behavioral balance, the aims of the study are to 1) generate Clk2 knockout mice specifically in GABA neurons (Clk2flox/flox.Vgat) and Clk2flox/flox and Vgat cre as controls. In these mice to investigate: 2) metabolic parameters such as weight gain and body composition (DEXA), food intake, energy expenditure, fasting blood glucose, insulinemia and leptinemia, glucose, insulin and pyruvate tolerance in animals receiving chow or High Fat Diet (HFD); 3) the hypothalamic action and signaling of leptin and insulin, as well as the gene expression of NPY, AgRP, and POMC in the hypothalamus of animals receiving chow or HFD; 4) the behavior through open field test, elevated cross maze test and water maze test of animals receiving chow or HFD. As a preliminary result of the animals receiving chow diet, we observed a reduction of around 50% of Clk2 in the mouse hypothalamus of Clk2flox/flox.Vgat compared to C57BL/6J mouse. In addition, the Glucose Tolerance Test (GTT) revealed that the Clk2flox/flox.Vgat group had glucose intolerance compared to its control (Clk2flox/flox). No changes in insulin or pyruvate tolerance tests were observed, suggesting that Clk2 in GABAergic neurons is essential for maintaining glucose metabolism. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ALVES, Sónia Maria Norberto. Specific deletion of CLK2 in GABA neurons: impact on the energy metabolism of mice. 2021. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.