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Hypothalamic CLK2 is important for energy homeostasis

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Author(s):
Paula Gabriele Fernandes Quaresma
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Patrícia de Oliveira Prada; Licio Augusto Velloso; Gabriel Forato Anhê; Renata Frazão; Silvana Bordin
Advisor: Patrícia de Oliveira Prada
Abstract

Obesity prevalence is increasing worldwide and it is characterized by excess of adipose tissue potentially harmful for health. The hormones insulin and leptin act in hypothalamus and through their intracellular signaling can modify neuropeptides expression, leading to the balance between food intake and energy expenditure. CLK2 was described in liver and BAT as a kinase responsive to insulin that regulates gluconeogenesis in liver and thermogenesis in BAT. Mice chronically fed with high-fat diet have shown impairment in CLK2 regulation in those tissues. In this sense, the aims of this study were to investigate CLK2 expression and regulation in hypothalamus in response to insulin and leptin and its hypothetical role in energy metabolism control. Our data shows for the first time that CLK2 is expressed in hypothalamic neurons and CLK2 threonine 343 phosphorylation was crucial for this kinase activity, furthermore, CLK2 phosphorylation was induced by refed after prolonged fasting and by ICV injections of insulin and leptin. This effect was dependent of PI3K and AKT. Clk2 threonine 343 phosphorylation, in response to insulin and leptin, was decreased in HFD-fed and dbdb mice. Pharmacological inhibition as well as deletion of CLK2 expression in hypothalamus induced obesity due, at least in part, to hyperphagia and energy expenditure depletion. On the other hand, CLK2 overexpression in hypothalamus of obese mice led to body weight, adiposity and food intake decrease and energy expenditure increase. Data shown herein suggest that CLK2 integrates hypothalamic insulin and leptin signaling, and contributes for energy homeostasis control, being a promising molecule for new therapeutic approaches for obesity (AU)

FAPESP's process: 12/10058-3 - STUDY OF CLK2 REGULATION IN HYPOTHALAMUS OF OBESE MICE
Grantee:Paula Gabriele Fernandes Quaresma Bergonsi
Support Opportunities: Scholarships in Brazil - Doctorate