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Implication of the serine/threonine kinase SIK2 in the control of lipid synthesis - role in the development of hepatic steatosis – SIKTOSE

Submission summary

Maintaining blood glucose concentrations within physiological ranges constitutes a major challenge for mammalian organisms, which have to face important variations in their nutritional status during the day. The importance of this regulation is underlined by the adverse consequences of chronic hyperglycemia, which exerts dramatic effects on insulin target tissues, resulting in alteration of insulin signaling and a further decrease in insulin sensitivity. Insulin is a key hormone for the maintenance of glucose and lipid homeostasis. Insulin action is initiated through the binding to and the activation of its cell-surface receptor involving a series of intra-molecular transphosphorylation reactions. The insulin signal is further propagated through a phosphorylation network implicating intracellular proteins leading to the various metabolic actions of insulin on target tissues such as skeletal muscles, white adipose tissue and liver. After a meal, upon insulin action, a large fraction of glucose absorbed from the small intestine is immediately taken up by the liver, which converts it into glycogen. When glycogen stores are restored any additional glucose taken up by the hepatocytes is shunted into metabolic pathways leading to synthesis of fatty acids through de novo lipogenesis. An adequate control of fatty acid synthesis in liver is crucial since dysregulated lipogenesis has been shown to contribute to the pathogenic development of hepatic steatosis and insulin resistance in both humans and mice. In addition, chronic hyperglycemia per se has deleterious effects on pancreatic ' cells, resulting in impaired insulin secretion and further worsening of glucose intolerance. This phenomenon, known as glucotoxicity, initiates a vicious circle in which chronically elevated blood glucose will eventually lead to overt type 2 diabetes. Several mechanisms appear to be involved in the adverse effects of hyperglycemia, including glycation of proteins, activation of protein kinase C isoforms, increased production of reactive oxygen species, O-linked N-acetylglucosaminylation (O-GlcNac-glycosylation) on serine and threonine residues and acetylation on lysine. This last mechanism represents a growing area of research in the field of diabetes and obesity. In a way very similar to serine/threonine phosphorylation, addition of acetylated residue to lysine on proteins represents a reversible mechanism of regulation that concerns various aspects of cell biology including gene regulation of both glucose and lipid metabolism. Our project will focus on the cellular events and/or molecular factors involved in insulin and glucose signaling as well as in the metabolic alterations caused by gluco- and lipotoxicity in tissues and more particularly in liver. Our ultimate goal is to provide a better understanding of the metabolic pathway and molecular mechanisms leading to the synthesis of fatty acids in liver and to identify novel potential therapeutic targets that could lead to the improvement of hyperglycemia, insulin sensitivity and hepatic steatosis in a state of obesity and/or type 2 diabetes. We will more precisely focus our attention on the role of a recently identified new serine/threonine kinase named SIK2 (Salt Inducible kinase2) in the regulation of glucose and lipid homeostasis in liver and its potential role in the development of hepatic steatosis in a state of obesity and type 2 diabetes. In the past few years, we have for the first time identified SIK2 as an important regulator of glucose homeostasis in liver. Indeed we have shown that SIK2 control gluconeogenesis in liver during fasting and refeeding by regulating the activity of the CREB coactivator TORC2. We have shown that SIK2 is activated and mediates insulin action in liver on glucose production, showing a new and original mechanism for the inhibition of glucose production by insulin during feeding. In addition, we recently demonstrated that SIK2 not only mediates insulin action in liver but also might regulate gene expression in cells by modulating the levels of acetylation through the regulation of p300 acetyltransferase activity. It is clear from our previous finding that SIK2 may have an important role in glucose and lipid homeostasis and might become important therapeutic targets for severe endocrine disorders such as defective glucose and fat metabolism associated with obesity and/or type 2 diabetes in the future. All the findings and tools develop these past few years by our group concerning the identification and characterization of SIK2 in liver will help us to determine more precisely its function in vivo and in the development of metabolic syndrome in a state of obesity and/or insulin resistance and place our group as a team leader in the field to study the role of this kinase in the physiology and physiopathology of the liver

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The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

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