1. Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model.
- Author
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Amrutkar M, Cansby E, Chursa U, Nuñez-Durán E, Chanclón B, Ståhlman M, Fridén V, Mannerås-Holm L, Wickman A, Smith U, Bäckhed F, Borén J, Howell BW, and Mahlapuu M
- Subjects
- Acetyl-CoA Carboxylase metabolism, Animals, Blood Glucose metabolism, Body Composition genetics, Body Weight genetics, Diabetes Mellitus, Type 2 etiology, Diabetes Mellitus, Type 2 genetics, Fatty Liver genetics, Fatty Liver metabolism, Glucose Tolerance Test, Hyperglycemia genetics, Hyperglycemia metabolism, Hyperinsulinism genetics, Hyperinsulinism metabolism, Insulin metabolism, Intracellular Signaling Peptides and Proteins metabolism, Lipid Metabolism genetics, Liver metabolism, Male, Mice, Mice, Knockout, Protein Serine-Threonine Kinases metabolism, Diabetes Mellitus, Type 2 metabolism, Diet, High-Fat, Gluconeogenesis genetics, Insulin Resistance genetics, Intracellular Signaling Peptides and Proteins genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25(-/-) mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25(-/-) skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. The findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for the treatment of type 2 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
- Published
- 2015
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