Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model

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Manoj Amrutkar, Emmelie Cansby, Urszula Chursa, Esther Nuñez-Durán, Belén Chanclón, Marcus Ståhlman, Vincent Fridén, Louise Mannerås-Holm, Anna Wickman, Ulf Smith, Gert Fredrik Bäckhed, Jan Borén, Brian W Howell, Margit Mahlapuu

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.
Original languageEnglish
JournalDiabetes
Volume64
Issue number8
Pages (from-to)2791-804
Number of pages14
ISSN0012-1797
DOIs
Publication statusPublished - Aug 2015

    Research areas

  • Acetyl-CoA Carboxylase, Animals, Blood Glucose, Body Composition, Body Weight, Diabetes Mellitus, Type 2, Diet, High-Fat, Fatty Liver, Gluconeogenesis, Glucose Tolerance Test, Hyperglycemia, Hyperinsulinism, Insulin, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Liver, Male, Mice, Mice, Knockout, Protein-Serine-Threonine Kinases

ID: 156087818