Journal
DIABETES
Volume 64, Issue 8, Pages 2791-2804Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db15-0060
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Funding
- Swedish Research Council
- European Foundation for the Study of Diabetes/Lilly research grant
- European Foundation for the Study of Diabetes
- Novo Nordisk Partnership for Diabetes Research in Europe
- Novo Nordisk Foundation
- Swedish Heart and Lung Foundation
- Diabetes Wellness Network Sweden
- Swedish Diabetes Foundation
- Petrus and Augusta Hedlunds Foundation
- Ake Wiberg Foundation
- Adlerbert Research Foundation
- Magnus Bergvalls Foundation
- Inger Hultman Foundation
- National Institute of Neurological Disorders and Stroke [NS-073662]
- Novo Nordisk Fonden [NNF14OC0010799, NNF14OC0009667, NNF15OC0016484] Funding Source: researchfish
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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.
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