The MST3/STK24 kinase mediates impaired fasting blood glucose after a high-fat diet
The identification of mediators in the pathogenesis of type 2 diabetes mellitus is essential for the full understanding of this disease. Protein kinases are especially important because of their potential as pharmacological targets. The goal of this study was to investigate whether mammalian sterile-20 3 (MST3/STK24), a stress-regulated kinase, is involved in metabolic alterations in obesity.
Glucose regulation of Mst3 (also known as Stk24)-knockout mice was analysed both in 129;C57 mixed background mice and in C57/BL6J mice fed normally or with a high-fat diet (HFD). This work was complemented with an analysis of the insulin signalling pathway in cultured human liver cells made deficient in MST3 using RNA interference.
MST3 is phosphorylated in the livers of mice subject to an obesity-promoting HFD, and its deficiency lowers the hyperglycaemia, hyperinsulinaemia and insulin resistance that the animals develop with this diet, an effect that is seen even without complete inactivation of the kinase. Lack of MST3 results in activation of the insulin signalling pathway downstream of IRS1, in both cultured liver cells and the liver of animals after HFD. This effect increases the inhibition of forkhead box (FOX)O1, with subsequent downregulation of the expression of gluconeogenic enzymes.
MST3 inhibits the insulin signalling pathway and is important in the development of insulin resistance and impaired blood glucose levels after an HFD.
KeywordsG6PC GCKIII kinases Gluconeogenesis Impaired fasting glucose Insulin resistance
Akt serine/threonine kinase
AMP-activated protein kinase
N6,2′-O-dibutyryladenosine 3′,5′-cyclic monophosphate
Extracellular signal-regulated kinase 1
FGR proto-oncogene, Src family tyrosine kinase
Germinal centre kinase III
Glycogen synthase kinase 3β
Insulin tolerance test
c-Jun N-terminal Kinase
Glucose disappearance rate
N-MYC downstream regulated gene 1
Protein kinase A
Pyruvate tolerance test
Small hairpin (RNA)
Ste20/oxidant stress response kinase 1
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