The MST3/STK24 kinase mediates impaired fasting blood glucose after a high-fat diet
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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
We thank: all members of the MeMoEn Research Group for helpful discussions, and C. Diéguez (Departamento de Fisioloxía, Universidade de Santiago de Compostela, Spain) for critically reading the manuscript; D. Wu (Department of Vascular Biology and Therapeutic Program, Yale School of Medicine, USA) for advice on PCR genotyping; and P. Ramadoss (Beth Israel Deaconess Medical Center, USA), for the G6PC promoter plasmid.
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Financial support is gratefully acknowledged from: the Ministerio de Economía y Competitividad (SAF2011-24940 and SAF2014-56899-R and BFU2015-70664R); the Consellería de Cultura, Educación e Ordenación Universitaria (GPC2013/032, ED431B 2016, 2015-CP080 and 2016-PG057); the Astra Zeneca Foundation; the European Foundation for the Study of Diabetes; Centro Singular de Investigación de Galicia (accreditation 2016–2019, ED431G/05); the European Regional Development Fund (ERDF); and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds. CI and EF are recipients of a predoctoral contract from Xunta de Galicia; DS is recipient of an Erasmus plus fellowship, financed by the EU. JZ and CMP are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Duality of interests
The authors declare that there is no duality of interest associated with this manuscript.
CI, ST, RN, CMP and JZ made substantial contributions to conception and design of the study. CI, EF, MS, BP, MF, AG, DS, JC and ST contributed substantially to the acquisition of data. CI, ST, RN, CMP and JZ contributed substantially to the analysis and interpretation of data. ST, RN, CMP and JZ drafted the manuscript. All authors critically revised the manuscript for important intellectual content. All authors gave final approval of the version to be published. JZ and CMP are responsible for the integrity of the work as a whole.
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