Diabetologia

, Volume 60, Issue 12, pp 2453–2462 | Cite as

The MST3/STK24 kinase mediates impaired fasting blood glucose after a high-fat diet

  • Cristina Iglesias
  • Ebel Floridia
  • Miriam Sartages
  • Begoña Porteiro
  • María Fraile
  • Ana Guerrero
  • Diana Santos
  • Juan Cuñarro
  • Sulay Tovar
  • Rubén Nogueiras
  • Celia M. Pombo
  • Juan Zalvide
Article

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

MST3 inhibits the insulin signalling pathway and is important in the development of insulin resistance and impaired blood glucose levels after an HFD.

Keywords

G6PC GCKIII kinases Gluconeogenesis Impaired fasting glucose Insulin resistance 

Abbreviations

Akt

Akt serine/threonine kinase

AMPK

AMP-activated protein kinase

dbcAMP

N6,2′-O-dibutyryladenosine 3′,5′-cyclic monophosphate

ERK1

Extracellular signal-regulated kinase 1

FGR

FGR proto-oncogene, Src family tyrosine kinase

FOX

Forkhead box

GAPDH

Glyceraldehyde-3-phospate dehydrogenase

GCKIII

Germinal centre kinase III

GSK3β

Glycogen synthase kinase 3β

HFD

High-fat diet

IR

Insulin receptor

ITT

Insulin tolerance test

JNK

c-Jun N-terminal Kinase

KITT

Glucose disappearance rate

MST

Mammalian sterile-20

NDRG1

N-MYC downstream regulated gene 1

PI3K

Phosphoinositide 3-kinase

PKA

Protein kinase A

PTT

Pyruvate tolerance test

shNT

Non-targeting shRNA

sh(RNA)

Small hairpin (RNA)

SOK1

Ste20/oxidant stress response kinase 1

Ste20

Sterile-20

STK

Serine–threonine kinase

WT

Wild-type

Supplementary material

125_2017_4433_MOESM1_ESM.pdf (7.7 mb)
ESM(PDF 7839 kb)

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular e Enfermedades Crónicas (CIMUS), Instituto de Investigación Sanitaria de Santiago (IDIS)Universidade de Santiago de CompostelaSantiago de CompostelaSpain
  2. 2.CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)Santiago de CompostelaSpain
  3. 3.Cell Proliferation Group, MRC Clinical Sciences CentreImperial College LondonLondonUK

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