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Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.

Journal article
Authors Emmelie Cansby
Manoj Amrutkar
Louise Mannerås Holm
Annika Nerstedt
Azadeh Reyahi
Elin Stenfeldt
Jan Borén
Peter Carlsson
Ulf Smith
Juleen R Zierath
Margit Mahlapuu
Published in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume 27
Issue 9
Pages 3660-3671
ISSN 1530-6860
Publication year 2013
Published at Wallenberg Laboratory
Department of Chemistry and Molecular Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 3660-3671
Language en
Links dx.doi.org/10.1096/fj.13-228494
Keywords serine/threonine protein kinase 25, type 2 diabetes, metabolic balance
Subject categories Medical cell biology, Cell and Molecular Biology

Abstract

Partial depletion of serine/threonine protein kinase 25 (STK25), a member of the Ste20 superfamily of kinases, increases lipid oxidation and glucose uptake in rodent myoblasts. Here we show that transgenic mice overexpressing STK25, when challenged with a high-fat diet, develop reduced glucose tolerance and insulin sensitivity compared to wild-type siblings, as evidenced by impairment in glucose and insulin tolerance tests as well as in euglycemic-hyperinsulinemic clamp studies. The fasting plasma insulin concentration was elevated in Stk25 transgenic mice compared to wild-type littermates (4.9±0.8 vs. 2.6±0.4 ng/ml after 17 wk on high-fat diet, P<0.05). Overexpression of STK25 decreased energy expenditure during the dark phase of observation (P<0.05), despite increased spontaneous activity. The oxidative capacity of skeletal muscle of transgenic carriers was reduced, as evidenced by altered expression of Cpt1, Acox1, and ACC. Hepatic triglycerides and glycogen were elevated (1.6- and 1.4-fold, respectively; P<0.05) and expression of key enzymes regulating lipogenesis (Fasn), glycogen synthesis (Gck), and gluconeogenesis (G6pc, Fbp1) was increased in the liver of the transgenic mice. Our findings suggest that overexpression of STK25 in conditions of excess dietary fuels associates with a shift in the metabolic balance in peripheral tissues from lipid oxidation to storage, leading to a systemic insulin resistance.-Cansby, E., Amrutkar, M., Mannerås Holm, L., Nerstedt, A., Reyahi, A., Stenfeldt, E., Borén, J., Carlsson, P., Smith, U., Zierath, J.R., Mahlapuu, M. Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.

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