title: Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet.
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.
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Blå stråket 5, SE-41345 Gothenburg, Sweden.
authors.forename: Emmelie
authors.initials: E
authors.lastname: Cansby
authors.forename: Manoj
authors.initials: M
authors.lastname: Amrutkar
authors.forename: Louise
authors.initials: L
authors.lastname: Mannerås Holm
authors.forename: Annika
authors.initials: A
authors.lastname: Nerstedt
authors.forename: Azadeh
authors.initials: A
authors.lastname: Reyahi
authors.forename: Elin
authors.initials: E
authors.lastname: Stenfeldt
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.forename: Peter
authors.initials: P
authors.lastname: Carlsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.forename: Margit
authors.initials: M
authors.lastname: Mahlapuu
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D002153:Calorimetry, Indirect; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099317:Hippo Kinases
chemical_list: D005947:Glucose; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C530661:Stk25 protein, mouse; D000099317:Hippo Kinases
keywords: metabolic balance; serine/threonine protein kinase 25; type 2 diabetes