title: Exercise training decreases mitogen-activated protein kinase phosphatase-3 expression and suppresses hepatic gluconeogenesis in obese mice.
abstract: Insulin plays an important role in the control of hepatic glucose production. Insulin resistant states are commonly associated with excessive hepatic glucose production, which contributes to both fasting hyperglycaemia and exaggerated postprandial hyperglycaemia. In this regard, increased activity of phosphatases may contribute to the dysregulation of gluconeogenesis. Mitogen-activated protein kinase phosphatase-3 (MKP-3) is a key protein involved in the control of gluconeogenesis. MKP-3-mediated dephosphorylation activates FoxO1 (a member of the forkhead family of transcription factors) and subsequently promotes its nuclear translocation and binding to the promoters of gluconeogenic genes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In this study, we investigated the effects of exercise training on the expression of MKP-3 and its interaction with FoxO1 in the livers of obese animals. We found that exercised obese mice had a lower expression of MKP-3 and FoxO1/MKP-3 association in the liver. Further, the exercise training decreased FoxO1 phosphorylation and protein levels of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and gluconeogenic enzymes (PEPCK and G6Pase). These molecular results were accompanied by physiological changes, including increased insulin sensitivity and reduced hyperglycaemia, which were not caused by reductions in total body mass. Similar results were also observed with oligonucleotide antisense (ASO) treatment. However, our results showed that only exercise training could reduce an obesity-induced increase in HNF-4α protein levels while ASO treatment alone had no effect. These findings could explain, at least in part, why additive effects of exercise training treatment and ASO treatment were not observed. Finally, the suppressive effects of exercise training on MKP-3 protein levels appear to be related, at least in part, to the reduced phosphorylation of Extracellular signal-regulated kinases (ERK) in the livers of obese mice.
authors.affiliation: School of Applied Science, University of Campinas (UNICAMP), Limeira, São Paulo, Brazil. eduardoropelle@gmail.com.
authors.forename: Luciana Santos
authors.initials: LS
authors.lastname: Souza Pauli
authors.forename: Eloize Cristina Chiarreotto
authors.initials: EC
authors.lastname: Ropelle
authors.forename: Claudio Teodoro
authors.initials: CT
authors.lastname: de Souza
authors.forename: Dennys Esper
authors.initials: DE
authors.lastname: Cintra
authors.forename: Adelino Sanchez Ramos
authors.initials: AS
authors.lastname: da Silva
authors.forename: Bárbara
authors.initials: B
authors.lastname: de Almeida Rodrigues
authors.forename: Leandro Pereira
authors.initials: LP
authors.lastname: de Moura
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Marinho
authors.forename: Vanessa
authors.initials: V
authors.lastname: de Oliveira
authors.forename: Carlos Kiyoshi
authors.initials: CK
authors.lastname: Katashima
authors.forename: José Rodrigo
authors.initials: JR
authors.lastname: Pauli
authors.forename: Eduardo Rochete
authors.initials: ER
authors.lastname: Ropelle
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D054642:Dual Specificity Phosphatase 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005943:Gluconeogenesis / Q000502:physiology*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D020319:Oligodeoxyribonucleotides, Antisense; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse