Exercise training decreases mitogen‐activated protein kinase phosphatase‐3 expression and suppresses hepatic gluconeogenesis in obese mice

Abstract

Key points summaryr When the hepatic insulin signaling is compromised, there is an inadequate suppression of gluconeogenic pathways, leading the organism to high levels of glucose.r Studies with animals with obesity induced by high fat diet or genetically modified showed increased MKP-3 expression and MKP-3/Foxo1 association in liver, with a consequent increase in blood glucose concentration, development of insulin resistance and DM2.r As a non-pharmacological strategy recognized and indicated for prevention and treatment of diabetes is the regular practice of physical exercise.r In this study we demostrated that physical training is an important tool capable of reducing insulin resistance in the liver by reducing the inflammatory process, including the inhibition of MKP-3 and, therefore, suppress gluconeogenic program in obesity rats.r The understanding of these new mechanisms by which physical training regulates glucose homeostasis has critical importance to health professionals for the understanding and prevention of diabetes.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...

Acute exercise restores insulin clearance in diet-induced obese mice

“…Based on these results, we propose that the increased insulin clearance and IDE activity, in skeletal muscle, may be an additional mechanism, whereby acute exercise reduces plasma insulin levels in obese mice. In DIO rodents, reduced insulinemia following exercise has been reported (Chiarreotto- Ropelle et al 2013, Souza Pauli et al 2014. Here, by analyzing insulin secretion in isolated islet from DIO + EXE mice, we confirm that the secretion was reduced (Fig.…”

“…This amelioration involves mechanisms such as reduction in the inflammatory state (Handschin & Spiegelman 2008), decreased phosphatase expression and activity (Khadir et al 2014, Souza Pauli et al 2014, and increased mitochondrial capacity (Joseph & Hood 2014). Endurance exercisemediated reduction in insulinemia is explained, at least in part, by a decrease in insulin secretion (Aarnio et al 2001).…”

Short-term strength training reduces gluconeogenesis and NAFLD in obese mice

“…The reduction of hepatic lipogenesis in the STO group was linked to increased hepatic insulin sensitivity and reduced HGP. Previous studies have found lower glycemic values during the ipPTT for obese mice that swam for 8 weeks compared to the sedentary control group (Marinho et al 2012, Souza Pauli et al 2014). Nevertheless, both aerobic training and the acute aerobic session can improve hepatic insulin sensitivity (de Moura et al 2013, Muñoz et al 2018.…”

Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia

“…binding of PGC-1α and HNF4A to well-characterized cis-elements on the promoters of Pck1 and G6pc (3,4). Consistent with impaired insulin-mediated suppression of HGP in T2D, the expression of Hnf4a, Pck1, and G6pc was increased in the liver of multiple animal models of diabetes (5)(6)(7).…”