Currently there are no medications or modalities to reduce
Currently, there are no medications or modalities to reduce both visceral adiposity as well as chronic inflammation in MS or T2DM subjects. Recently, we (Morino et al., 2008a; Adachi et al., 2010) and others (Chung et al., 2008; Gupte et al., 2009) have shown that the beneficial metabolic advantages of heat shock response (HSR) activation, which appears to mainly involve heat shock protein (HSP) 72. HSP72 induction by mild electrical stimulation (MES) with heat shock (HS) (Morino et al., 2008a; Kondo et al., 2012), a transgenic system (Chung et al., 2008), heat treatment (Gupte et al., 2009; Kavanagh et al., 2011) or chemical inducers (Adachi et al., 2010) ameliorated abnormal metabolic features in animal models of T2DM, such as insulin resistance, hyperglycemia and visceral fat accumulation. Mild electrical stimulation enhances heat induction of HSP72 (Morino et al., 2008b) and may directly activate insulin signaling by modulating the insulin receptor localization of membrane components (Yano et al., 2010; Morino-Koga et al., 2013). In this study, we investigated the effects of MES+HS on purchase AZD4547 homeostasis, insulin resistance, visceral adiposity and inflammatory cytokine levels in male subjects with MS or T2DM. In addition, inflammatory characteristics of circulating monocytes were examined. This novel combination therapy may provide an additional treatment strategy to improve metabolic abnormalities in lifestyle-related diseases.
Materials and Methods
Discussion Obesity due to sedentary lifestyle and/or unbalanced diet causes lifestyle-related diseases such as MS or T2DM, characterized by elevated blood glucose, often accompanied by dyslipidemia and hypertension with chronic inflammation resulting from an over-accumulation of visceral fat (Alberti et al., 2005). In this study, we demonstrated that MES+HS, which activates the heat shock response (Morino et al., 2008a; Kondo et al., 2012), significantly improved visceral adiposity, insulin resistance, glucose homeostasis and cytokine levels in males with MS or T2DM. MES+HS treatment significantly improved insulin resistance in subjects with MS or T2DM. Particularly in T2DM, we have identified significant improvements in HbA1c, FPG, postprandial glucose excursion and insulin resistance. More than half of the T2DM subjects achieved HbA1c less than 7.0%. Insulin resistance is a central feature of these MS and T2DM, and impaired insulin signaling may be associated with attenuated HSP72 production (Bruce et al., 2003; Kurucz et al., 2002). HSP72 is a cytoplasmic molecular chaperone, which is induced by several stimuli such as heat shock, viral infection or heavy metal contamination etc., and protects cells from apoptosis or cellular dysfunction caused by such cell stresses (Hooper et al., 2014). Phosphorylation of GSK-3β blocks the GSK-3 inactivation of HSF-1 and thereby increases activity of HSF-1 (Hooper et al., 2014). It is known that HSP72 inhibits JNK activity, resulting in the attenuation of inflammatory signals. However, chronic activation of stress signals down-regulates HSP72 levels through insulin resistance, and results in further activation of inflammatory milieu. This vicious metabolic cycle characterized by systemic inflammation, impaired insulin signaling and attenuated HSR is proposed to occur in MS and T2DM (Hooper, 2009). These components could be improved by the activation of HSR. Indeed, induction of HSP72 by several modalities such as MES+HS, whole-body hyperthermia, muscle-specific HSP72 overexpression, and HSP inducers has been shown to improve insulin signaling in mice, monkeys and humans (Morino et al., 2008a; Adachi et al., 2010; Chung et al., 2008; Kondo et al., 2012; Kavanagh et al., 2011; Literati-Nagy et al., 2009). The beneficial effects of HSP72 in insulin signaling may be partly explained by the suppression of JNK (Chung et al., 2008). Deletion of JNK1 protects mice from high-fat diet-induced insulin resistance, in part through decreased adiposity. Indeed, suppression of JNK in diabetic mice ameliorates insulin resistance and glucose intolerance (Kaneto et al., 2004). It has also been reported that an HSP72 polymorphism is linked to increased obesity and diabetes risk in humans (Zouari Bouassida et al., 2004). Induction of HSP72 enhances mitochondrial capacity and/or function (Chung et al., 2008; Henstridge et al., 2014), and suppresses JNK activity (Morino et al., 2008a; Kondo et al., 2012). In addition, uncoupling protein-1 mRNA expression in brown adipose tissue was increased in MES+HS-treated diabetic animals (Morino et al., 2008a). Moreover, MES+HS treatment activates AMPK in mice (Kondo et al., 2012). In fact, AMPK α1 knockouts showed increased visceral adiposity with insulin resistance (Zhang et al., 2012). As we have identified the activation of AMPK in monocytes, this may contribute to reduce visceral adiposity. In addition, testosterone treatment ameliorates metabolic abnormalities, including adipocyte hypertrophy, adipose tissue dysfunction, tissue hypoxia and insulin resistance (Maneschi et al., 2012). Heat treatment activates androgen effect especially in lipid peroxidation, indicating that activation of androgen signal through HSR activation may also participate in the beneficial effects of MES+HS. These mechanisms may participate in the reduction of visceral adiposity by MES+HS treatment, which need further investigation.