Increased production of pro inflammatory cytokines is
Increased production of pro-inflammatory cytokines is associated with impaired lck inhibitor sensitivity (Tamakoshi et al., 2003). We previously reported that activation of the HSR by MES+HS in diabetic mice was associated with metabolic benefits, accompanied by improvements in inflammatory cytokine productions (Morino et al., 2008a). In this study, we observed similar cytokine changes in human subjects with MS and T2DM. Although this may be partly explained by the reduction in visceral adiposity, we also reported significant reductions in CRP and TNF-α levels by MES+HS in healthy subjects without any body composition changes (Kondo et al., 2010). These results suggest a possible direct association between HSR activation and suppression of systemic inflammation. High serum CRP levels are associated with reduced HSP72 levels (Armutcu et al., 2008), and are positively regulated by NF-κB, which can be attenuated by HSP72. Indeed, we observed a significant increase in HSP72 with reduction of NF-κB nuclear accumulation in monocytes after MES+HS treatment. HSP72 also decreases TNF-α levels by suppression of NF-κB as well. Therefore, induction of HSP72 by MES+HS could decrease inflammatory cytokines through suppression of NF-κB activation. It is also possible that an anti-inflammatory effect of MES+HS could be achieved by AMPK activation, because AMPK α1 deficiency in macrophages markedly increases the pro-inflammatory status (Zhang et al., 2012). As chronic activation of inflammatory status is associated with atherogenesis, anti-inflammatory effect of MES+HS may contribute to limit future vascular complications.
Because visceral fat produces angiotensinogen and increases sympathetic nervous activity, MS and T2DM are often associated with hypertension. In this regard, reduction in blood pressure as a result of MES+HS treatment could be explained, at least in part, by a reduction in visceral adiposity. Recently, it has been shown that heat treatment in high fat-fed mice augmented angiotensin (Shichiri et al., 2000; Alberti et al., 2005; Ohman et al., 2009; Tamakoshi et al., 2003; Morino et al., 2008a; Adachi et al., 2010; Chung et al., 2008), which counteracts against angiotensin II, through Mas receptor/eNOS axis that may improve blood pressure and endothelial dysfunction (Karpe and Tikoo, 2014). Therefore, both reductions in visceral fat and eNOS activation may contribute to ameliorate hypertension upon MES+HS treatment.
Hepatic steatosis is considered to be one of the phenotypes of lifestyle-related diseases. Our results indicate that activation of the HSR by MES+HS improved surrogate markers of fatty liver. Although precise interaction between HSR activation and improvement of fatty liver is still unknown, naringin, a bioflavonoid isolated from grapefruit, activates HSP72 and attenuates hepatic steatosis (Sharma et al., 2011). Alternatively, endoplasmic reticulum (ER) stress attenuation by HSR activation may be involved in this process, because HSP72 enhances ER capacity, and hepatic lipid accumulation is correlated with ER stress (Gupta et al., 2010).
The molecular mechanisms involved in metabolic benefits of MES+HS appear to be similar to those observed in exercise, particularly in HSP72 induction and AMPK activation (Zhang et al., 2009). Indeed, 8weeks of endurance training in diabetic rats increased HSP72 expression (Atalay et al., 2004). It is also proposed that HSR activators share metabolic pathways associated with exercise with activation of AMPK (Hooper et al., 2014).
Thus, MES+HS treatment may mimic exercise training sharing with similar mechanisms and results.
Conclusion MES+HS treatment exerts anti-visceral obesity, anti-hypertensive, anti-diabetic and anti-inflammatory effects with no harmfulness, possibly through HSP72 induction and AMPK activation. Moreover, it can also be used in physically handicapped or bed-ridden patients who are unable to follow an exercise regimen. MES+HS could be analogous to exercise training in terms of HSP72 induction and AMPK activation, and might confer additional benefits, such as anti-atherogenic effect. HSR activation by physical MES+HS system may be an alternative and beneficial therapeutic approach to the treatment of lifestyle-related diseases.