On the other hand, both VIT and MIT interventions during the second half of the 16-wk HFD course resulted in a protective effect against the NAFLD outcomes. HFD + VIT and HFD + MIT mice had significantly lower body and liver weight, lower body-to-liver mass ratios, lower serum levels of NEFA, TC, glucose, insulin, ALT, leptin, and lower AUC for GTT and ITT than HFD mice (Table 1 and Fig. 2A). HFD + VIT and HFD + MIT mice also had significantly lower hepatic TAG content and less hepatic steatosis than those of HFD mice that did not undergo VIT or MIT (Fig. 2B and C). Interestingly, HFD + VIT mice had significantly lower TAG contents and less hepatic steatosis in conjunction with lower serum levels of TC and glucose than those of HFD + MIT mice (Table 1 and Fig. 2A), suggesting that the protective effect of exercise training against HFD-induced hepatic steatosis is in an intensity-dependent manner.
VIT confers a protective effect against HFD-related hypoadiponectinemia and downregulation of hepatic AdipoR2 to a greater extent than MIT
HFD mice had significantly lower levels of CCAAT/enhancer-binding protein (C/EBP) α—a key transcription factor for full activation of adiponectin gene in mature adipose tissue—messenger RNA (mRNA), adiponectin mRNA, and protein expression in adipose tissue (Fig. 3B) and lower levels of serum total and HMW adiponectin (Fig. 3A) in conjunction with lower levels of AdipoR2 mRNA and protein expression in the liver (Fig. 3C and D) than those of SCD mice, suggesting that chronic exposure to HFD resulted in hypoadiponectinemia and downregulation of hepatic AdipoR2 expression.
On the other hand, the VIT and MIT interventions during the second half of the 16-wk HFD course resulted in a protective effect against hypoadiponectinemia and downregulation of the AdipoR2 signaling pathway in the liver. HFD + VIT and HFD + MIT mice had significantly higher adipose tissue adiponectin mRNA and protein expression and higher serum total and HMW adiponectin in conjunction with higher hepatic AdipoR2 mRNA and protein expression than those of HFD mice. In addition, HFD + VIT mice had significantly higher adipose tissue C/EBPα mRNA, higher adipose tissue adiponectin mRNA and protein expression, higher serum levels of total and HMW adiponectin, and higher hepatic AdipoR2 mRNA and protein expression than those of HFD + MIT mice (Fig. 3A–D), suggesting that the protective effect of exercise training against hypoadiponectinemia and downregulation of the hepatic AdipoR2 signaling pathway secondary to HFD is in an intensity-dependent manner.
VIT confers a protective effect against HFD-related dysregulation of hepatic AdipoR2 downstream targets to a greater extent than MIT
HFD mice had significantly lower levels of pAMPK/AMPK ratio, SIRT1 mRNA and protein expression, pACC/ACC ratio, and glycogen contents in the liver than SCD mice (Fig. 4A–C). HFD mice also had significantly lower hepatic mRNA levels of PPARα, CPT1a, Cyp4a10, Cyp2e1, NRF, Tfam, Cox4i1, and Irs2 (Fig. 4D) in conjunction with significantly higher hepatic mRNA levels of SREBP1c, FAS, CD36, and lipin1 (Fig. 4E) than those of SCD mice, suggesting that chronic exposure to HFD results in dysregulation of downstream targets of the adiponectin-AdipoR2 signaling pathway in the liver that are associated with fatty acid oxidation and/or mitochondrial biogenesis as well as de novo lipogenesis and/or TAG accumulation.
On the other hand, both VIT and MIT interventions during the second half of the 16-wk HFD course resulted in a protective effect against HFD-related dysregulation of the adiponectin-AdipoR2 downstream targets in the liver. HFD + VIT and HFD + MIT mice had significantly higher hepatic protein expression of SIRT1 and higher hepatic mRNA levels of PPARα, CPT1a, Cyp2e1, and Irs2 in conjunction with significantly lower hepatic glycogen and lower hepatic mRNA levels of SREBP1c, FAS, CD36, and lipin1 than those of HFD mice (Fig. 4B–D). In particular, HFD + VIT mice had significantly higher levels of pAMPK/AMPK ratio, SIRT1 mRNA and protein expression, and p-ACC/ACC ratio in the liver along with lower hepatic glycogen contents than HFD + MIT mice (Fig. 4A and B). In addition, HFD + VIT mice had significantly higher hepatic mRNA levels of PPARα, CPT1a, Irs2, and Cox4i1 (Fig. 4C) in conjunction with significantly lower hepatic mRNA levels of FAS, CD36, and lipin1 (Fig. 4D) than HFD + MIT mice, suggesting that the protective effect of exercise training against HFD-related dysregulation of the adiponectin-AdipoR2 downstream targets in the liver is in an intensity-dependent manner.
VIT confers a protective effect against HFD-related upregulation of hepatic NF-κB signaling pathway to a greater extent than MIT
HFD mice had significantly higher serum levels of TNF-α and IL-6, higher hepatic TBARS levels, higher hepatic nuclear NF-κB p65 protein in conjunction with significantly higher hepatic mRNA levels of lgals3, ly6d, timp1, and col1a1 than those of SCD mice (Fig. 5A–F), suggesting that chronic exposure to HFD results in upregulation of the NF-κB signaling pathway in the liver that is associated with inflammation and/or fibrosis.
On the other hand, both VIT and MIT interventions during the second half of the 16-wk HFD course resulted in a protective effect against HFD-related upregulation of the hepatic NF-κB signaling pathway (Fig. 5A). HFD + VIT and HFD + MIT mice had significantly lower serum levels of TNF-α and IL-6, lower hepatic TBARS levels, and lower hepatic nuclear NF-κB p65 protein than those of HFD mice (Fig. 5B–E). Interestingly enough, HFD + VIT mice had significantly lower serum levels of TNF-α and IL-6, lower hepatic TBARS levels, and lower hepatic nucleus NF-κB p65 protein expression in conjunction with higher cytosolic IκBα protein expression than those of HFD + MIT mice (Fig. 5B–E). In addition, HFD + VIT mice had significantly lower hepatic mRNA levels of lgals3, ly6d, timp1, and col1a1 than those of HFD + MIT mice (Fig. 5F), suggesting that the protective effect of exercise training against upregulation of the NF-κB downstream targets in the liver is in an intensity-dependent manner.
In this study, we found that mice fed with HFD for a period of 16 wk developed obesity, dyslipidemia, hyperglycemia and hyperinsulinemia, impaired whole body insulin sensitivity, elevated expression of markers for the liver damage, and histology-based hepatic steatosis. In particular, hypoadiponectinemia and downregulation of hepatic AdipoR2 and its downstream targets as well as upregulation of hepatic NF-κB and its downstream targets were observed concurrently with these NAFLD outcomes. Together, the current findings suggested that chronic exposure to HFD results in reduced oxidation of fatty acids and/or mitochondrial biogenesis (27) as well as enhanced de novo lipogenesis and/or TAG accumulation in the liver (51), collectively contributing to the development of hepatic steatosis in conjunction with an obese and impaired glucose homeostasis in C57B/6 mice. The current findings also suggested that chronic exposure to HFD may enhance the severity of NAFLD by activating the NF-κB signaling pathway and/or suppressing the adiponectin-AdipoR2 signaling pathway in the liver (26,39).
To study the effectiveness of exercise training intensity on the NAFLD outcomes associated with HFD, VIT and MIT were introduced during the second half of the 16-wk HFD regimen. We are the first to report that although both VIT and MIT were effective at alleviating hepatic steatosis as well as the obese and impaired glucose tolerance phenotype, the therapeutic effect of exercise training against hepatic steatosis was in an intensity-dependent manner. In addition, we find that the intensity-dependent protective effect of exercise training against hepatic steatosis was associated with greater activation on hepatic AMPK and its downstream targets as well as greater suppressive effect on hypoadiponectinemia, downregulation of hepatic AdipoR2, and dysregulation of its downstream targets as well as upregulation of NF-κB–associated proteins in the liver compared with those in MIT.
AMPK is activated in the liver by metabolic changes imposed by acute and chronic nutritional stresses (17,48), leading to increased oxidation of fatty acids and simultaneous inhibition of hepatic de novo lipogenesis, cholesterol synthesis, and glucose production as well as enhanced expression of genes involved in mitochondrial biogenesis (17,48). In addition, HMW adiponectin has greater binding affinity for AdipoR2 in the liver. Signaling molecules activated by adiponectin include AMPK, p-38 MARK, and PPARα. Of them, AMPK acts as a major downstream component of adiponectin signaling (18). Together, the findings of this study suggest that there may be an exercise intensity threshold for enhancing gene expression associated with fatty acid oxidation and/or mitochondrial biogenesis (i.e., PPARα, CPT1a, Cyp4a10, Cyp2e1, and Cox4i1) in the liver (27) and for suppressing gene expression associated with de novo lipogenesis and/or TAG accumulation (i.e., SREBP1c, ACC, FAS, Irs2, CD36, and lipin1) (8) as well as inflammation and/or fibrosis (i.e., NF-κB, lgals3, ly6d, timp1, and col1a1) in the liver (3).
Our findings are consistent with the findings reported by Haram et al. (11). Haram et al. (11) compared the effectiveness of aerobic interval training versus continuous moderate-intensity exercise on the metabolic syndrome of rats artificially selected for low aerobic capacity. Both aerobic interval training and continuous moderate-intensity exercise were found to reduce cardiovascular risk factors associated with the metabolic syndrome and the magnitude of the suppressive effect was in an intensity-dependent manner, especially at improving insulin sensitivity in the liver, improving endothelial function in the aorta, and reducing uptake of free fatty acids and de novo lipogenesis in fat tissue. On the other hand, Linden et al. (25) investigated whether high-intensity and interval training was as effective as moderate-intensity and continuous exercise training at alleviating NAFLD outcomes in an obese and diabetic phenotype using Otsuka Long-Evans Tokushima fatty rats. In this study, both MIT and VIT were found to be effective at alleviating the metabolic complications of NAFLD, including simple hepatic steatosis, inflammation, and fibrosis. In contrast to our current findings, however, they did not find any significant intensity-dependent difference in the benefits of exercise training on NAFLD outcomes in this animal model.
Several explanations can be given for this discrepancy regarding the intensity-dependent benefit of exercise training at alleviating hepatic steatosis. First, differences in metabolic responses and/or adaptations to the training protocols might be an explanation for the discrepancy. We found that HFD + MIT and HFD + VIT mice had significant lower liver glycogen contents and higher hepatic p-AMPK/APMK ratios than those of HFD mice. However, Linden et al. (25) found no significant differences in liver glycogen contents or hepatic p-AMPK/AMPK ratios between the two training and control mice. Because exercise intensity may play a critical role in activating AMPK and thereby by magnifying oxidation of fatty acids and/or inhibition of TAG synthesis (4,6), the differences in activation of hepatic AMPK in response to exercise training may explain the discrepancy in the intensity-dependent benefit of exercise training against hepatic steatosis between the two studies.
Second, differences in severity of NAFLD outcomes between the different model systems, i.e., mice with an obese and impaired glucose tolerance phenotype versus rats with an obese and diabetic phenotype, may be another explanation for the observed discrepancy in the intensity-dependent benefit of exercise training
Third, we did not investigate the functional consequences of molecular markers associated with the intensity-dependent benefit of exercise training for NAFLD, including fatty acid oxidation, mitochondrial biogenesis, de novo lipogenesis, or TAG synthesis. This is also a limitation of the current study. Thus, more studies are necessary for drawing conclusions regarding the observed discrepancy.
Finally, our protocol to deliver exercise intensity was not based on calories expended but on distance covered. However, there is an inverse relation between exercise intensity and exercise economy due to increased dependence in Type II muscle fibers (16) or other reason(s) (52), implying the possibility that matching for distance covered does not necessarily mean matching for caloric expenditure. If so, we cannot rule out the possibility that the greater benefit for NAFLD observed in the HFD + VIT mice over the HFD + MIT mice might be due to a difference in energy expenditure rather than exercise intensity. And this is a limitation to the current study, which remains to be investigated in a future study.
AdipoR1 is primarily expressed in the testis, heart, and skeletal muscle, whereas AdipoR2 is highly expressed in the liver, testis, and small intestine (44). Levels of AdipoR1 and AdipoR2 mRNAs in the skeletal muscle and liver are increased by fasting and decreased by refeeding (44). Changes in the hepatic expression of AdipoR have been found in NAFLD and NASH. For example, decreased expression of AdipoR2 was found in the liver of patients with NAFLD (35), NASH, and patients with chronic hepatitis B and steatosis (20,35). Expression of both AdipoR1 and AdipoR2 was significantly decreased in the liver of obese fa/fa Zucker rats after exposure of these rats to a high-fat and high-cholesterol diet for 8 wk (26). By studying mice fed a methionine-deficient and choline-deficient diet, Tomita et al. (41) found that inhibition of hepatic AdipoR2 expression exacerbated NASH from the early stage (i.e., fatty liver) to the progression of inflammation and fibrosis and that enhancement of AdipoR2 expression improved NASH at each pathological stage. Yamauchi et al. (50) found that expression of AdipoR1 and AdipoR2 was significantly decreased in the liver of Lepr−/− mice, a genetic animal model of human obesity, compared with that in wild-type mice. These previous studies suggest that AdipoR1 and AdipoR2 are the predominant receptors for adiponectin in vivo in the liver and thereby play important roles in the regulation of glucose and lipid metabolism as well as inflammation and fibrosis associated with the pathology of NASH (41,50).
Consequently, strategies to enhance insulin-sensitizing actions of adiponectin, including replenishment of adiponectin, have been proven to improve and/or reverse metabolic complications associated with insulin resistance and the pathology of NAFLD and NASH. Administration of recombinant adiponectin increased glucose tolerance and insulin sensitivity by suppressing hepatic glucose production and significantly alleviated hepatomegaly, hepatic steatosis, and elevated serum ALT associated with NAFLD (49). Adiponectin receptors were also shown to inhibit inflammation by suppressing NF-κB in human umbilical vein endothelial cells (49). In addition, recent studies have begun to examine the potential roles of adiponectin in mediating insulin-sensitizing action, hepatic fatty acid oxidation, anti-inflammation, and anti-fibrosis of exercise training by investigating changes in tissue-specific expression of adiponectin receptors (18). A single bout of exercise increased the expression levels of AdipoR1 mRNA and decreased the expression levels of AdipoR2 mRNA in both the skeletal muscle and liver of healthy C57BL/6 mice (15). Binding of adiponectin to AdipoR2 not only enhances fatty acids oxidation but also suppresses inflammation and/or fibrosis via activation of AMPK and its downstream targets (30), which provides rationale for the greater protective effect of VIT against NAFLD, compared with that of MIT, observed in this study.
Under normal conditions, physical activity can increase the AMP-to-ATP ratio required to activate AMPK (4). In the skeletal muscle, AMPK is activated in an intensity-dependent manner such that it is acutely activated at exercise intensities above approximately 60% of maximal aerobic capacity (6). Likewise, administration of adiponectin has been shown to increase the phosphorylation of AMPK in the liver of both AdipoR1-knockout mice and control littermates (50). Increased activation of AMPK has been demonstrated in the liver following acute exercise (31) and long-term exercise (39), suggesting a role for hepatic AMPK in exercise training-induced hepatic adaptations.
Taken together, our observation that VIT induces a greater protective effect against hepatic steatosis associated with an obese and type 2 diabetic phenotype than MIT in an animal model suggests that there are intensity-dependent difference in the ability of exercise training to modulate adiponectin-mediated activation of AdipoR2 and its downstream signaling targets AMPK and SIRT1, which control energy metabolism, inflammation, and matrix deposition (33).
SIRT1, which is regulated by adiponectin-AdipoR2 and AMPK signaling in the liver, plays a key role in regulating hepatic energy metabolism (36). SIRT1 expression in the liver is significantly decreased in an NAFLD model of rats fed HFD (7) and in an NASH model of leptin-receptor deficient mice fed HFD (10), whereas moderate SIRT1 overexpression was shown to protect mice from developing NAFLD (14) and hepatic overexpression of SIRT1 reduced steatosis and glucose intolerance in obese mice (24). Together, these findings indicate that VIT, but not MIT, is a better lifestyle modification strategy that can be used to treat NAFLD via activation of hepatic SIRT1 and upregulation of target molecules associated with fatty acid oxidation and/or mitochondrial biogenesis as well as downregulation of target molecules associated with de novo lipogenesis and/or TAG accumulation, perhaps secondary to adiponectin-AdipoR2–mediated activation of AMPK.
Finally, hepatic oxidative stress is thought to be a key factor inducing hepatocyte injury and leading to the development of NASH. For example, overexpression of hepatic TNF-α has been found to decrease hepatic insulin sensitivity and induce hepatic inflammation and fibrosis in both patients with NASH (5) and an animal model (2). However, HFD-induced NASH was significantly attenuated by exercise in rats fed HFD (13). This exercise training-induced alleviation against NASH was found to be associated with a reduction in TNF-α mRNA in the adipose tissue (3) and the liver (51) of rats and a reduction of circulating TNF-α levels in rats (51). In addition, lipid peroxidation including the generation of reactive oxygen species, transforming growth factor-β, and TNF-α can be implicated as a cause of NASH (27). In this study, elevated hepatic TBARS along with increased serum TNF-α and IL-6 was found in HFD mice. Both MIT and VIT alleviated those elevated levels of liver injury markers, to a greater extent with VIT than with MIT. Consequently, our observations that 1) both HFD + MIT and HFD + VIT mice have significantly lower levels of serum TNF-α and IL-6, hepatic TBARS, and NF-κB–associated proteins and its downstream targets (i.e., lgals3, ly6d, timp1, col1a1) compared with those of HFD mice and 2) VIT suppresses the liver damage markers to a greater extent than MIT suggest that VIT is more effective at suppressing inflammation and retarding fibrosis progression in HFD-related fatty liver than MIT (23,42).
In summary, our study findings suggest that upregulation of the adiponectin-AdipoR2 signaling pathway and downregulation of the NF-κB signaling pathway in the liver may play key roles in mediating the intensity-dependent benefit of exercise training against NAFLD via enhanced fatty acid oxidation and/or mitochondrial biogenesis and suppressed de novo lipogenesis and/or TAG accumulation as well as anti-inflammation and/or antifibrosis in HFD-induced obese mice. This provides a rationale for promoting vigorous physical activity as a better nonpharmacological strategy against liver disease in clinical settings.
The National Research Foundation grant funded by the Korean government supported this work (NRF-2013S1A2A2034953).
The authors have no conflicts of interest to disclose.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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Keywords:© 2015 American College of Sports Medicine
PHYSICAL ACTIVITY; ADIPONECTIN SIGNALING; FATTY LIVER; METABOLIC COMPLICATIONS