Linking aerobic fitness, nonalcoholic fatty liver disease and the metabolic syndrome

The incidence of obesity and associated metabolic diseases are on the rise and lifestyle factors including physical inactivity and poor dietary choices are playing a causative role. Concurrently, the incidence of two relatively new diagnoses, nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome, are also increasing. It has been postulated that NAFLD is the hepatic manifestation of the metabolic syndrome, but emerging evidence suggests that fatty liver may be an initial event contributing to the development of the metabolic syndrome. This leads to further questions regarding NAFLD and the metabolic syndrome including: what factors predispose or cause the two conditions, and is there a unifying pathophysiology? This editorial will address these questions and present evidence that reduced physical activity and/or low aerobic fitness plays a prominent role in the development of NAFLD and the metabolic syndrome.

Reaven first described ‘syndrome X’ or the ‘insulin-resistance syndrome’ in 1988 as a cluster of interrelated metabolic abnormalities (insulin resistance, abdominal obesity, dyslipidemia and hypertension) that often coexist and work in synergy to increase the risk for cardiovascular disease (CVD) [1]. Since then, ‘metabolic syndrome’ has become the standard unifying term for the condition and differing clinical diagnoses have been developed by health organizations. There is strong evidence that the presence of the metabolic syndrome increases risk for Type 2 diabetes and CVD (reviewed in [2]); therefore, it is alarming that approximately 25% of the American adult population have the metabolic syndrome.

Nonalcoholic fatty liver disease is a progressive disease with a histological spectrum ranging from hepatic steatosis (excess fat storage in the liver) to nonalcoholic steatohepatitis, advanced fibrosis and cirrhosis. Once hepatic steatosis is present, inflammation and oxidative stress are thought to promote the progression of NAFLD to include nonalcoholic steatohepatitis, fibrosis and necrosis [3,4]. As stated previously, NAFLD is intimately linked to the metabolic syndrome, with approximately 90% of patients with NAFLD having one or more characteristics of the metabolic syndrome [2]. As with the metabolic syndrome, NAFLD statistics are staggering. It is estimated that approximately one third of all US adults (90 million) have fatty livers, with prevalence rates as high as 75–100% in the obese and morbidly obese [2].

Accumulating evidence suggests that we have engineered physical activity out of our normal daily living activity. We and others believe that physical inactivity is a primary cause of obesity and associated metabolic diseases [2,5,6]. The CDC estimate that 25% of US adults are completely inactive in their leisure time, and it has been shown that the lack of regular exercise or physical inactivity is an ‘actual cause of death’ [7]. It is largely underappreciated that low aerobic fitness (also called aerobic capacity), independent of physical activity levels, BMI or other risk factors, is the best overall predictor of early mortality [8,9]. Physical inactivity leads to low aerobic fitness while regular exercise will improve or maintain aerobic fitness. In the absence of regular exercise, up to 70% of the variation in intrinsic aerobic fitness is genetic. Low aerobic fitness has been strongly linked to the development of Type 2 diabetes [10] and CVD [8] and, most recently, to NAFLD [11–14]. These studies collectively suggest that low aerobic fitness has a direct negative impact on hepatic metabolism or on peripheral factors (insulin resistance or visceral adiposity) that lead to fatty liver. We have recently gained mechanistic insight into these observations by studying two rodent models of NAFLD that allow us to dissect the impact of daily exercise and aerobic fitness on NAFLD and the metabolic syndrome. These models are the Otsuka Long-Evans Tokushima fatty (OLETF) rats, which are studied in the absence or presence of daily exercise, and the high- and low-capacity running (HCR and LCR) rats, which possess intrinsically high or low aerobic fitness in a sedentary condition.

The OLETF rats are hyperphagic (due to spontaneous mutation), become obese and develop insulin resistance, Type 2 diabetes, the metabolic syndrome and NAFLD. However, when young OLETF rats are allowed to exercise on voluntary running wheels, each of these detrimental phenomena and the other components of the metabolic syndrome can be prevented [15–17]. Utilizing this model, we have found that daily exercise also enhances hepatic mitochondrial function and hepatic fatty acid oxidation and suppresses key molecules involved in hepatic de novo lipogenesis [17]. Furthermore, when voluntary running was stopped for 7 days by locking the running wheels, we found that the beneficial effects of daily exercise declined rapidly, as demonstrated by a decrease in complete hepatic fatty acid oxidation, a loss of hepatic mitochondrial enzyme activity, a dramatic increase in proteins that drive de novohepatic fatty acid synthesis and evidence that central adiposity and metabolic syndrome characteristics were appearing [15]. These findings strongly support our contention that a sedentary lifestyle increases susceptibility, or in fact may be necessary for the development of NAFLD and the metabolic syndrome. Importantly, the OLETF findings are clinically significant, as these animals slowly develop obesity and insulin resistance in a similar pattern to sedentary obese humans.

Our second rodent model for studying NAFLD is the HCR/LCR rats, which were created by Steve Britton and Lauren Koch. These animals were selectively bred over several generations for high- and low-endurance running, resulting in two divergent strains with grossly different intrinsic endurance exercise capacities (∼sevenfold different) and aerobic fitness (∼30% difference) [18]. In a paper published in Science, Wisloff et al. showed that the sedentary LCR rats displayed a higher incidence of both CVD and metabolic syndrome risk factors than sedentary HCR rats [18]. The strengths of the model are that the contrasting aerobic capacities occur in a sedentary condition (cage only activity), avoiding the influence of exercise [18], and the strains develop polygenic phenotypes as opposed to single gene mutations like many transgenic animal models. Skeletal muscle mitochondrial oxidative capacity, which is high in the muscle of HCR and low in the LCR rats, was hypothesized to be the primary cause of the metabolic differences between strains. We sought to also investigate whether low aerobic capacity was linked to impaired hepatic metabolism and steatosis development. Indeed, hepatic mitochondrial content, function and fatty acid oxidation were significantly reduced in the LCR rats compared with the HCR rats [19]. These reductions in the LCR rats were associated with hepatic steatosis and lipid peroxidation at an early age, and elevated markers of liver injury at the time of natural death, findings not observed in the HCR rat [19]. The LCR rats also developed characteristics of the metabolic syndrome, including increased abdominal fat, hyperinsulinemia, hyperlipidemia and hypertension. These findings provide a possible mechanistic link between low aerobic fitness and increased liver fat levels observed in humans, and lead us to speculate that lower intrinsic aerobic capacity leads to reduced hepatic mitochondrial function and increases susceptibility to NAFLD and the metabolic syndrome.

So what is the link between NAFLD and the metabolic syndrome? As stated previously, NAFLD and the metabolic syndrome often occur in tandem and are both believed to be triggered by physical inactivity, dietary overconsumption and/or low aerobic capacity. Our hypothesis is that metabolic dysfunction in the liver is a central mediator in the development of the metabolic syndrome, as it contributes to three out of the five National Cholesterol Expert Program Adult Treatment Panel (NCEP ATP) III metabolic syndrome risk factors (altered blood lipids [low HDL-C and high fasting triglycerides] and fasting blood glucose). The next question is what causes fatty liver disease, and how does low aerobic fitness or physical inactivity play a role? We hypothesize that physical inactivity combined with dietary overconsumption leads to insulin resistance in skeletal muscle, requiring hyperinsulinemic responses to properly dispose of glucose in daily postprandial conditions. Under these conditions, we postulate that the phenotype of the liver drives subsequent metabolic complications. Elevated hepatic mitochondrial content and oxidative capacity due to exercise and/or high aerobic fitness likely protect the liver from fat storage by preferentially oxidizing circulating fatty acids or by increasing triglyceride turnover. This would further prevent liver-derived metabolic syndrome risk factors from increasing. By contrast, under conditions of low aerobic capacity or physical inactivity, the liver will display susceptibility to hyperinsulinemia, lipid synthesis and storage will overcome rates of oxidation, and hepatic steatosis will likely ensue. With reduced oxidative capacity, steatosis will then contribute to the increased production of atherogenic lipid products (very low-density lipoprotein triglycerides and cholesterol). In addition, the steatotic liver becomes insulin resistant and unable to suppress hepatic glucose production, which leads to increased gluconeogenesis and a feed-forward worsening of hyperinsulinemia. These conditions will collectively exacerbate the metabolic syndrome condition. Therefore, we believe that peripheral insulin resistance and hyperinsulinemia may serve as a trigger, but the metabolic phenotype of the liver predicts protection or susceptibility to the complications that follow.

Our recently published studies provide solid evidence that physical inactivity and low aerobic capacity are associated with a hepatic phenotype characterized by reduced mitochondrial content and oxidative capacity. We postulate that this leads to a greater susceptibility to NAFLD and the metabolic syndrome. By contrast, high aerobic fitness or physical activity protects against NAFLD and metabolic syndrome. Future work is needed to confirm these findings, including the examination of contrasting hepatic phenotypes described here in isolated cell culture systems, eliminating the impact of other circulating factors. In addition, complementary in vivo studies designed to investigate the muscle–liver–adipose tissue axis in response to inactivity or exercise is needed. In conclusion, clinical measurement of aerobic fitness or monitoring of physical activity levels may serve as a valuable prognostic tool for susceptibility to NAFLD and the metabolic syndrome. More importantly, because exercise training and/or increased physical activity is the proven method to increase aerobic fitness, and because it positively improves the metabolic function of multiple tissues, it should remain the cornerstone therapy for preventing and treating both NAFLD and the metabolic syndrome.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.