Obesity is reaching epidemic proportions and is associated with a number of co-morbidities, including non-alcoholic fatty liver disease (NAFLD). In NAFLD, hepatic steatosis is intricately linked with a number of metabolic alterations. However, the pathophysiology of the disease is not fully understood and it is unclear whether whole-body and hepatic fat oxidation (Fatox) are altered in this patient population. Lifestyle intervention is the most commonly promoted therapy for NAFLD, but the specific effects of exercise training (EX) and energy restriction (ER) on whole-body substrate oxidation rates, histological and metabolic features of NAFLD are unknown. Determination of Fatox during aerobic exercise is important because the metabolic demands of the whole-body are increased, and potential abnormalities not seen in resting conditions can become apparent. There is a paradigm that overweight and obese individuals have an impaired ability to oxidise fat during exercise compared to lean counterparts. However, given the lower levels of physical training commonly undertaken by overweight/obese individuals, it is unclear whether this difference persists when individuals with matching cardiorespiratory fitness (CRF) are compared. The aims of this thesis were to: i) measure whole-body substrate utilisation rates and investigate its relationship with severity of disease in adult patients with NAFLD; ii) to study the effect of 6 months of ER or EX on substrate utilisation rates on patients with NAFLD; and iii) to compare Fatox rates during exercise in lean and overweight individuals matched for CRF. Three studies were performed and results are presented in Chapters 3 to 5.
In Chapter 3, results from a cross-sectional analysis are presented. Substrate utilisation rates were studied in NAFLD during basal, insulin-stimulated and exercise conditions, and these outcomes were correlated with disease severity. Twenty overweight patients with NAFLD and 15 lean healthy controls were assessed. Respiratory quotient (RQ), whole-body Fatox and carbohydrate oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic–euglycaemic clamp) and exercise (cycling at the intensity eliciting maximal Fatox). Severity of disease and severity of steatosis were determined by liver histology. Hepatic Fatox was estimated from plasma β-hydroxybutyrate concentrations. CRF was expressed as peak oxygen consumption (VO2peak). Finally, body composition was measured by dual-energy X-ray absorptiometry and visceral adipose tissue by computed tomography. It was found that within the overweight NAFLD cohort, basal RQ was positively correlated with steatosis and was higher in patients with more severe disease (i.e. with higher NAFLD activity score). Both results were independent of visceral adipose tissue, %body fat and body mass index (BMI). Compared to the lean control group, patients with NAFLD had lower basal whole-body Fatox and lower basal hepatic Fatox. During exercise they achieved lower maximal Fatox (MFO) and lower VO2peak values than controls.
In Chapter 4, the results of a study comparing exercise and dietary therapy in patients with NAFLD are presented. Patients with NAFLD were randomised into either six months of EX or ER. EX involved 3 sessions per week of circuit exercise training without dietary restriction. ER involved weekly dietitian appointments aimed at achieving 5-10% weight loss, without change in daily physical activity. Changes in the outcome measures pre and post intervention were compared between EX and ER. It was found that EX and ER have distinct and complementary benefits on NAFLD: EX increased Fatox under basal and exercise conditions, improved insulin resistance, but did not lead to significant reduction in severity of liver disease. ER reduced the severity of liver disease but did not improve MFO or insulin resistance.
In Chapter 5, Fatox as a function of exercise intensity is comprehensively described in twelve recreationally trained overweight males and twelve lean counterparts matched for CRF. A graded exercise test on a cycle ergometer was performed. Maximal oxygen consumption (VO2max) and fat and carbohydrate oxidation rates were determined using indirect calorimetry. MFO and the exercise intensity that elicited MFO (Fatmax) were determined with a mathematical model (SIN) and % body fat was determined by air displacement plethysmography. MFO, Fatmax and Fatox rates over a wide range of exercise intensities were not significantly different between overweight and lean groups. In the overall cohort of twenty-four participants, MFO and Fatmax were correlated with VO2max, but not with % body fat or body mass index.
In summary, this thesis contributes to describe a potential mechanism involved in the pathogenesis of NAFLD (reduced whole-body Fatox). This alteration could represent a therapeutic avenue wherein treatments that enhance basal and exercise Fatox could help manage NAFLD. Secondly, this thesis shows that ER and EX have distinct effects on fat metabolism and disease severity in patients with NAFLD. Thirdly, it reveals the importance of accounting for CRF when comparing groups with different body compositions or disease stage, and highlights the importance of educating obese individuals on the benefits of improving CRF independent of body weight or body fatness. The findings of this research program provide insights into the development of treatment strategies for NAFLD and obesity.