Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease.

AIM: To investigate the independent effects of 6-mo of dietary energy restriction or exercise training on whole-body and hepatic fat oxidation of patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Participants were randomised into either circuit exercise training (EX; n = 13; 3 h/wk without changes in dietary habits), or dietary energy restriction (ER) without changes in structured physical activity (ER; n = 8). Respiratory quotient (RQ) and whole-body fat oxidation rates (Fatox) were determined by indirect calorimetry under basal, insulin-stimulated and exercise conditions. Severity of disease and steatosis was determined by liver histology; hepatic Fatox was estimated from plasma ß-hydroxybutyrate concentrations; cardiorespiratory fitness was expressed as VO2peak. Complete-case analysis was performed (EX: n = 10; ER: n = 6). RESULTS: Hepatic steatosis and NAFLD activity score decreased with ER but not with EX. ß-hydroxybutyrate concentrations increased significantly in response to ER (0.08 ± 0.02 mmol/L vs 0.12 ± 0.04 mmol/L, P = 0.03) but remained unchanged in response to EX (0.10 ± 0.03 mmol/L vs 0.11 ± 0.07 mmol/L, P = 0.39). Basal RQ decreased (P = 0.05) in response to EX, while this change was not significant after ER (P = 0.38). VO2peak (P < 0.001) and maximal Fatox during aerobic exercise (P = 0.03) improved with EX but not with ER (P > 0.05). The increase in ß-hydroxybutyrate concentrations was correlated with the reduction in hepatic steatosis (r = -0.56, P = 0.04). CONCLUSION: ER and EX lead to specific benefits on fat metabolism of patients with NAFLD. Increased hepatic Fatox in response to ER could be one mechanism through which the ER group achieved reduction in steatosis.

Effect of 1-h moderate-intensity aerobic exercise on intramyocellular lipids in obese men before and after a lifestyle intervention.

Intramyocellular lipids (IMCL) are depleted in response to an acute bout of exercise in lean endurance-trained individuals; however, it is unclear whether changes in IMCL content are also seen in response to acute and chronic exercise in obese individuals. We used magnetic resonance spectroscopy in 18 obese men and 5 normal-weight controls to assess IMCL content before and after an hour of cycling at the intensity corresponding with each participant's maximal whole-body rate of fat oxidation (Fatmax). Fatmax was determined via indirect calorimetry during a graded exercise test on a cycle ergometer. The same outcome measures were reassessed in the obese group after a 16-week lifestyle intervention comprising dietary calorie restriction and exercise training. At baseline, IMCL content decreased in response to 1 h of cycling at Fatmax in controls (2.8 ± 0.4 to 2.0 ± 0.3 A.U., -39%, p = 0.02), but not in obese (5.4 ± 2.1 vs. 5.2 ± 2.2 A.U., p = 0.42). The lifestyle intervention lead to weight loss (-10.0 ± 5.4 kg, p < 0.001), improvements in maximal aerobic power (+5.2 ± 3.4 mL/(kg·min)), maximal fat oxidation rate (+0.19 ± 0.22 g/min), and a 29% decrease in homeostasis model assessment score (all p < 0.05). However, when the 1 h of cycling at Fatmax was repeated after the lifestyle intervention, there remained no observable change in IMCL (4.6 ± 1.8 vs. 4.6 ± 1.9 A.U., p = 0.92). In summary, there was no IMCL depletion in response to 1 h of cycling at moderate intensity either before or after the lifestyle intervention in obese men. An effective lifestyle intervention including moderate-intensity exercise training did not impact rate of utilisation of IMCL during acute exercise in obese men.

Resveratrol does not benefit patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. METHODS: Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. RESULTS: Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. CONCLUSIONS: Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

The effect of 25-hydroxyvitamin D on insulin sensitivity in obesity: is it mediated via adiponectin?

There has been substantial recent interest in using vitamin D to improve insulin sensitivity and preventing/delaying diabetes in those at risk. There is little consensus on the physiological mechanisms and whether the association is direct or indirect through enhanced production of insulin-sensitising chemicals, including adiponectin. We examined cross-sectional associations between serum 25-hydroxyvitamin D (25(OH)D) and insulin sensitivity (Matsuda index), parathyroid hormone (PTH), waist circumference, body mass index (BMI), triglycerides (TG), total and high molecular weight (HMW) adiponectin, HMW : total adiponectin ratio (HMW : total adiponectin), and total cholesterol : HDL cholesterol ratio (TC:HDL cholesterol) in 137 Caucasian adults of mean age 43.3 ± 8.3 years and BMI 38.8 ± 6.9 kg/m(2). Total adiponectin (standardised ß = 0.446; p < 0.001), waist circumference (standardised ß = -0.216; p < 0.05), BMI (standardised ß = -0.212; p < 0.05), and age (standardised ß = -0.298; p < 0.001) were independently associated with insulin sensitivity. Serum 25(OH)D (standardised ß = 0.114; p = 0.164) was not associated with insulin sensitivity, total or HMW adiponectin, HMW : total adiponectin, or lipids. Our results provide the novel finding that 25(OH)D is not associated with HMW adiponectin or HMW : total adiponectin in nondiabetic, obese adults and support the lack of association between 25(OH)D and lipids noted by others in similar groups of patients.

Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease.

OBJECTIVES: In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. METHODS: 20 patients with NAFLD (mean ± SD body mass index (BMI) 34.1 ± 6.7 kg/m(2)) and 15 healthy controls (BMI 23.4 ± 2.7 kg/m(2)) were assessed. Respiratory quotient (RQ), whole-body fat (Fat ox) and carbohydrate (CHO ox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic-euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fat ox). Severity of disease and steatosis were determined by liver histology, hepatic Fat ox from plasma ß-hydroxybutyrate concentrations, aerobic fitness expressed as VO2 peak, and visceral adipose tissue (VAT) measured by computed tomography. RESULTS: Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fat ox to energy expenditure) in patients with NAFLD activity score (NAS) ≥ 5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fat ox (1.2 ± 0.3 vs 1.5 ± 0.4 mg/kg FFM/min, p=0.024) and lower basal hepatic Fat ox (ie, ß-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fat ox (2.5 ± 1.4 vs. 5.8 ± 3.7 mg/kg FFM/min, p=0.002) and lower VO2 peak (p<0.001) than controls. Fat ox during exercise was not associated with disease severity (p=0.79). CONCLUSIONS: Overweight/obese patients with NAFLD had reduced hepatic Fat ox and reduced whole-body Fat ox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS.

Altered clot kinetics in patients with non-alcoholic fatty liver disease.

BACKGROUND: Emerging evidence has linked the presence of non-alcoholic fatty liver disease (NAFLD) with an increased risk for cardiovascular events. We hypothesised that altered clot kinetics and platelet function may contribute to this increased risk. This study compared whole blood clotting kinetics in patients with 1) non-cirrhotic NAFLD (n = 28) and 2) healthy control subjects (n = 22). METHODS: Clotting kinetics were assessed in whole blood using thromboelastography (TEG) and assessed for correlations with cardiovascular risk factors. RESULTS: Clot kinetics in patients with NAFLD showed significantly stronger clot development (maximum amplitude (MA); 58.3 +/- 6.3 mm vs. 52.0 +/- 10.1 mm, p = 0.01) and reduced clot lysis in the presence of thrombin (35 +/- 30% vs. 51 +/- 26% clot lysis 30 minutes after MA, p = 0.03) compared to control subjects. Clot strength was independently positively associated with body mass index in NAFLD, but not in control subjects. There was a greater platelet contribution to clot strength in patients with NAFLD compared to controls despite similar platelet counts. There was no association between clot kinetics and features of the metabolic syndrome or presence of type 2 diabetes. CONCLUSION: Patients with NAFLD have disturbances in ex-vivo clot kinetics including increased clot strength and clots that are more resistant to thrombin-stimulated lysis.

Subclinical impairment of left ventricular function in young obese women: contributions of polycystic ovary disease and insulin resistance.

CONTEXT: Obesity and insulin resistance (IR) may produce disturbances of left ventricular (LV) function. Obese women with polycystic ovary syndrome (PCO), characterized by hormonal and metabolic abnormalities, are thought to be at particularly increased cardiovascular risk. OBJECTIVES: We sought to determine the influence of IR on LV function in obese young women with and without PCO and without other comorbidities. DESIGN: This was a cross-sectional study. SETTING: The study was performed at a university hospital. PATIENTS: A total of 150 women aged younger than 40 yr with a body mass index (BMI) of 30 kg/m(2) or more was classified into three groups: with both PCO and IR, without PCO and with IR, and without either PCO or IR. MAIN OUTCOME MEASURES: Tissue Doppler-derived myocardial velocities, strain-rate and strain, and metabolic and hormonal measurements were calculated. RESULTS: Subclinical impairment of LV systolic and diastolic function as indicated by lower peak strain (P < 0.001), peak systolic strain rate (P < 0.001), peak early diastolic strain rate (P < 0.001), and peak early diastolic velocity (P < 0.01) was demonstrated in both groups with IR. IR subjects with and without PCO did not differ in any LV function indices. Strain was independently associated with fasting insulin (beta = -0.39; P < 0.001), urinary albumin excretion (UAE) (beta = -0.36; P < 0.001), and BMI (beta = -0.22; P < 0.03), and peak early diastolic strain rate was associated with UAE (beta = -0.35; P < 0.001), fasting insulin (beta = -0.24; P < 0.02), BMI (beta = -0.23; P < 0.02), and SHBG (beta = 0.20; P < 0.04). CONCLUSIONS: In obese young women, fasting insulin, BMI, SHBG, and UAE are independent correlates of impaired LV performance. The contribution of PCO to LV function abnormalities is linked to IR, but not to other hormonal aberrations associated with this condition.

Thiazolidinediones and type 2 diabetes: new drugs for an old disease.

Thiazolidinediones are a new class of drugs for the treatment of type 2 diabetes, and act by improving insulin sensitivity in adipose tissue, liver and skeletal muscle. Rosiglitazone and pioglitazone are registered for use in monotherapy, and in combination with sulfonylureas and metformin. Pioglitazone is also licensed for use in combination with insulin. There is level II evidence that in patients with inadequate glycaemic control both drugs reduce the level of HbA1c and fasting plasma glucose (FPG) when used as monotherapy and in combination with sulfonylurea or metformin or insulin; and both drugs increase levels of HDL and LDL and lower free fatty acid levels, but only pioglitazone significantly lowers triglyceride levels. Both drugs lower fasting insulin and C-peptide levels. In monotherapy, they may be slightly less potent at reducing the level of HbA1c than sulfonylureas or metformin. The maximal effect of these agents may not be seen for 6-14 weeks after commencement. Both drugs are well tolerated but liver function must be checked at baseline every second month for the first year, and periodically thereafter. The drugs are currently contraindicated in patients with moderate to severe liver dysfunction and alanine aminotransferase levels more than 2.5 times normal, New York Heart Association III-IV cardiac status, pregnancy, lactation and in children. The main side effects include weight gain, oedema, and mild dilutional anaemia.