Exercise and insulin sensitivity: interaction with intrahepatic triglyceride and hepatokines

Insulin resistance is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Intrahepatic triglyceride (IHTG), the primary feature of NAFLD, strongly predicts insulin resistance in the liver and peripheral (skeletal muscle and adipose) tissues. Hepatokines (e.g. fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), follistatin, selenoprotein P, and fetuin-A) are liver-derived proteins with capacity to exert endocrine effects and may potentially modulate the link between IHTG and peripheral insulin sensitivity/glycaemic control. Exercise is integral to the management of NAFLD and T2DM, with evidence suggesting that high-intensity exercise may provide the greatest benefits. Chapter 4 of this thesis demonstrates that, in individuals without chronic metabolic disease, plasma concentrations of FGF21 and LECT2 are higher, and follistatin lower, in individuals with overweight or obesity compared with normal weight individuals. Furthermore, FGF21 and follistatin are transiently elevated for up to 6 h after acute aerobic exercise (60 min at 60% V̇O2 peak). The response of follistatin to acute moderate-intensity exercise is also present in individuals with impaired glucose regulation (Chapter 5), but the response of FGF21 is abolished. A single bout of low-volume high-intensity interval training has no effect on FGF21, follistatin or fetuin-A in individuals with dysglycaemia (Chapter 5). Chapter 6 demonstrates that six weeks of sprint interval training (SIT) is feasible for men with NAFLD and reduces IHTG despite no change in body weight. Peripheral insulin sensitivity tends to increase after SIT but hepatic insulin sensitivity and circulating hepatokines remain unchanged. Through meta-analyses, Chapter 7 confirms that exercise training reduces IHTG, even in the absence of weight loss. However, the magnitude of this effect is greater when weight loss occurs and benefits increase proportionally. Exercise training improves basal hepatic insulin sensitivity, but evidence in this area is currently limited (Chapter 7). Collectively, the studies in this thesis demonstrate that some hepatokines may be sensitive to acute and chronic changes in energy metabolism. However, further evidence is required before definitive statements can be made. Exercise training, including SIT, has the potential to reduce IHTG in men with NAFLD, even in the absence of weight loss. However, the greatest benefits on IHTG will likely be elicited when exercise training is performed in combination with dietary energy restriction to elicit sustained reduction in body weight

The effect of exercise intensity on circulating hepatokine concentrations in healthy men [Abstract]

The effect of exercise intensity on circulating hepatokine concentrations in healthy men [Abstract

A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans

Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance

Effect of exercise intensity on circulating hepatokine concentrations in healthy men

Fibroblast growth factor 21 (FGF21), follistatin and leukocyte cell-derived chemotaxin 2 (LECT2) are novel hepatokines which are modulated by metabolic stresses. This study investigated whether exercise intensity modulates the hepatokine response to acute exercise. Ten young, healthy men undertook three 8-h experimental trials: moderate-intensity exercise (MOD; 55% V̇O2 peak), high-intensity exercise (HIGH; 75% V̇O2 peak) and control (CON; rest), in a randomised, counterbalanced order. Exercise trials commenced with a treadmill run of varied duration to match gross exercise energy expenditure between trials (MOD vs HIGH; 2475 ± 70 vs 2488 ± 58 kJ). Circulating FGF21, follistatin, LECT2, glucagon, insulin, glucose and non-esterified fatty acids (NEFA) were measured before exercise and at 0, 1, 2, 4 and 7 h post-exercise. Plasma FGF21 concentrations were increased up to 4 h post-exercise compared to CON (P ≤ 0.022) with greater increases observed at 1, 2 and 4 h post-exercise during HIGH vs MOD (P ≤ 0.025). Irrespective of intensity (P ≥ 0.606), plasma follistatin concentrations were elevated at 4 and 7 h post-exercise (P ≤ 0.053). Plasma LECT2 concentrations were increased immediately post-exercise (P ≤ 0.046) but were not significant after correcting for plasma volume shifts. Plasma glucagon (1 h; P = 0.032) and NEFA (4 and 7 h; P ≤ 0.029) responses to exercise were accentuated in HIGH vs MOD. These findings demonstrate that acute exercise augments circulating FGF21 and follistatin. Exercise-induced changes in FGF21 are intensity-dependent and may support the greater metabolic benefit of high-intensity exercise

Influence of short-term hyperenergetic, high-fat feeding on appetite, appetite-related hormones, and food reward in healthy men

Short-term overfeeding may provoke compensatory appetite responses to correct the energy surplus. However, the initial time-course of appetite, appetite-related hormone, and reward-related responses to hyperenergetic, high-fat diets (HE-HFD) are poorly characterised. Twelve young healthy men consumed a HE-HFD (+50% energy, 65% fat) or control diet (36% fat) for seven days in a randomised crossover design. Mean appetite perceptions were determined during an oral glucose tolerance test (OGTT) before and after each diet. Fasted appetite perceptions, appetite-related hormones, and reward parameters were measured pre-diet and after 1-, 3- and 7-days of each diet. The HE-HFD induced a pre-to-post diet suppression in mean appetite during the OGTT (all ratings p ≤ 0.058, effect size (d) ≥ 0.31), and reduced the preference for high-fat vs. low-fat foods (main effect diet p = 0.036, d = 0.32). Fasted leptin was higher in the HE-HFD than control diet (main effect diet p < 0.001, d = 0.30), whilst a diet-by-time interaction (p = 0.036) revealed fasted acylated ghrelin was reduced after 1-, 3- and 7-days of the HE-HFD (all p ≤ 0.040, d ≥ 0.50 vs. pre-diet). Appetite perceptions and total peptide YY in the fasted state exhibited similar temporal patterns between the diets (diet-by-time interaction p ≥ 0.077). Seven days of high-fat overfeeding provokes modest compensatory changes in subjective, hormonal, and reward-related appetite parameters

24 h severe energy restriction impairs post-prandial glycaemic control in young, lean males

Intermittent energy restriction (IER) involves short periods of severe energy restriction interspersed with periods of adequate energy intake, and can induce weight loss. Insulin sensitivity is impaired by short-term, complete energy restriction, but the effects of IER are not well known. In randomised order, 14 lean men (age: 25 (SD 4) y; BMI: 24 (SD 2) kg·m-2; body fat: 17 (4) %) consumed 24 h diets providing 100% (10441 (SD 812) kJ; EB) or 25% (2622 (SD 204) kJ; ER) of estimated energy requirements, followed by an oral glucose tolerance test (OGTT; 75g glucose drink) overnight fasted. Plasma/ serum glucose, insulin, non-esterified fatty acids (NEFA), glucagon-like peptide-1 (GLP-1), glucose-dependant insulinotropic peptide (GIP) and fibroblast growth factor-21 (FGF21) were assessed before and after (0 h) each 24 h dietary intervention, and throughout the 2 h OGTT. Homeostatic model assessment of insulin resistance (HOMA2-IR) assessed the fasted response and incremental (iAUC) or total (tAUC) area under the curve were calculated during the OGTT. At 0 h, HOMA2-IR was 23% lower after ER compared to EB (P<0.05). During the OGTT, serum glucose iAUC (P<0.001) serum insulin iAUC (P<0.05) and plasma NEFA tAUC (P<0.01) were greater during ER, but GLP-1 (P=0.161), GIP (P=0.473) and FGF21 (P=0.497) tAUC were similar between trials. These results demonstrate that severe energy restriction acutely impairs postprandial glycaemic control in lean men, despite reducing HOMA2-IR. Chronic intervention studies are required to elucidate the long-term effects of IER on indices of insulin sensitivity, particularly in the absence of weight loss

Influence of hyper-energetic, high-fat feeding on circulating hepatokines in healthy men: a randomised crossover study [Abstract]

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The influence of adiposity and acute exercise on circulating hepatokines in normal weight and overweight/obese men

Hepatokines are liver-secreted proteins with potential to influence glucose regulation and other metabolic parameters. This study investigated differences in adiposity status on five novel hepatokines and characterised their response to acute moderate-intensity exercise in groups of normal weight and overweight/obese men. Twenty-two men were recruited into normal weight and overweight/obese groups (BMI: 18.5 to 24.9 and 25.0 to 34.9 kg∙m-2). Each completed two experimental trials, exercise and control. During exercise trials, participants performed 60 min of moderate-intensity treadmill exercise (~60% V̇O2 peak) and then rested for 6 h. Participants rested throughout control trials. Circulating fibroblast growth factor-21 (FGF21), follistatin, leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A and selenoprotein-P (SeP) were measured throughout. Fasted (resting) FGF21 and LECT2 were higher in overweight/obese individuals (129% and 55%; P ≤ 0.01) and correlated with indices of adiposity and insulin resistance; whereas circulating follistatin was lower in overweight/obese individuals throughout trial days (17%, P < 0.05). In both groups, circulating concentrations of FGF21 and follistatin were transiently elevated after exercise for up to 6 h (P ≤ 0.02). Circulating fetuin-A and SeP were no different between groups (P ≥ 0.19) and, along with LECT2, were unaffected by exercise (P ≥ 0.06). These findings show that increased adiposity is associated with a modified hepatokine profile, which may represent a novel mechanism linking excess adiposity to metabolic health. Furthermore, acute perturbations in circulating FGF21 and follistatin after exercise may contribute to the health benefits of an active lifestyle

The effect of exercise training on intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review and meta-analysis

This systematic review and meta-analysis determined the impact of structured exercise training, and the influence of associated weight loss, on intrahepatic triglyceride (IHTG) in individuals with non-alcoholic fatty liver disease (NAFLD). It also examined its effect on hepatic insulin sensitivity in individuals with or at increased risk of NAFLD. Analyses were restricted to studies using magnetic resonance spectroscopy or liver biopsy for the measurement of IHTG and isotope-labelled glucose tracer for assessment of hepatic insulin sensitivity. Pooling data from 17 studies (373 exercising participants), exercise training for one to 24 weeks (mode: 12weeks) elicits an absolute reduction in IHTG of 3.31% (95% CI: -4.41 to -2.22%). Exercise reduces IHTG independent of significant weight change (-2.16 [-2.87 to -1.44]%), but benefits are substantially greater when weight loss occurs (-4.87 [-6.64 to -3.11]%). Furthermore, meta-regression identified a positive association between percentage weight loss and absolute reduction in IHTG (β = 0.99 [0.62 to 1.36], P<0.001). Pooling of six studies (94 participants) suggests that exercise training also improves basal hepatic insulin sensitivity (mean change in hepatic insulin sensitivity index: 0.13 [0.05 to 0.21] mg•m-2•min-1 per μU•mL-1), but available evidence is limited and the impact of exercise on insulin-stimulated hepatic insulin sensitivity remains unclear