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

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

Secondary Structure, a Missing Component of Sequence- Based Minimotif Definitions

Minimotifs are short contiguous segments of proteins that have a known biological function. The hundreds of thousands of minimotifs discovered thus far are an important part of the theoretical understanding of the specificity of protein-protein interactions, posttranslational modifications, and signal transduction that occur in cells. However, a longstanding problem is that the different abstractions of the sequence definitions do not accurately capture the specificity, despite decades of effort by many labs. We present evidence that structure is an essential component of minimotif specificity, yet is not used in minimotif definitions. Our analysis of several known minimotifs as case studies, analysis of occurrences of minimotifs in structured and disordered regions of proteins, and review of the literature support a new model for minimotif definitions that includes sequence, structure, and function

Observational Study Design in Veterinary Pathology, Part 1: Study Design

Observational studies are the basis for much of our knowledge of veterinary pathology and are highly relevant to the daily practice of pathology. However, recommendations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offer advice on planning and conducting an observational study with examples from the veterinary pathology literature. Investigators should recognize the importance of creativity, insight, and innovation in devising studies that solve problems and fill important gaps in knowledge. Studies should focus on specific and testable hypotheses, questions, or objectives. The methodology is developed to support these goals. We consider the merits and limitations of different types of analytic and descriptive studies, as well as of prospective vs retrospective enrollment. Investigators should define clear inclusion and exclusion criteria and select adequate numbers of study subjects, including careful selection of the most appropriate controls. Studies of causality must consider the temporal relationships between variables and the advantages of measuring incident cases rather than prevalent cases. Investigators must consider unique aspects of studies based on archived laboratory case material and take particular care to consider and mitigate the potential for selection bias and information bias. We close by discussing approaches to adding value and impact to observational studies. Part 2 of the series focuses on methodology and validation of methods

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

The Hepatokine Leukocyte Cell-Derived Chemotaxin-2 Is Elevated in People with Impaired Glycaemic Regulation and Augmented by Acute Exercise

Background and Objectives: The hepatokine leukocyte cell-derived chemotaxin-2 (LECT2) promotes insulin resistance and hepatic fibrogenesis. In rodents, acute exercise suppresses circulating LECT2; however, human data are lacking. This study compared circulating LECT2 across populations with varying glycaemic control and explored whether acute exercise impacts circulating LECT2.Methods: In Part A (n=43), data were pooled into groups from three experimental studies: healthy individuals, individuals with impaired glycaemic regulation (IGR), and individuals with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (T2DM-MASLD). Generalised linear models assessed differences in circulating LECT2 between groups. Part B (n=20) involved two acute experimental trials in the healthy and IGR groups: exercise (30-min, 65% peak oxygen uptake) and control (resting). Circulating LECT2 was measured before and at 0,1,2 and 3h post-exercise. Generalised estimating equations assessed differences in LECT2 responses to the trials between groups. Results: In Part A, circulating LECT2 was 28.7% and 37.3% higher in the IGR and T2DM-MASLD groups, vs. healthy individuals (p≤0.038). Age (p=0.003) and BMI (p=0.001) were positively associated, and peak oxygen uptake (p=0.004) was inversely associated with circulating LECT2, with BMI identified as the main predictor (p=0.008). In Part B, average circulating LECT2 concentrations were 6.3% higher after exercise vs. control (p<0.001), with similar responses between groups (p=0.079). In the combined cohort, circulating LECT2 was elevated 1-3h after exercise vs. control (p≤0.009).Conclusions: LECT2 is elevated in people with dysglycaemia, with BMI as a leading predictor. Contrary to previous rodent work, acute exercise augments rather than suppresses circulating LECT2 in humans

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

Minimotifs are short contiguous segments of proteins that have a known biological function. The hundreds of thousands of minimotifs discovered thus far are an important part of the theoretical understanding of the specificity of protein-protein interactions, posttranslational modifications, and signal transduction that occur in cells. However, a longstanding problem is that the different abstractions of the sequence definitions do not accurately capture the specificity, despite decades of effort by many labs. We present evidence that structure is an essential component of minimotif specificity, yet is not used in minimotif definitions. Our analysis of several known minimotifs as case studies, analysis of occurrences of minimotifs in structured and disordered regions of proteins, and review of the literature support a new model for minimotif definitions that includes sequence, structure, and function. © 2012 Sargeant et al

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

Greater hepatic lipid saturation is associated with impaired glycaemic regulation in men with metabolic dysfunction‐associated steatotic liver disease but is not altered by 6 weeks of exercise training

Aims: To examine the impact of impaired glycaemic regulation (IGR) and exercise training on hepatic lipid composition in men with metabolic dysfunction‐associated steatotic liver disease (MASLD). Materials and Methods: In Part A (cross‐sectional design), 40 men with MASLD (liver proton density fat fraction [PDFF] ≥5.56%) were recruited to one of two groups: (1) normal glycaemic regulation (NGR) group (glycated haemoglobin [HbA1c] < 42 mmol∙mol−1 [<6.0%]; n = 14) or (2) IGR group (HbA1c ≥ 42 mmol∙mol−1 [≥6.0%]; n = 26). In Part B (randomized controlled trial design), participants in the IGR group were randomized to one of two 6‐week interventions: (1) exercise training (EX; 70%–75% maximum heart rate; four sessions/week; n = 13) or (2) non‐exercise control (CON; n = 13). Saturated (SI; primary outcome), unsaturated (UI) and polyunsaturated (PUI) hepatic lipid indices were determined using proton magnetic resonance spectroscopy. Additional secondary outcomes included liver PDFF, HbA1c, fasting plasma glucose (FPG), homeostatic model assessment of insulin resistance (HOMA‐IR), peak oxygen uptake (VO2 peak), and plasma cytokeratin‐18 (CK18) M65, among others. Results: In Part A, hepatic SI was higher and hepatic UI was lower in the IGR versus the NGR group (p = 0.038), and this hepatic lipid profile was associated with higher HbA1c levels, FPG levels, HOMA‐IR and plasma CK18 M65 levels (r s ≥0.320). In Part B, hepatic lipid composition and liver PDFF were unchanged after EX versus CON (p ≥ 0.257), while FPG was reduced and VO2 peak was increased (p ≤ 0.030). ΔVO2 peak was inversely associated with Δhepatic SI (r = −0.433) and positively associated with Δhepatic UI and Δhepatic PUI (r ≥ 0.433). Conclusions: Impaired glycaemic regulation in MASLD is characterized by greater hepatic lipid saturation; however, this composition is not altered by 6 weeks of moderate‐intensity exercise training