Hepatokines and hepatic lipids: interaction with exercise, diet and metabolic health

Non-alcoholic fatty liver disease (NAFLD) is associated with several metabolic comorbidities, and the excessive accumulation of hepatic lipids is strongly related to both hepatic and peripheral insulin resistance. The mechanisms underpinning the link between metabolic dysfunction and NAFLD, however, are not fully understood. Hepatokines such as fibroblast growth factor 21 (FGF21), follistatin, leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B and selenoprotein P (SeP) have been identified as liver-secreted factors which may influence metabolic homeostasis in distal tissues. Energy balance plays a key role in the regulation of these hepatokines and further research is required in humans to determine the responsiveness of these proteins to acute exercise and dietary interventions. Hepatic lipid composition, which can now be assessed using proton magnetic resonance spectroscopy (1H- MRS), has also been highlighted as a potential factor impacting metabolic health in NAFLD. A hepatic lipid profile consisting of more saturated and less polyunsaturated lipids is thought to be more metabolically harmful, and the relationship between hepatic lipid composition and metabolic dysfunction in NAFLD requires further characterisation.Chapter 3 of this thesis demonstrates that a single bout of continuous, aerobic exercise transiently increases circulating FGF21 and follistatin concentrations in healthy men; with the FGF21 response being intensity-dependent. Chapters 4 and 5 show that circulating concentrations of FGF21, LECT2 and fetuin-A are elevated following short-term (1-7 days), high-fat overfeeding in healthy men; however, the time-course varies considerably between hepatokines. Specifically, the FGF21 response is rapid and transient; whilst the LECT2 response is more gradual and sustained over seven days. Initial increases in circulating fetuin- A may also begin to occur after seven days. Chapter 6 demonstrates that 1H-MRS at 3.0 tesla is a valid tool to non-invasively assess hepatic lipid composition in NAFLD; however, the technique may not be suitable for fat fractions below 5.56%. Using this methodology, Chapter 7 found that in men with NAFLD, the hepatic lipid composition of individuals with impaired glucose regulation consists of a greater proportion of saturated and a lower proportion of unsaturated/polyunsaturated lipids compared to individuals with normal glucose regulation. Furthermore, this hepatic lipid profile is associated with a lower cardiorespiratory fitness and lower levels of daily physical activity.Collectively, the studies in this thesis demonstrate that hepatokines such as FGF21, follistatin, LECT2 and fetuin-A are sensitive to acute perturbations in energy balance induced through exercise and/or overnutrition. Furthermore, H-MRS is a valid tool to assess hepatic lipid composition in NAFLD, which appears to be more saturated and less polyunsaturated in those with impaired glucose regulation compared to those with normal glucose regulation. These findings may support a potential a role of these two factors (i.e. hepatokines and hepatic lipid composition) in the link between NAFLD and impaired metabolic health; however, further experimental evidence in humans is required. Future research should investigate the impact of more chronic lifestyle interventions on these factors to explore their potential as therapeutic targets for improving metabolic health in NAFLD.</div

One week of high-fat overfeeding alters bone metabolism in healthy males: A pilot study

Objective: Short-periods of excessive consumption of indulgent high-fat foods are common in Western society, but the effect this has on bone is unknown. The aim of this pilot study was to explore how a seven-day hyperenergetic, high-fat diet affects candidate biomarkers of bone metabolism. Research Methods & Procedures: Twelve healthy males [mean (SD): age, 24 (4) y; BMI (kg/m2), 24.1 (1.5)] consumed a 7-day hyperenergetic, high-fat diet [HE-HFD; 20.9 (0.8) MJ; 65% total energy as fat] and control diet (10.9 (2.0) MJ; 36% total energy as fat), in randomised, crossover order, with each trial separated by 3 weeks. Markers of bone formation (P1NP) and bone resorption (CTx) were measured at baseline and after 1, 3 and 7 days of each diet. Bone metabolic responses were analysed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons. Results: There was a main effect of time (PConclusions: A 7-day hyperenergetic, high-fat diet reduces a marker of bone formation but does not affect markers of bone resorption. This pilot study suggests that short-periods of excessive energy and fat consumption may detrimentally affect bone health

Accentuated early postprandial satiety in people with SCI versus able-bodied controls

In persons with spinal cord injury (SCI), reduced fat-free mass and movement-related energy expenditure increase obesity risk. Although plausible mechanisms exist, it remains unknown whether impaired appetite regulation potentiates obesity risk in SCI. This study compared postprandial responses of appetite-related hormones, appetite perceptions and the sensitivity of appetite to covert preload energy manipulation in persons with SCI and able-bodied (AB) controls. In a counterbalanced order, 12 men with high-level SCI (≥T6 vertebrae) and 12 AB controls completed two trials, consuming covert high-energy (HE; 2513 kJ) and low-energy (LE; 1008 kJ) preloads on separate occasions. Subjective appetite perceptions were assessed at 30 min intervals following preload consumption (up to 150 min) and energy intake was determined from ad libitum test meals. Appetite-related hormone (total PYY, GLP-1 and acylated ghrelin) responses were measured in the HE trial only. Within the early postprandial phase (0-60 min), subjective ratings of fullness (d = 0.83) and satisfaction (d = 0.87) were higher (P ≤ 0.028) in the group with SCI. No group differences in PYY, GLP-1 or acylated ghrelin were detected in a fasted state or postprandially (d ≤ 0.64; p ≥ 0.053). Ad libitum energy intake was lower in the SCI group (1086 vs. 1713 kJ, respectively, d = 1.00; P = 0.020) but no effect of trial (preload) was found. These findings suggest that, following isocaloric preloads, postprandial satiety may be augmented, rather than attenuated, in people with SCI

The role of hepatic lipid composition in obesity-related metabolic disease

Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions

The effect of exercise training on adipose tissue insulin sensitivity: a systematic review and meta-analysis [Abstract]

The effect of exercise training on adipose tissue insulin sensitivity: a systematic review and meta-analysis [Abstract]</p

The effect of exercise training on adipose tissue insulin sensitivity: A systematic review and meta-analysis

This systematic review and meta-analysis determined the impact of exercise training on adipose tissue insulin sensitivity in adults. Its scope extended to studies measuring whole-body and localised subcutaneous adipose tissue insulin sensitivity using validated techniques. Consensus from four studies demonstrates that exercise training improved whole-body adipose tissue insulin sensitivity when measured via stable-isotope lipid tracers (rate of appearance suppression in response to hyperinsulinaemia). Meta-analysis of 20 studies (26 intervention arms) employing the adipose tissue insulin resistance index (ADIPO-IR) supported these findings (-10.63 [-14.12 to – 7.15] pmol.L-1 x mmol.L-1). With ADIPO-IR, this response was greater in studies documenting weight loss and shorter sampling time (≤ 48 h) post-training. Overall, exercise training did not affect whole-body adipose tissue insulin sensitivity in 7 studies (11 intervention arms) measuring the suppression of circulating non-esterified fatty acid in response to insulin infusion (1.51 [-0.12 to – 3.14] %); however, sub-group analysis identified an enhanced suppression post-training in trials reporting weight loss. From four microdialysis studies, consensus indicates no effect of exercise training on localised (abdominal/femoral) adipose tissue insulin sensitivity; potentially suggesting that enhanced whole-body responses are related to improvements in central adipose depots. However, heterogeneity within microdialysis protocols dictates that findings must be viewed with caution

Are there interindividual responses of cardiovascular disease risk markers to acute exercise? A replicated crossover study

Purpose: Using a replicated crossover design, we quantified the response heterogeneity of postprandial cardiovascular disease (CVD) risk marker responses to acute exercise. Methods: Twenty men (mean (SD) age, 26 (6) years; BMI, 23.9 (2.4) kg·m-2) completed four, 2-day conditions (two control, two exercise) in randomised orders. On days 1 and 2, participants rested and consumed two high-fat meals over 9-h. Participants ran for 60-mins (61 (7)% of peak oxygen uptake) on day 1 (6.5-7.5 h) of both exercise conditions. Time-averaged total-area-under-the-curve (TAUC) for triacylglycerol (TAG), glucose and insulin were calculated from 11 venous blood samples on day 2. Arterial stiffness and blood pressure responses were calculated from measurements at baseline on day 1 and at 2.5-h on day 2. Consistency of individual differences was explored by correlating the two replicates of control-adjusted exercise responses for each outcome. Within-participant covariate-adjusted linear mixed models quantified participant-by-condition interactions and individual-response SDs. Results: Acute exercise reduced mean TAUC-TAG (-0.27 mmol·L-1 h; Cohen’s d = 0.29, P = 0.017) and TAUC-insulin (-24.45 pmol·L-1 h; Cohen’s d = 0.35, P = 0.022) vs. control, but led to negligible changes in TAUC-glucose and the vascular outcomes (Cohen’s d ≤ 0.41, P ≥ 0.106). Small-to-moderate, but nonsignificant, correlations were observed between the two response replicates (r = -0.40 to 0.15, P ≥ 0.066). We did not detect any individual response heterogeneity. All participant-by-condition interactions were P ≥ 0.137, and all individual-response SDs were small with wide 95% confidence intervals overlapping zero. Conclusion: Large trial-to-trial within-subject variability inhibited detection of consistent inter-individual variability in postprandial metabolic and vascular responses to acute exercise.</p

The hepatokine leukocyte cell-derived chemotaxin-2 is elevated in people with impaired glycaemic control and augmented by acute exercise [Abstract]

Conference abstract presented at EASL SLD (Steatotic Liver Disease) Summit 2023.</p

The hepatokine leukocyte cell-derived chemotaxin-2 is elevated in people with impaired glycaemic regulation and augmented by acute exercise

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 and explored whether acute exercise impacts circulating LECT2. In Part A (n = 43), data were pooled from three experimental studies, regarding the following groups: 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 among groups. Part B (n = 20) involved exercise (30 min, 65% peak oxygen uptake) and control (resting) trials in the healthy and IGR groups. Circulating LECT2 was measured before and at 0, 1, 2 and 3 h post-exercise. Generalised estimating equations assessed differences in LECT2 responses to the trials among groups. In Part A, circulating LECT2 levels were 28.7% and 37.3% higher in the IGR and T2DM-MASLD groups, vs. healthy individuals (p ≤ 0.038), with BMI identified as the main predictor (p = 0.008). In Part B, average circulating LECT2 levels were 6.3% higher after exercise vs. in the control (p p = 0.829). In the combined cohort, circulating LECT2 levels were elevated 1–3 h after exercise vs. control (p ≤ 0.009). 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. </p