Vitamin C supplementation showed greater effects on systolic blood pressure in hypertensive and diabetic patients: an updated systematic review and meta-analysis of randomised clinical trials.

Results from randomised controlled trials (RCTs) testing the effect of vitamin C supplementation on blood pressure (BP) have been inconsistent. This systematic review evaluated the effects of vitamin C supplementation on BP and included RCTs testing the effects of vitamin C supplementation alone, on systolic and diastolic BP in adult participants (≥18 years). Random-effect models were conducted to estimate the pooled effects of vitamin C supplementation on BP. A total of 20 studies with 890 participants were included. The median dose of vitamin C was 757.5 mg/d, the median duration was 6 weeks. Vitamin C supplementation was found to reduce systolic BP by -3.0 mmHg (95%CI: -4.7, -1.3 mmHg; p = 0.001). Subgroup analysis showed a more pronounced effect on systolic BP in patients with hypertension (-3.2 mmHg, 95%CI -5.2, -1.2 mmHg, p = 0.002) and diabetes (-4.6 mmHg, 95%CI -8.9, -0.3 mmHg, p = 0.03). Further research needs to evaluate the long-term effect of vitamin C on BP in populations with impaired cardio-metabolic health.

FGF21 contributes to metabolic improvements elicited by combination therapy with exenatide and pioglitazone in patients with type 2 diabetes.

Fibroblast growth factor 21 (FGF21) is increased acutely by carbohydrate ingestion and is elevated in patients with type 2 diabetes (T2D). However, the physiological significance of increased FGF21 in humans remains largely unknown. We examined whether FGF21 contributed to the metabolic improvements observed following treatment of patients with T2D with either triple (metformin/pioglitazone/exenatide) or conventional (metformin/insulin/glipizide) therapy for 3 yr. Forty-six patients with T2D were randomized to receive either triple or conventional therapy to maintain HbA1c < 6.5%. A 2-h 75-g oral glucose tolerance test (OGTT) was performed at baseline and following 3 years of treatment to assess glucose tolerance, insulin sensitivity, and ß-cell function. Plasma total and bioactive FGF21 levels were quantitated before and during the OGTT at both visits. Patients in both treatment arms experienced significant improvements in glucose control, but insulin sensitivity and ß-cell function were markedly increased after triple therapy. At baseline, FGF21 levels were regulated acutely during the OGTT in both groups. After treatment, fasting total and bioactive FGF21 levels were significantly reduced in patients receiving triple therapy, but there was a relative increase in the proportion of bioactive FGF21 compared with that observed in conventionally treated subjects. Relative to baseline studies, triple therapy treatment also significantly modified FGF21 levels in response to a glucose load. These changes in circulating FGF21 were correlated with markers of improved glucose control and insulin sensitivity. Alterations in the plasma FGF21 profile may contribute to the beneficial metabolic effects of pioglitazone and exenatide in human patients with T2D.NEW & NOTEWORTHY In patients with T2D treated with a combination of metformin/pioglitazone/exenatide (triple therapy), we observed reduced total and bioactive plasma FGF21 levels and a relative increase in the proportion of circulating bioactive FGF21 compared with that in patients treated with metformin and sequential addition of glipizide and basal insulin glargine (conventional therapy). These data suggest that FGF21 may contribute, at least in part, to the glycemic benefits observed following combination therapy in patients with T2D.

Sarcopenic obesity is associated with telomere shortening: findings from the NHANES 1999-2002.

Sarcopenic obesity (SO) is characterised by the concurrent presence of sarcopenia and excess adiposity. Telomere shortening has been associated with sarcopenia and obesity alone but the association between SO and telomere length (TL) has not been investigated. This study aimed to investigate SO and TL in an adult population. Data were from 5397 individuals (mean age = 44.7 years, 51.3% male) enrolled in the National Health and Nutrition Examination Survey. Body composition (BC) was assessed by Dual Energy X-Ray Absorptiometry. Two models were used to assess SO: a BC model including four phenotypes derived from the combination of high or low adiposity and muscle mass; and, a truncal fat mass to appendicular skeletal mass ratio (TrFM/ASM). TL was assessed using quantitative polymerase chain reaction and expressed as base pairs. The mean TL, relative to the reference DNA, was calculated and expressed as the mean T/S ratio. A General Linear Model was applied to determine associations between TL for SO. In adjusted analysis, only individuals with SO, defined as the presence of high adiposity-low muscle mass (four-phenotype model), had significantly shorter telomeres (p = 0.05) than the reference group (i.e. low adiposity-high muscle mass), with a mean T/S ratio of 1.02 (95%CI: 0.98-1.05) compared to 1.05 (95%CI: 1.01-1.09), respectively. TrFM/ASM was not associated with TL. Preliminary findings suggest that sarcopenia and obesity may act synergistically to shorten telomeres.

Effect of acute and short-term dietary fat ingestion on postprandial skeletal muscle protein synthesis rates in middle-aged, overweight, and obese men.

Muscle anabolic resistance to dietary protein is associated with obesity and insulin resistance. However, the contribution of excess consumption of fat to anabolic resistance is not well studied. The aim of these studies was to test the hypothesis that acute and short-term dietary fat overload will impair the skeletal muscle protein synthetic response to dietary protein ingestion. Eight overweight/obese men [46.4 ± 1.4 yr, body mass index (BMI) 32.3 ± 5.4 kg/m2] participated in the acute feeding study, which consisted of two randomized crossover trials. On each occasion, subjects ingested an oral meal (with and without fat emulsion), 4 h before the coingestion of milk protein, intrinsically labeled with [1-13C]phenylalanine, and dextrose. Nine overweight/obese men (44.0 ± 1.7 yr, BMI 30.1 ± 1.1 kg/m2) participated in the chronic study, which consisted of a baseline, 1-wk isocaloric diet, followed by a 2-wk high-fat diet (+25% energy excess). Acutely, incorporation of dietary amino acids into the skeletal muscle was twofold higher (P < 0.05) in the lipid trial compared with control. There was no effect of prior lipid ingestion on indices of insulin sensitivity (muscle glucose uptake, pyruvate dehydrogenase complex activity, and Akt phosphorylation) in response to the protein/dextrose drink. Fat overfeeding had no effect on muscle protein synthesis or glucose disposal in response to whey protein ingestion, despite increased muscle diacylglycerol C16:0 (P = 0.06) and ceramide C16:0 (P < 0.01) levels. Neither acute nor short-term dietary fat overload has a detrimental effect on the skeletal muscle protein synthetic response to dietary protein ingestion in overweight/obese men, suggesting that dietary-induced accumulation of intramuscular lipids per se is not associated with anabolic resistance.

Effect of carbohydrate-protein supplementation on endurance training adaptations.

PURPOSE: To examine the influence of post-exercise protein feeding upon the adaptive response to endurance exercise training. METHODS: In a randomised parallel group design, 25 healthy men and women completed 6 weeks of endurance exercise training by running on a treadmill for 30-60 min at 70-75% maximal oxygen uptake (VO2max) 4 times/week. Participants ingested 1.6 g per kilogram of body mass (g kg BM-1) of carbohydrate (CHO) or an isocaloric carbohydrate-protein solution (CHO-P; 0.8 g carbohydrate kg BM-1 + 0.8 g protein kg BM-1) immediately and 1 h post-exercise. Expired gas, blood and muscle biopsy samples were taken at baseline and follow-up. RESULTS: Exercise training improved VO2max in both groups (p ≤ 0.001), but this increment was not different between groups either in absolute terms or relative to body mass (0.2 ± 0.2 L min-1 and 3.0 ± 2 mL kg-1 min-1, respectively). No change occurred in plasma albumin concentration from baseline to follow-up with CHO-P (4.18 ± 0.18 to 4.23 ± 0.17 g dL-1) or CHO (4.17 ± 0.17 to 4.12 ± 0.22 g dL-1; interaction: p > 0.05). Mechanistic target of rapamycin (mTOR) gene expression was up-regulated in CHO-P (+ 46%; p = 0.025) relative to CHO (+ 4%) following exercise training. CONCLUSION: Post-exercise protein supplementation up-regulated the expression of mTOR in skeletal muscle over 6 weeks of endurance exercise training. However, the magnitude of improvement in VO2max was similar between groups.

Frequent Carbohydrate Ingestion Reduces Muscle Glycogen Depletion and Postpones Fatigue Relative to a Single Bolus.

The timing of carbohydrate ingestion and how this influences net muscle glycogen utilization and fatigue has only been investigated in prolonged cycling. Past findings may not translate to running because each exercise mode is distinct both in the metabolic response to carbohydrate ingestion and in the practicalities of carbohydrate ingestion. To this end, a randomized, cross-over design was employed to contrast ingestion of the same sucrose dose either at frequent intervals (15 × 5 g every 5 min) or at a late bolus (1 × 75 g after 75 min) during prolonged treadmill running to exhaustion in six well-trained runners (V˙O2max 61 ± 4 ml·kg-1·min-1). The muscle glycogen utilization rate was lower in every participant over the first 75 min of running (Δ 0.51 mmol·kg dm-1·min-1; 95% confidence interval [-0.02, 1.04] mmol·kg dm-1·min-1) and, subsequently, all were able to run for longer when carbohydrate had been ingested frequently from the start of exercise compared with when carbohydrate was ingested as a single bolus toward the end of exercise (105.6 ± 3.0 vs. 96.4 ± 5.0 min, respectively; Δ 9.3 min, 95% confidence interval [2.8, 15.8] min). A moderate positive correlation was apparent between the magnitude of glycogen sparing over the first 75 min and the improvement in running capacity (r = .58), with no significant difference in muscle glycogen concentrations at the point of exhaustion. This study indicates that failure to ingest carbohydrates from the outset of prolonged running increases reliance on limited endogenous muscle glycogen stores-the ergolytic effects of which cannot be rectified by subsequent carbohydrate ingestion late in exercise.

Molecular adaptations of adipose tissue to 6 weeks of morning fasting vs. daily breakfast consumption in lean and obese adults.

KEY POINTS: In lean individuals, 6 weeks of extended morning fasting increases the expression of genes involved in lipid turnover (ACADM) and insulin signalling (IRS2) in subcutaneous abdominal adipose tissue. In obese individuals, 6 weeks of extended morning fasting increases IRS2 expression in subcutaneous abdominal adipose tissue. The content and activation status of key proteins involved in insulin signalling and glucose transport (GLUT4, Akt1 and Akt2) were unaffected by extended morning fasting. Therefore, any observations of altered adipose tissue insulin sensitivity with extended morning fasting do not necessarily require changes in insulin signalling proximal to Akt. Insulin-stimulated adipose tissue glucose uptake rates are lower in obese versus lean individuals, but this difference is abolished when values are normalised to whole-body fat mass. This suggests a novel hypothesis which proposes that the reduced adipose glucose uptake in obesity is a physiological down-regulation to prevent excessive de novo lipogenesis. ABSTRACT: This study assessed molecular responses of human subcutaneous abdominal adipose tissue (SCAT) to 6 weeks of morning fasting. Forty-nine healthy lean (n = 29) and obese (n = 20) adults provided SCAT biopsies before and after 6 weeks of morning fasting (FAST; 0 kcal until 12.00 h) or daily breakfast consumption (BFAST; ≥700 kcal before 11.00 h). Biopsies were analysed for mRNA levels of selected genes, and GLUT4 and Akt protein content. Basal and insulin-stimulated Akt activation and tissue glucose uptake rates were also determined. In lean individuals, lipid turnover and insulin signalling genes (ACADM and IRS2) were up-regulated with FAST versus BFAST (ACADM: 1.14 (95% CI: 0.97-1.30) versus 0.80 (95% CI: 0.64-0.96), P = 0.007; IRS2: 1.75 (95% CI: 1.33-2.16) versus 1.09 (95% CI: 0.67-1.51), P = 0.03, respectively). In obese individuals, no differential (FAST versus BFAST) expression was observed in genes involved in lipid turnover (all P > 0.1). GLUT4, Akt protein content and insulin-stimulated Akt phosphorylation were unaffected by FAST versus BFAST in both lean and obese cohorts (all P > 0.1). Lower insulin-stimulated glucose uptake rates in obese versus lean individuals were eradicated when normalised to whole-body fat mass (P = 0.416). We conclude that morning fasting up-regulates lipid turnover genes in SCAT of lean individuals. Secondly, altered SCAT insulin sensitivity with morning fasting is unlikely to be explained by signalling proximal to Akt. Finally, lower insulin-stimulated SCAT glucose uptake rates in obese individuals are proportional to whole-body fat mass, suggesting a compensatory down-regulation, presumably to prevent excessive de novo lipogenesis in adipose tissue. This trial was registered as ISRCTN31521726.

Metabolic and molecular changes associated with the increased skeletal muscle insulin action 24-48†h after exercise in young and old humans.

The molecular and metabolic mechanisms underlying the increase in insulin sensitivity (i.e. increased insulin-stimulated skeletal muscle glucose uptake, phosphorylation and storage as glycogen) observed from 12 to 48 h following a single bout of exercise in humans remain unresolved. Moreover, whether these mechanisms differ with age is unclear. It is well established that a single bout of exercise increases the translocation of the glucose transporter, GLUT4, to the plasma membrane. Previous research using unilateral limb muscle contraction models in combination with hyperinsulinaemia has demonstrated that the increase in insulin sensitivity and glycogen synthesis 24 h after exercise is also associated with an increase in hexokinase II (HKII) mRNA and protein content, suggesting an increase in the capacity of the muscle to phosphorylate glucose and divert it towards glycogen synthesis. Interestingly, this response is altered in older individuals for up to 48 h post exercise and is associated with molecular changes in skeletal muscle tissue that are indicative of reduced lipid oxidation, increased lipogenesis, increased inflammation and a relative inflexibility of changes in intramyocellular lipid (IMCL) content. Reduced insulin sensitivity (insulin resistance) is generally related to IMCL content, particularly in the subsarcolemmal (SSL) region, and both are associated with increasing age. Recent research has demonstrated that ageing per se appears to cause an exacerbated lipolytic response to exercise that may result in SSL IMCL accumulation. Further research is required to determine if increased IMCL content affects HKII expression in the days after exercise in older individuals, and the effect of this on skeletal muscle insulin action.

Postprandial Metabolism and Appetite Do Not Differ between Lean Adults that Eat Breakfast or Morning Fast for 6 Weeks.

Background: It remains unknown whether sustained daily feeding-fasting patterns modify the acute response to specific feedings on a given day. Objective: We conducted a randomized controlled trial to establish if daily breakfast consumption or fasting until noon modifies the acute metabolic and appetitive responses to a fixed breakfast and ad libitum lunch. Methods: With the use of a parallel group design, we randomly assigned 31 healthy, lean men and women (22-56 y) to 6 wk of either consuming ≥700 kcal of self-selected items before 1100 or fasting (0 kcal) until 1200 daily. Following 48 h of diet and physical activity standardization, we examined metabolic and appetite responses to a standardized breakfast and ad libitum lunch before and after the intervention. Data were analyzed using 3- and 2-way ANCOVA. Results: Systemic concentrations of energy balance regulatory hormones total and acylated ghrelin, leptin, and peptide tyrosine-tyrosine) responded similarly to breakfast and lunch before and after 6 wk of either morning fasting or regular breakfast, with the exception of a tendency for increased glucagon-like peptide-1 concentrations from baseline to follow-up in the Breakfast Group compared with a decrease over that period in the Fasting Group [P = 0.06, partial eta squared value (ƞ2) = 0.16]. Subjective appetite sensations also did not differ over the course of the day, and ad libitum energy intake at lunch was not systematically affected by either intervention, decreasing by 27 kcal (95% CI: -203, 149 kcal) with fasting and by 77 kcal (95% CI: -210, 56 kcal) with breakfast. Similarly, glycemic, insulinemic, lipemic, and thermogenic responses to breakfast and lunch were very stable at baseline and follow-up and, thus, did not differ between treatment groups. Conclusions: Our results indicate that a sustained period of either extended morning fasting or eating a daily breakfast has minimal effect upon acute metabolic and appetite responses in lean adults. This trial was registered at www.isrctn.org as ISRCTN31521726.

Eccentric exercise increases circulating fibroblast activation protein α but not bioactive fibroblast growth factor 21 in healthy humans.

NEW FINDINGS: What is the central question of this study? The role of FGF21 as an exercise-induced myokine remains controversial. The aim of this study was to determine whether eccentric exercise would augment the release of FGF21 and/or its regulatory enzyme, fibroblast activation protein α (FAP), from skeletal muscle tissue into the systemic circulation of healthy human volunteers. What is the main finding and its importance? Eccentric exercise does not release total or bioactive FGF21 from human skeletal muscle. However, exercise releases its regulatory enzyme, FAP, from tissue(s) other than muscle, which might play a role in the inactivation of FGF21. ABSTRACT: The primary aim of the investigation was to determine whether eccentric exercise would augment the release of the myokine fibroblast growth factor 21 (FGF21) and/or its regulatory enzyme, fibroblast activation protein α (FAP), from skeletal muscle tissue into the systemic circulation of healthy human volunteers. Physically active young healthy male volunteers (age 25.0 ± 10.7 years; body mass index 23.1 ± 7.9 kg m-2 ) completed three sets of 25 repetitions (with 5 min rest in between) of single-leg maximal eccentric contractions using their non-dominant leg, whilst the dominant leg served as a control. Arterialized blood samples from a hand vein and deep venous blood samples from the common femoral vein of the exercised leg, along with blood flow of the superficial femoral artery using Doppler ultrasound, were obtained before and after each exercise bout and every 20 min during the 3 h recovery period. Muscle biopsy samples were taken at baseline, immediately and 3 and 48 h postexercise. The main findings showed that there was no significant increase in total or bioactive FGF21 secreted from skeletal muscle into the systemic circulation in response to exercise. Furthermore, skeletal muscle FGF21 protein content was unchanged in response to exercise. However, there was a significant increase in arterialized and venous FAP concentrations, with no apparent contribution to its release from the exercised leg. These findings raise the possibility that the elevated levels of FAP might play a role in the inactivation of FGF21 during exercise.

Influence of Post-Exercise Carbohydrate-Protein Ingestion on Muscle Glycogen Metabolism in Recovery and Subsequent Running Exercise.

We examined whether carbohydrate-protein ingestion influences muscle glycogen metabolism during short-term recovery from exhaustive treadmill running and subsequent exercise. Six endurance-trained individuals underwent two trials in a randomized double-blind design, each involving an initial run-to-exhaustion at 70% VO2max (Run-1) followed by 4-h recovery (REC) and subsequent run-to-exhaustion at 70% VO2max (Run-2). Carbohydrate-protein (CHO-P; 0.8 g carbohydrate·kg body mass [BM-1]·h-1 plus 0.4 g protein·kg BM-1·h-1) or isocaloric carbohydrate (CHO; 1.2 g carbohydrate·kg BM-1·h-1) beverages were ingested at 30-min intervals during recovery. Muscle biopsies were taken upon cessation of Run-1, postrecovery and fatigue in Run-2. Time-to-exhaustion in Run-1 was similar with CHO and CHO-P (81 ± 17 and 84 ± 19 min, respectively). Muscle glycogen concentrations were similar between treatments after Run-1 (99 ± 3 mmol·kg dry mass [dm-1]). During REC, muscle glycogen concentrations increased to 252 ± 45 mmol·kg dm-1 in CHO and 266 ± 30 mmol·kg dm-1 in CHO-P (p = .44). Muscle glycogen degradation during Run-2 was similar between trials (3.3 ± 1.4 versus 3.5 ± 1.9 mmol·kg dm-1·min-1 in CHO and CHO-P, respectively) and no differences were observed at the respective points of exhaustion (93 ± 21 versus 100 ± 11 mmol·kg dm-1; CHO and CHO-P, respectively). Similarly, time-to-exhaustion was not different between treatments in Run-2 (51 ± 13 and 49 ± 15 min in CHO and CHO-P, respectively). Carbohydrate-protein ingestion equally accelerates muscle glycogen resynthesis during short-term recovery from exhaustive running as when 1.2 g carbohydrate·kg BM-1·h-1 are ingested. The addition of protein did not alter muscle glycogen utilization or time to fatigue during repeated exhaustive running.

Carbohydrate-rich breakfast attenuates glycaemic, insulinaemic and ghrelin response to ad libitum lunch relative to morning fasting in lean adults.

Breakfast omission is associated with obesity and CVD/diabetes, but the acute effects of extended morning fasting upon subsequent energy intake and metabolic/hormonal responses have received less attention. In a randomised cross-over design, thirty-five lean men (n 14) and women (n 21) extended their overnight fast or ingested a typical carbohydrate-rich breakfast in quantities relative to RMR (i.e. 1963 (sd 238) kJ), before an ad libitum lunch 3 h later. Blood samples were obtained hourly throughout the day until 3 h post-lunch, with subjective appetite measures assessed. Lunch intake was greater following extended fasting (640 (sd 1042) kJ, P< 0.01) but incompletely compensated for the omitted breakfast, with total intake lower than the breakfast trial (3887 (sd 1326) v. 5213 (sd 1590) kJ, P< 0.001). Systemic concentrations of peptide tyrosine-tyrosine and leptin were greater during the afternoon following breakfast (both P< 0.05) but neither acylated/total ghrelin concentrations were suppressed by the ad libitum lunch in the breakfast trial, remaining greater than the morning fasting trial throughout the afternoon (all P< 0.05). Insulin concentrations were greater during the afternoon in the morning fasting trial (all P< 0.01). There were no differences between trials in subjective appetite during the afternoon. In conclusion, morning fasting caused incomplete energy compensation at an ad libitum lunch. Breakfast increased some anorectic hormones during the afternoon but paradoxically abolished ghrelin suppression by the second meal. Extending morning fasting until lunch altered subsequent metabolic and hormonal responses but without greater appetite during the afternoon. The present study clarifies the impact of acute breakfast omission and adds novel insights into second-meal metabolism.

Fish oil omega-3 fatty acids partially prevent lipid-induced insulin resistance in human skeletal muscle without limiting acylcarnitine accumulation.

Acylcarnitine accumulation in skeletal muscle and plasma has been observed in numerous models of mitochondrial lipid overload and insulin resistance. Fish oil n3PUFA (omega-3 polyunsaturated fatty acids) are thought to protect against lipid-induced insulin resistance. The present study tested the hypothesis that the addition of n3PUFA to an intravenous lipid emulsion would limit muscle acylcarnitine accumulation and reduce the inhibitory effect of lipid overload on insulin action. On three occasions, six healthy young men underwent a 6-h euglycaemic-hyperinsulinaemic clamp accompanied by intravenous infusion of saline (Control), 10% Intralipid® [n6PUFA (omega-6 polyunsaturated fatty acids)] or 10% Intralipid®+10% Omegaven® (2:1; n3PUFA). The decline in insulin-stimulated whole-body glucose infusion rate, muscle PDCa (pyruvate dehydrogenase complex activation) and glycogen storage associated with n6PUFA compared with Control was prevented with n3PUFA. Muscle acetyl-CoA accumulation was greater following n6PUFA compared with Control and n3PUFA, suggesting that mitochondrial lipid overload was responsible for the lower insulin action observed. Despite these favourable metabolic effects of n3PUFA, accumulation of total muscle acylcarnitine was not attenuated when compared with n6PUFA. These findings demonstrate that n3PUFA exert beneficial effects on insulin-stimulated skeletal muscle glucose storage and oxidation independently of total acylcarnitine accumulation, which does not always reflect mitochondrial lipid overload.

Photoperiodic regulation of FGF21 production in the Siberian hamster.

This article is part of a Special Issue "Energy Balance". FGF21 is an endocrine member of the fibroblast growth factor superfamily that has been shown to play an important role in the physiological response to nutrient deprivation. Food restriction enhances hepatic FGF21 production, which serves to engage an integrated response to energy deficit. Specifically, elevated FGF21 levels lead to reduced gluconeogenesis and increased hepatic ketogenesis. However, circulating FGF21 concentrations also paradoxically rise in states of metabolic dysfunction such as obesity. Furthermore, multiple peripheral tissues also produce FGF21 in addition to the liver, raising questions as to its endocrine and paracrine roles in the control of energy metabolism. The objectives of this study were to measure plasma FGF21 concentrations in the Siberian hamster, a rodent which undergoes a seasonal cycle of fattening and body weight gain in the long days (LD) of summer, followed by reduction of appetite and fat catabolism in the short days (SD) of winter. Groups of adult male hamsters were raised in long days, and then exposed to SD for up to 12 weeks. Chronic exposure of LD animals to SD led to a significant increase in circulating FGF21 concentrations. This elevation of circulating FGF21 was preceded by an increase in liver FGF21 protein production evident as early as 4 weeks of exposure to SD. FGF21 protein abundance was also increased significantly in interscapular brown adipose tissue, with a positive correlation between plasma levels of FGF21 and BAT protein abundance throughout the experimental period. Epididymal white adipose tissue and skeletal muscle (gastrocnemius) also produced FGF21, but levels did not change in response to a change in photoperiod. In summary, a natural programmed state of fat catabolism was associated with increased FGF21 production in the liver and BAT, consistent with the view that FGF21 has a role in adapting hamsters to the hypophagic winter state.

Association between body mass index and age of disease onset with clinical outcomes in paediatric-onset Crohn's Disease (CD): a UK nation-wide analyses using the NIHR-IBD BioResource.

BACKGROUND: The evidence on the relationship between adiposity and disease outcomes in paediatric Crohn's disease (CD) is limited and lacks consensus. AIM: To investigate the relationship between (a) body mass index (BMI) and clinical CD outcomes (hospitalisation, surgery, disease behaviour, biologic use, extra-intestinal manifestations (EIMs)) and (b) the age of CD onset with clinical outcomes. DESIGN: Clinical outcomes were examined in CD patients diagnosed at age <17 years and enroled in the National Institute for Health Research IBD-UK BioResource at a median age of 24 years. All outcomes and BMI were recorded at the time of enrolment. Participants were categorised into normal (<25 kg/m2) and high (≥25 kg/m2) BMI. Age at disease diagnosis was categorised into pre-puberty/early puberty (<11 years), puberty (11-14 years) and post-puberty (15-17 years). Spearman rank correlation was used to test the associations between continuous variables and chi-square test to compare categorical variables. RESULTS: 848 participants with CD were included (51.8% males) and median age at diagnosis was 14 years. Participants with high BMI experienced a greater frequency of EIMs (P = 0.05) than those with low BMI (1 type of EIM: 18.5% vs. 13.2%, respectively; ≥2 types of EIMs: 7.8% vs. 5.6%, respectively). Age at diagnosis and BMI showed weak correlations with corticosteroid use (ρ = 0.08, P = 0.03 and ρ = -0.09, P = 0.01; respectively). An early diagnosis (<11 years) was associated with higher occurrence of stenosing and penetrating disease behaviour (P = 0.01) and hospitalisations (P < 0.001). CONCLUSIONS: A higher BMI and an earlier age of disease onset are associated with worse CD clinical presentation.

Skeletal muscle myostatin mRNA expression is upregulated in aged human adults with excess adiposity but is not associated with insulin resistance and ageing.

Myostatin negatively regulates skeletal muscle growth and appears upregulated in human obesity and associated with insulin resistance. However, observations are confounded by ageing, and the mechanisms responsible are unknown. The aim of this study was to delineate between the effects of excess adiposity, insulin resistance and ageing on myostatin mRNA expression in human skeletal muscle and to investigate causative factors using in vitro models. An in vivo cross-sectional analysis of human skeletal muscle was undertaken to isolate effects of excess adiposity and ageing per se on myostatin expression. In vitro studies employed human primary myotubes to investigate the potential involvement of cross-talk between subcutaneous adipose tissue (SAT) and skeletal muscle, and lipid-induced insulin resistance. Skeletal muscle myostatin mRNA expression was greater in aged adults with excess adiposity than age-matched adults with normal adiposity (2.0-fold higher; P < 0.05) and occurred concurrently with altered expression of genes involved in the maintenance of muscle mass but did not differ between younger and aged adults with normal adiposity. Neither chronic exposure to obese SAT secretome nor acute elevation of fatty acid availability (which induced insulin resistance) replicated the obesity-mediated upregulation of myostatin mRNA expression in vitro. In conclusion, skeletal muscle myostatin mRNA expression is uniquely upregulated in aged adults with excess adiposity and insulin resistance but not by ageing alone. This does not appear to be mediated by the SAT secretome or by lipid-induced insulin resistance. Thus, factors intrinsic to skeletal muscle may be responsible for the obesity-mediated upregulation of myostatin, and future work to establish causality is required.

Characterising 24-h skeletal muscle gene expression alongside metabolic & endocrine responses under diurnal conditions.

CONTEXT: Skeletal muscle plays a central role in the storage, synthesis, and breakdown of nutrients, yet little research has explored temporal responses of this human tissue, especially with concurrent measures of systemic biomarkers of metabolism. OBJECTIVE: To characterise temporal profiles in skeletal muscle expression of genes involved in carbohydrate metabolism, lipid metabolism, circadian clocks, and autophagy and descriptively relate them to systemic metabolites and hormones during a controlled laboratory protocol. METHODS: Ten healthy adults (9M/1F, mean ± SD: age: 30 ± 10 y; BMI: 24.1 ± 2.7 kg·m-2) rested in the laboratory for 37 hours with all data collected during the final 24 hours of this period (i.e., 0800-0800 h). Participants ingested hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 2200-0700 h. Blood samples were collected hourly for endocrine and metabolite analyses, with muscle biopsies occurring every 4 h from 1200 h to 0800 h the following day to quantify gene expression. RESULTS: Plasma insulin displayed diurnal rhythmicity peaking at 1804 h. Expression of skeletal muscle genes involved in carbohydrate metabolism (Name - Acrophase; GLUT4 - 1440 h; PPARGC1A -1613 h; HK2 - 1824 h) and lipid metabolism (FABP3 - 1237 h; PDK4 - 0530 h; CPT1B - 1258 h) displayed 24 h rhythmicity that reflected the temporal rhythm of insulin. Equally, circulating glucose (0019 h), NEFA (0456 h), glycerol (0432 h), triglyceride (2314 h), urea (0046 h), CTX (0507 h) and cortisol concentrations (2250 h) also all displayed diurnal rhythmicity. CONCLUSION: Diurnal rhythms were present in human skeletal muscle gene expression as well systemic metabolites and hormones under controlled diurnal conditions. The temporal patterns of genes relating to carbohydrate and lipid metabolism alongside circulating insulin are consistent with diurnal rhythms being driven in part by the diurnal influence of cyclic feeding and fasting.

Independent and combined effects of acute physiological hyperglycaemia and hyperinsulinaemia on metabolic gene expression in human skeletal muscle.

Physiological hyperglycaemia and hyperinsulinaemia are strong modulators of gene expression, which underpins some of their well-known effects on insulin action and energy metabolism. The aim of the present study was to examine whether acute in vivo exposure of healthy humans to hyperinsulinaemia and hyperglycaemia have independent or additive effects on expression of key metabolic genes in skeletal muscle. On three randomized occasions, seven young subjects underwent a 4 h (i) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) hyperglycaemic (10 mmol/l) clamp (HIHG), (ii) hyperglycaemic (10 mmol/l) euinsulinaemic (5 m-units·m⁻²·min⁻¹) clamp (LIHG) and (iii) hyperinsulinaemic (50 m-units·m⁻²·min⁻¹) euglycaemic (4.5 mmol/l) clamp (HING). Muscle biopsies were obtained before and after each clamp for the determination of expression of genes involved in energy metabolism, and phosphorylation of key insulin signalling proteins. Hyperinsulinaemia and hyperglycaemia exerted independent effects with similar direction of modulation on PI3KR1 (phosphatidylinositol 3-kinase, regulatory 1), LXRα (liver X receptor α), PDK4 (pyruvate dehydrogenase kinase 4) and FOXO1 (forkhead box O1A) and produced an additive effect on PI3KR1, the gene that encodes the p85α subunit of PI3K in human skeletal muscle. Acute hyperglycaemia itself altered the expression of genes involved in fatty acid transport and oxidation [fatty acid transporter (CD36), LCAD (long-chain acyl-CoA dehydrogenase) and FOXO1], and lipogenesis [LXRα, ChREBP (carbohydrate-responseelement-binding protein), ABCA1 (ATP-binding cassette transporter A1) and G6PD (glucose-6-phosphate dehydrogenase). Surperimposing hyperinsulinaemia on hyperglycaemia modulated a number of genes involved in insulin signalling, glucose metabolism and intracellular lipid accumulation and exerted an additive effect on PI3KR1. These may be early molecular events that precede the development of glucolipotoxicity and insulin resistance normally associated with more prolonged periods of hyperglycaemia and hyperinsulinaemia.

Systematic review: Sarcopenia in paediatric inflammatory bowel disease.

BACKGROUND: Low skeletal muscle mass (MM) and deteriorated function (sarcopenia) can be a frequent complication in paediatric inflammatory bowel disease (IBD). AIM: To conduct a systematic review of the paediatric IBD literature on skeletal muscle function and mass and identify interventions that could affect them. METHODS: Systematic searches (EMBASE, Medline, Cochrane library central for registered control trials and Web of Science) were conducted using the terms 'lean body mass' (LM), 'fat free mass' (FFM) or 'MM' and 'IBD'. RESULTS: Fourteenth studies were included, presenting data from 439 Crohn's disease (CD), 139 ulcerative colitis (UC) and 2 IBD-unclassified participants compared with healthy matched or unmatched groups or reference populations. Six out of 14 studies reported lower LM, whilst 7 studies observed lower MM and FFM in CD patients compared to healthy controls. Research in UC patients reported lower LM in 3 studies, lower MM in 3 studies and lower FFM in 4 studies. Three prospective studies measured the impact of enteral feeding and showed improvement on disease activity and LM or FFM, while one retrospective study did not show any impact on LM. CONCLUSION: Despite the variety of experimental approaches and methods used to assess sarcopenia, most studies showed reduction in MM, LM and FFM in IBD. Nutritional intervention may have a positive effect on LM and FFM. Future research should focus on standardizing the terminology and methodologies used in assessing body composition and investigating sarcopenia in diseased and matched healthy control cohorts in adequately powered studies with a longitudinal design.

Effects of intermittent (5:2) or continuous energy restriction on basal and postprandial metabolism: a randomised study in normal-weight, young participants.

BACKGROUND/OBJECTIVES: Intermittent energy restriction (IER) may overcome poor long-term adherence with continuous energy restriction (CER), for weight reduction. We compared the effects of IER with CER for fasting and postprandial metabolism and appetite in metabolically healthy participants, in whom excess weight would not confound intrinsic metabolic differences. SUBJECTS/METHODS: In a 2-week randomised, parallel trial, 16 young, healthy-weight participants were assigned to either CER (20% below estimated energy requirements (EER)) or 5:2 IER (70% below EER on 2 non-consecutive days; 5 days at EER, per week). Metabolic and appetite regulation markers were assessed before and for 3 h after a liquid breakfast; followed by an ad libitum lunch; pre- and post-intervention. RESULTS: Weight loss was similar in both groups: -2.5 (95% CI, -3.4, -1.6) kg for 5:2 IER vs. -2.3 (-2.9, -1.7) kg for CER. There were no differences between groups for postprandial incremental area under the curve for serum insulin, blood glucose or subjective appetite ratings. Compared with CER, 5:2 IER led to a reduction in fasting blood glucose concentrations (treatment-by-time interaction, P = 0.018, η2p = 0.14). Similarly, compared with CER, there were beneficial changes in fasting composite appetite scores after 5:2 IER (treatment-by-time interaction, P = 0.0003, η2p = 0.35). CONCLUSIONS: There were no significant differences in postprandial insulinaemic, glycaemic or appetite responses between treatments. However, 5:2 IER resulted in greater improvements in fasting blood glucose, and beneficial changes in fasting subjective appetite ratings.