Altering the temporal distribution of energy intake (EI) and introducing periods of intermittent fasting (IF) exert important metabolic effects. Restricting EI to earlier in the day early ...time-restricted feeding (eTRF) is a novel type of IF.
We assessed the chronic effects of eTRF compared with an energy-matched control on whole-body and skeletal muscle insulin and anabolic sensitivity.
Sixteen healthy males (aged 23 ± 1 y; BMI 24.0 ± 0.6 kg·m−2) were assigned to 2 groups that underwent either 2 wk of eTRF (n = 8) or control/caloric restriction (CON:CR; n = 8) diet. The eTRF diet was consumed ad libitum and the intervention was conducted before the CON:CR, in which the diet was provided to match the reduction in EI and body weight observed in eTRF. During eTRF, daily EI was restricted to between 08:00 and 16:00, which prolonged the overnight fast by ∼5 h. The metabolic responses to a carbohydrate/protein drink were assessed pre- and post-interventions following a 12-h overnight fast.
When compared with CON:CR, eTRF improved whole-body insulin sensitivity between-group difference (95% CI): 1.89 (0.18, 3.60); P = 0.03; η2p = 0.29 and skeletal muscle uptake of glucose between-group difference (95% CI): 4266 (261, 8270) μmol·min−1·kg−1·180 min; P = 0.04; η2p = 0.31 and branched-chain amino acids (BCAAs) between-group difference (95% CI): 266 (77, 455) nmol·min−1·kg−1·180 min; P = 0.01; η2p = 0.44. eTRF caused a reduction in EI (∼400 kcal·d−1) and weight loss (−1.04 ± 0.25 kg; P = 0.01) that was matched in CON:CR (−1.24 ± 0.35 kg; P = 0.01).
Under free-living conditions, eTRF improves whole-body insulin sensitivity and increases skeletal muscle glucose and BCAA uptake. The metabolic benefits of eTRF are independent of its effects on weight loss and represent chronic adaptations rather than the effect of the last bout of overnight fast. This trial was registered at clinicaltrials.gov as NCT03969745.
Going Back to the Biology of FGF21: New Insights Lewis, Jo E.; Ebling, Francis J.P.; Samms, Ricardo J. ...
Trends in endocrinology and metabolism,
August 2019, 2019-08-00, 20190801, Letnik:
30, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Fibroblast growth factor 21 (FGF21) is a protein highly synthesized in the liver that exerts paracrine and endocrine control of many aspects of energy homeostasis in multiple tissues. In preclinical ...models of obesity and type 2 diabetes, treatment with FGF21 improves glucose homeostasis and promotes weight loss, and, as a result, FGF21 has attracted considerable attention as a therapeutic agent for the treatment of metabolic syndrome in humans. An improved understanding of the biological role of FGF21 may help to explain why its therapeutic potential in humans has not been fully realized. This review will cover the complexities in FGF21 biology in rodents and humans, with emphasis on its role in protection from central and peripheral facets of obesity.
FGF21 is an endocrine factor shown to impact whole-body metabolism in preclinical species and adult humans.FGF21 is under investigation as a novel therapeutic agent for the treatment of diabetes and its associated comorbidities. Expression of the FGF21 receptor/β-klotho complex (FGFR1-KLB) determines target tissue specificity; adipose tissue, liver, and the central nervous system have emerged as key target organs.Engineered FGF21 analogs, at pharmacological levels, show considerable improvement in the metabolic syndrome phenotype in animal models. However, only some of these effects (reduced dyslipidemia and body weight) are evident in humans. This represents a significant challenge for the translational potential of engineered FGF21-based therapeutics.
The causal nature of associations between breakfast and health remain unclear in obese individuals.
We sought to conduct a randomized controlled trial to examine causal links between breakfast habits ...and components of energy balance in free-living obese humans.
The Bath Breakfast Project is a randomized controlled trial with repeated measures at baseline and follow-up among a cohort in South West England aged 21-60 y with dual-energy X-ray absorptiometry-derived fat mass indexes of ≥13 kg/m(2) for women (n = 15) and ≥9 kg/m(2) for men (n = 8). Components of energy balance (resting metabolic rate, physical activity thermogenesis, diet-induced thermogenesis, and energy intake) were measured under free-living conditions with random allocation to daily breakfast (≥700 kcal before 1100) or extended fasting (0 kcal until 1200) for 6 wk, with baseline and follow-up measures of health markers (e.g., hematology/adipose biopsies).
Breakfast resulted in greater physical activity thermogenesis during the morning than when fasting during that period (difference: 188 kcal/d; 95% CI: 40, 335) but without any consistent effect on 24-h physical activity thermogenesis (difference: 272 kcal/d; 95% CI: -254, 798). Energy intake was not significantly greater with breakfast than fasting (difference: 338 kcal/d; 95% CI: -313, 988). Body mass increased across both groups over time but with no treatment effects on body composition or any change in resting metabolic rate (stable within 8 kcal/d). Metabolic/cardiovascular health also did not respond to treatments, except for a reduced insulinemic response to an oral-glucose-tolerance test over time with daily breakfast relative to an increase with daily fasting (P = 0.05).
In obese adults, daily breakfast leads to greater physical activity during the morning, whereas morning fasting results in partial dietary compensation (i.e., greater energy intake) later in the day. There were no differences between groups in weight change and most health outcomes, but insulin sensitivity increased with breakfast relative to fasting. This trial was registered at www.isrctn.org as ISRCTN31521726.
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.
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.
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, η
= 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, η
= 0.35).
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.
Background: Popular beliefs that breakfast is the most important meal of the day are grounded in cross-sectional observations that link breakfast to health, the causal nature of which remains to be ...explored under real-life conditions.Objective: The aim was to conduct a randomized controlled trial examining causal links between breakfast habits and all components of energy balance in free-living humans.Design: The Bath Breakfast Project is a randomized controlled trial with repeated-measures at baseline and follow-up in a cohort in southwest England aged 21–60 y with dual-energy X-ray absorptiometry–derived fat mass indexes ≤11 kg/m2 in women (n = 21) and ≤7.5 kg/m2 in men (n = 12). Components of energy balance (resting metabolic rate, physical activity thermogenesis, energy intake) and 24-h glycemic responses were measured under free-living conditions with random allocation to daily breakfast (≥700 kcal before 1100) or extended fasting (0 kcal until 1200) for 6 wk, with baseline and follow-up measures of health markers (eg, hematology/biopsies).Results: Contrary to popular belief, there was no metabolic adaptation to breakfast (eg, resting metabolic rate stable within 11 kcal/d), with limited subsequent suppression of appetite (energy intake remained 539 kcal/d greater than after fasting; 95% CI: 157, 920 kcal/d). Rather, physical activity thermogenesis was markedly higher with breakfast than with fasting (442 kcal/d; 95% CI: 34, 851 kcal/d). Body mass and adiposity did not differ between treatments at baseline or follow-up and neither did adipose tissue glucose uptake or systemic indexes of cardiovascular health. Continuously measured glycemia was more variable during the afternoon and evening with fasting than with breakfast by the final week of the intervention (CV: 3.9%; 95% CI: 0.1%, 7.8%).Conclusions: Daily breakfast is causally linked to higher physical activity thermogenesis in lean adults, with greater overall dietary energy intake but no change in resting metabolism. Cardiovascular health indexes were unaffected by either of the treatments, but breakfast maintained more stable afternoon and evening glycemia than did fasting. This trial was registered at www.isrctn.org as ISRCTN31521726.
Circadian regulation of transcriptional processes has a broad impact on cell metabolism. Here, we compared the diurnal transcriptome of human skeletal muscle conducted on serial muscle biopsies in ...vivo with profiles of human skeletal myotubes synchronized in vitro. More extensive rhythmic transcription was observed in human skeletal muscle compared to in vitro cell culture as a large part of the in vivo mRNA rhythmicity was lost in vitro. siRNA-mediated clock disruption in primary myotubes significantly affected the expression of ~8% of all genes, with impact on glucose homeostasis and lipid metabolism. Genes involved in GLUT4 expression, translocation and recycling were negatively affected, whereas lipid metabolic genes were altered to promote activation of lipid utilization. Moreover, basal and insulin-stimulated glucose uptake were significantly reduced upon
depletion. Our findings suggest an essential role for the circadian coordination of skeletal muscle glucose homeostasis and lipid metabolism in humans.
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.
Studies in murine cell lines and in mouse models suggest that IL-15 promotes myogenesis and may protect against the inflammation-mediated skeletal muscle atrophy which occurs in sarcopenia and ...cachexia. The effects of IL-15 on human skeletal muscle growth and development remain largely uncharacterised. Myogenic cultures were isolated from the skeletal muscle of young and elderly subjects. Myoblasts were differentiated for 8 d, with or without the addition of recombinant cytokines (rIL-15, rTNFα) and an IL-15 receptor neutralising antibody. Although myotubes were 19% thinner in cultures derived from elderly subjects, rIL-15 increased the thickness of myotubes (MTT) from both age groups to a similar extent. Neutralisation of the high-affinity IL-15 receptor binding subunit, IL-15rα in elderly myotubes confirmed that autocrine concentrations of IL-15 also support myogenesis. Co-incubation of differentiating myoblasts with rIL-15 and rTNFα, limited the reduction in MTT and nuclear fusion index (NFI) associated with rTNFα stimulation alone. IL-15rα neutralisation and rTNFα decreased MTT and NFI further. This, coupled with our observation that myotubes secrete IL-15 in response to TNFα stimulation supports the notion that IL-15 serves to mitigate inflammatory skeletal muscle loss. IL-15 may be an effective therapeutic target for the attenuation of inflammation-mediated skeletal muscle atrophy.
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.
Sarcopenia, broadly defined as the age-related decline in skeletal muscle mass, quality, and function, is associated with chronic low-grade inflammation and an increased likelihood of adverse health ...outcomes. The regulation of skeletal muscle mass with ageing is complex and necessitates a delicate balance between muscle protein synthesis and degradation. The secretion and transfer of cytokines, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), both discretely and within extracellular vesicles, have emerged as important communication channels between tissues. Some of these factors have been implicated in regulating skeletal muscle mass, function, and pathologies and may be perturbed by excessive adiposity. Indeed, adipose tissue participates in a broad spectrum of inter-organ communication and obesity promotes the accumulation of macrophages, cellular senescence, and the production and secretion of pro-inflammatory factors. Pertinently, age-related sarcopenia has been reported to be more prevalent in obesity; however, such effects are confounded by comorbidities and physical activity level. In this review, we provide evidence that adiposity may exacerbate age-related sarcopenia and outline some emerging concepts of adipose-skeletal muscle communication including the secretion and processing of novel myokines and adipokines and the role of extracellular vesicles in mediating inter-tissue cross talk via lncRNAs and miRNAs in the context of sarcopenia, ageing, and obesity. Further research using advances in proteomics, transcriptomics, and techniques to investigate extracellular vesicles, with an emphasis on translational, longitudinal human studies, is required to better understand the physiological significance of these factors, the impact of obesity upon them, and their potential as therapeutic targets in combating muscle wasting.
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