FGF21 exerts profound metabolic effects in Siberian hamsters exposed to long day (LD) photoperiods that increase appetite and adiposity, however these effects are attenuated in short day (SD) animals ...that display hypophagia and reduced adiposity. The aim of this study was to investigate whether the beneficial effects of a novel mimetic of FGF21 in the LD state are a consequence of increased adiposity or of the central photoperiodic state. This was achieved by investigating effects of FGF21 in aged hamsters, which is associated with reduced adiposity. In LD hamsters with increased adiposity, FGF21 lowered body weight as a result of both reduced daily food intake and increased caloric expenditure, driven by an increase in whole-body fat oxidation. However, in LD animals with reduced adiposity, the effect of FGF21 on body weight, caloric intake and fat oxidation were significantly attenuated or absent when compared to those with increased adiposity. These attenuated/absent effects were underpinned by the inability of FGF21 to increase the expression of key thermogenic genes in interscapular and visceral WAT. Our study demonstrates the efficacy of a novel FGF21 mimetic in hamsters, but reveals attenuated effects in the animal model where adiposity is reduced naturally independent of photoperiod.
Fibroblast growth factor 21 (FGF21) has been shown to rapidly lower body weight in the Siberian hamster, a preclinical model of adiposity. This induced negative energy balance mediated by FGF21 is ...associated with both lowered caloric intake and increased energy expenditure. Previous research demonstrated that adipose tissue (AT) is one of the primary sites of FGF21 action and may be responsible for its ability to increase the whole-body metabolic rate. The present study sought to determine the relative importance of white (subcutaneous AT sWAT and visceral AT vWAT), and brown (interscapular brown AT iBAT) in governing FGF21-mediated metabolic improvements using the tissue-specific uptake of glucose and lipids as a proxy for metabolic activity.
We used positron emission tomography-computed tomography (PET-CT) imaging in combination with both glucose (18F-fluorodeoxyglucose) and lipid (18F-4-thiapalmitate) tracers to assess the effect of FGF21 on the tissue-specific uptake of these metabolites and compared responses to a control group pair-fed to match the food intake of the FGF21-treated group. In vivo imaging was combined with ex vivo tissue-specific functional, biochemical, and molecular analyses of the nutrient uptake and signaling pathways.
Consistent with previous findings, FGF21 reduced body weight via reduced caloric intake and increased energy expenditure in the Siberian hamster. PET-CT studies demonstrated that FGF21 increased the uptake of glucose in BAT and WAT independently of reduced food intake and body weight as demonstrated by imaging of the pair-fed group. Furthermore, FGF21 increased glucose uptake in the primary adipocytes, confirming that these in vivo effects may be due to a direct action of FGF21 at the level of the adipocytes. Mechanistically, the effects of FGF21 are associated with activation of the ERK signaling pathway and upregulation of GLUT4 protein content in all fat depots. In response to treatment with FGF21, we observed an increase in the markers of lipolysis and lipogenesis in both the subcutaneous and visceral WAT depots. In contrast, FGF21 was only able to directly increase the uptake of lipid into BAT.
These data identify brown and white fat depots as primary peripheral sites of action of FGF21 in promoting glucose uptake and also indicate that FGF21 selectively stimulates lipid uptake in brown fat, which may fuel thermogenesis.
•FGF21 increases glucose and lipid uptake in adipose tissue.•The selective FGF21-induced increase in lipid uptake in BAT may fuel thermogenesis.•Unlike BAT, glucose uptake in WAT may be used for lipogenesis.
This study investigated the molecular alterations underlying the physiological adaptations to starvation and refeeding in
human skeletal muscle. Forty-eight hours' starvation reduced whole-body ...insulin sensitivity by 42% and produced marked changes
in expression of key carbohydrate (CHO) regulatory genes and proteins: SREBP1c and hexokinase II (HKII) were downregulated
2.5- and 5-fold, respectively, whereas the pyruvate dexydrogenase kinase 4 (PDK4) was upregulated 4-fold. These responses
were not dependent on the phosphorylation status of Akt and FOXO1. On the other hand, starvation and the concomitant increase
in circulating free fatty acids did not upregulate the expression of transcription factors and genes involved in fat metabolism.
Twenty-four hours' refeeding with a CHO-rich diet completely reversed the changes in PDK4, HKII and SREBP1c expression in
human skeletal muscle but failed to fully restore whole-body insulin sensitivity. Thus, during starvation in healthy humans,
unlike rodents, regulation of fat metabolism does not require an adaptive response at transcriptional level, but adaptive
changes in gene expression are required to switch off oxidative glucose disposal. Lack of effect on key proteins in the insulin-signalling
pathway may indicate that changes in intracellular substrate availability/flux may be responsible for these adaptive changes
in glucose metabolism. This may represent an important aspect of the molecular basis of the development of insulin resistance
in metabolic conditions characterized by energy restriction.
Aim: We investigated the effect of elevated plasma free fatty acid and insulin concentrations on PDK4 mRNA transcript and protein content and long-chain acyl-coenzyme A accumulation in human skeletal ...muscle.
Methods: On two occasions, 10 healthy men underwent hyperinsulinemic-euglycemic clamps for 6 h with (LIPID) and without (CON) iv Intralipid (20% at 90 ml/h) plus heparin (200 U prime + 600 U/h) infusion.
Results: Glucose disposal was approximately 50% lower at the end of the clamp in the LIPID compared with the CON trial (37.8 ± 4.4 and 79.6 ± 4.0 μmol/kg lean mass·min, respectively; P < 0.01). In the LIPID trial, muscle long-chain acyl-coenzyme A concentration increased after 6 h, but not 3 h of lipid infusion (P < 0.01). Muscle PDK4 mRNA, but not protein, was down-regulated by 2-fold within 3 h in both clamps and decreased further (6-fold; P < 0.01) at 6 h in the CON but not the LIPID clamp. The lipid-induced attenuation in the suppression of PDK4 gene expression was not dependent on the activation of the Akt/FOXO3 pathway.
Conclusion: Accumulation of im lipids plays a more important role than impaired activation of Akt-mediated pathways in the regulation of muscle PDK4 gene expression in lipid-induced acute insulin-resistant states.
This study investigated how acute restoration of normoglycaemia affected energy metabolism during exercise in nonobese patients with type 2 diabetes. Six subjects (mean ± SEM) aged 56.2 ± 2.7 years, ...with a BMI of 24.5 ± 1.5 kg/m2 and a VO2 peak of 28.7 ml/kg/min, attended the lab on two randomised occasions for a four-hour resting infusion of insulin or saline, followed by 30 minutes cycling at 50% VO2 peak. During the 4 h resting infusion, there was a greater (P<0.0001) reduction in blood glucose in insulin treatment (INS) (from 11.2 ± 0.6 to 5.6 ± 0.1 mmol/l) than in saline treatment/control (CON) (from 11.5 ± 0.7 to 8.5 ± 0.6 mmol/l). This was associated with a lower (P<0.05) resting metabolic rate in INS (3.87 ± 0.17) than in CON (4.39 ± 0.30 kJ/min). During subsequent exercise, blood glucose increased significantly in INS from 5.6 ± 0.1 at 0 min to 6.3 ± 0.3 mmol/l at 30 min (P<0.01), which was accompanied by a lower blood lactate response (P<0.05). Oxygen uptake, rates of substrate utilization, heart rate, and ratings of perceived exertion were not different between trials. Insulin-induced normoglycaemia increased blood glucose during subsequent exercise without altering overall substrate utilization.
Summary
Obesity is associated with chronic low‐grade inflammation that affects the phenotype of multiple tissues and therefore is implicated in the development and progression of several age‐related ...chronic inflammatory disorders. Importantly, a new family of noncoding RNAs, termed long noncoding RNAs (lncRNAs), have been identified as key regulators of inflammatory signalling pathways that can mediate both pretranscriptional and posttranscriptional gene regulation. Furthermore, several lncRNAs have been identified, which are differentially expressed in multiple tissue types in individuals who are obese or in preclinical models of obesity. In this review, we examine the evidence for the role of several of the most well‐studied lncRNAs in the regulation of inflammatory pathways associated with obesity. We highlight the evidence for their differential expression in the obese state and in age‐related conditions including insulin resistance, type 2 diabetes (T2D), sarcopenia, osteoarthritis and rheumatoid arthritis, where obesity plays a significant role. Determining the expression and functional role of lncRNAs in mediating obesity‐associated chronic inflammation will advance our understanding of the epigenetic regulatory pathways that underlie age‐related inflammatory diseases and may also ultimately identify new targets for therapeutic intervention.
The evidence on the relationship between adiposity and disease outcomes in paediatric Crohn's disease (CD) is limited and lacks consensus.
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.
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/m
) and high (≥25 kg/m
) 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.
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).
A higher BMI and an earlier age of disease onset are associated with worse CD clinical presentation.
Context: Murine fibroblast growth factor (FGF) 21 is a nutritionally regulated hormone secreted by the liver principally in response to peroxisome proliferator-activated receptor-α (PPARα) ...activation, which plays a critical role in regulating metabolism during ketosis. FGF21 is also a PPARγ target gene in mouse adipose tissue. Little information is available on FGF21 functions in humans.
Objective: The aim of the study was to measure plasma FGF21 during fasting, ketogenic diet, and PPAR agonist treatment in humans.
Design and Setting: We conducted a prospective study involving three patient groups at two university hospitals.
Patients: Eight healthy male volunteers underwent a 48-h period of starvation followed by 24-h refeeding (group 1); seven obese individuals were allocated to a low-carbohydrate diet for 3 months (group 2); and three groups of healthy, overweight or obese male volunteers received treatment with a PPARα (20 μg/d GW590735) (n=6), PPARδ (10 mg/d GW501516) (n=6), or PPARγ agonist (rosiglitazone) (n=10) for 2 wk (group 3).
Main Outcome Measures: Fasting plasma FGF21 and serum 3-hydroxybutyrate were measured.
Results: There was no significant variation in human plasma FGF21 during fasting and refeeding. A 3-month ketogenic diet was associated with a 42% decline in plasma FGF21 levels. Circulating FGF21 increased significantly in response to treatment with PPARα (39%) and PPARδ (32%), but not PPARγ agonists.
Conclusion: FGF21 does not play a major role in regulating the fasting response or ketosis in man. However, plasma FGF21 is elevated in response to pharmacological activation of PPARα and PPARδ and may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds.
FGF21 is not critical in regulating the fasting response or ketosis, but its serum level rises in response to PPARα and PPARδ agonist treatment.
Current guidance regarding the role of daily breakfast in human health is largely grounded in cross-sectional observations. However, the causal nature of these relationships has not been fully ...explored and what limited information is emerging from controlled laboratory-based experiments appears inconsistent with much existing data. Further progress in our understanding therefore requires a direct examination of how daily breakfast impacts human health under free-living conditions.
The Bath Breakfast Project (BBP) is a randomised controlled trial comparing the effects of daily breakfast consumption relative to extended fasting on energy balance and human health. Approximately 70 men and women will undergo extensive laboratory-based assessments of their acute metabolic responses under fasted and post-prandial conditions, to include: resting metabolic rate, substrate oxidation, dietary-induced thermogenesis and systemic concentrations of key metabolites/hormones. Physiological and psychological indices of appetite will also be monitored both over the first few hours of the day (i.e. whether fed or fasted) and also following a standardised test lunch used to assess voluntary energy intake under controlled conditions. Baseline measurements of participants' anthropometric characteristics (e.g. DEXA) will be recorded prior to intervention, along with an oral glucose tolerance test and acquisition of adipose tissue samples to determine expression of key genes and estimates of tissue-specific insulin action. Participants will then be randomly assigned either to a group prescribed an energy intake of ≥3000 kJ before 1100 each day or a group to extend their overnight fast by abstaining from ingestion of energy-providing nutrients until 1200 each day, with all laboratory-based measurements followed-up 6 weeks later. Free-living assessments of energy intake (via direct weighed food diaries) and energy expenditure (via combined heart-rate/accelerometry) will be made during the first and last week of intervention, with continuous glucose monitors worn both to document chronic glycaemic responses to the intervention and to verify compliance.
The aim of this study was to determine the chronic (≥72 h postexercise) effects of high-intensity interval training (HIIT) on postprandial lipemia and metabolic markers in healthy volunteers. Eight ...physically active young men (mean ± SD: age 22 ± 3 yr, height 1.77 ± 0.07 m, body mass 67.7 ± 6.2 kg) underwent two 6-h mixed-meal tolerance tests and resting vastus lateralis muscle biopsies before the first session and ≥72 h after the final session of 4 wk of HIIT 16 sessions in total; 10 × 60-s bouts of cycling at 90% maximal oxygen uptake (V̇o
), interspersed with 60-s intervals at 45% V̇o
. Arterialized and deep venous blood samples from across the forearm, brachial artery blood flow measurements, and whole-body indirect calorimetry data were obtained before, and at regular intervals for 6 h after, consumption of a standardized mixed meal. The main findings revealed that, when assessed ≥72 h postexercise, postprandial free fatty acid (FFA) uptake across the forearm was increased in response to exercise training (
= 0.025). However, 4 wk of HIIT did not alter fasting or postprandial circulating triglyceride concentrations or their tissue uptake, despite a 10.2% ± 7.7% improvement in V̇o
(
= 0.004). Protein content of adipose triglyceride lipase in the vastus lateralis at rest was reduced by 25% ± 21% (
= 0.01). Collectively, these findings suggest that 4 wk of HIIT enhances postprandial clearance of FFA when assessed ≥72 h postexercise but does not confer persisting (training) adaptations in postprandial triglyceridemia.
When assessed ≥72 h after the last exercise session, 4 wk of high-intensity interval training (HIIT) did not improve triglyceridemia but enhanced free fatty acid uptake into muscle with a concurrent reduction in skeletal muscle adipose triglyceride lipase protein content. This suggests that previously reported acute reductions in postprandial triglyceridemia following a single bout of HIIT do not translate to sustained improvements after 4 wk of HIIT, supporting the concept of frequent exercise for the maintenance of lipemic control.
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