Associations of resting and peak fat oxidation with sex hormone profile and blood glucose control in middle-aged women.

BACKGROUND AND AIMS: Menopause may reduce fat oxidation. We investigated whether sex hormone profile explains resting fat oxidation (RFO) or peak fat oxidation (PFO) during incremental cycling in middle-aged women. Secondarily, we studied associations of RFO and PFO with glucose regulation. METHOD AND RESULTS: We measured RFO and PFO of 42 women (age 52-58 years) with indirect calorimetry. Seven participants were pre- or perimenopausal, 26 were postmenopausal, and nine were postmenopausal hormone therapy users. Serum estradiol (E2), follicle-stimulating hormone, progesterone, and testosterone levels were quantified with immunoassays. Insulin sensitivity (Matsuda index) and glucose tolerance (area under the curve) were determined by glucose tolerance testing. Body composition was assessed with dual-energy X-ray absorptiometry; physical activity with self-report and accelerometry; and diet, with food diaries. Menopausal status or sex hormone levels were not associated with the fat oxidation outcomes. RFO determinants were fat mass (ß = 0.44, P = 0.006) and preceding energy intake (ß = -0.40, P = 0.019). Cardiorespiratory fitness (ß = 0.59, P = 0.002), lean mass (ß = 0.49, P = 0.002) and physical activity (self-reported ß = 0.37, P = 0.020; accelerometer-measured ß = 0.35, P = 0.024) explained PFO. RFO and PFO were not related to insulin sensitivity. Higher RFO was associated with poorer glucose tolerance (ß = 0.52, P = 0.002). CONCLUSION: Among studied middle-aged women, sex hormone profile did not explain RFO or PFO, and higher fat oxidation capacity did not indicate better glucose control.

Fat oxidation at rest and during exercise in male monozygotic twins.

PURPOSE: We aimed to investigate if hereditary factors, leisure-time physical activity (LTPA) and metabolic health interact with resting fat oxidation (RFO) and peak fat oxidation (PFO) during ergometer cycling. METHODS: We recruited 23 male monozygotic twin pairs (aged 32-37 years) and determined their RFO and PFO with indirect calorimetry for 21 and 19 twin pairs and for 43 and 41 twin individuals, respectively. Using physical activity interviews and the Baecke questionnaire, we identified 10 twin pairs as LTPA discordant for the past 3 years. Of the twin pairs, 8 pairs participated in both RFO and PFO measurements, and 2 pairs participated in either of the measurements. We quantified the participants' metabolic health with a 2-h oral glucose tolerance test. RESULTS: Fat oxidation within co-twins was correlated at rest [intraclass correlation coefficient (ICC) = 0.54, 95% confidence interval (CI) 0.15-0.78] and during exercise (ICC = 0.67, 95% CI 0.33-0.86). The LTPA-discordant pairs had no pairwise differences in RFO or PFO. In the twin individual-based analysis, PFO was positively correlated with the past 12-month LTPA (r = 0.26, p = 0.034) and the Baecke score (r = 0.40, p = 0.022) and negatively correlated with the area under the curve of insulin (r = - 0.42, p = 0.015) and glucose (r = - 0.31, p = 0.050) during the oral glucose tolerance test. CONCLUSIONS: Hereditary factors were more important than LTPA for determining fat oxidation at rest and during exercise. Additionally, PFO, but not RFO, was associated with better metabolic health.

Associations of Objectively Measured Physical Activity and Sedentary Time With Arterial Stiffness in Pre-Pubertal Children.

PURPOSE: To investigate the relationships of objectively measured physical activity (PA) and sedentary time (ST) to arterial stiffness in prepubertal children. METHOD: Altogether 136 children (57 boys, 79 girls) aged 6-8-years participated in the study. Stiffness index (SI) was assessed by pulse contour analysis based on photoplethysmography. ST, light PA, moderate PA, and vigorous PA were assessed using combined acceleration and heart rate monitoring. We investigated the associations of ST (<1.5METs) and time spent in intensity level of PA above 2-7METs in min/d with SI using linear regression analysis. We studied the optimal duration and intensity of PA to identify children being in the highest quarter of SI using Receiver Operating Characteristics curves. RESULTS: Moderate PA, vigorous PA, and cumulative time spent in PA above 3 (ß=-0.279, p = .002), 4 (ß =-0.341, P<0.001), 5 (ß =-0.349, P<0.001), 6 (ß =-0.312, P<0.001), and 7 (ß =-0.254, p = .005) METs were inversely associated with SI after adjustment for age, sex, and monitor wear time. The cutoffs for identifying children being in the highest quarter of SI <68 min/d for PA exceeding 5 METs and <26 min/d for PA exceeding 6 METs. CONCLUSION: Lower levels of PA exceeding 3-6 METs were related to higher arterial stiffness in children.

Associations of disordered sleep with body fat distribution, physical activity and diet among overweight middle-aged men.

This cross-sectional study aimed to investigate whether body fat distribution, physical activity levels and dietary intakes are associated with insomnia and/or obstructive sleep apnea among overweight middle-aged men. Participants were 211 Finnish men aged 30-65 years. Among the 163 overweight or obese participants, 40 had insomnia only, 23 had obstructive sleep apnea only, 24 had comorbid insomnia and obstructive sleep apnea and 76 were without sleep disorder. The remaining 48 participants had normal weight without sleep disorder. Fat mass, levels of physical activity and diet were assessed by dual-energy X-ray densitometry, physical activity questionnaire and 3-day food diary, respectively. Among the overweight participants, we found that: (i) groups with sleep disorders had higher fat mass in trunk and android regions than the group without sleep disorder (P = 0.048-0.004); (ii) the insomnia-only group showed a lower level of leisure-time physical activity (436.9 versus 986.5 MET min week(-1) , P = 0.009) and higher intake of saturated fatty acids (14.8 versus 12.7 E%, P = 0.011) than the group without sleep disorder; and (iii) the comorbid group had a lower level of leisure-time physical activity (344.4 versus 986.5 MET min week(-1) , P = 0.007) and lower folate intake (118.9 versus 152.1 µg, P = 0.002) than the group without sleep disorder, which were independent of body mass index. The results suggest that central obesity is associated with insomnia and/or obstructive sleep apnea. In addition, low levels of leisure-time physical activity and poor dietary intakes are related to insomnia or comorbid insomnia and obstructive sleep apnea among overweight men.

Gut-adipose tissue axis in hepatic fat accumulation in humans.

BACKGROUND & AIMS: Recent evidence suggests that in animals gut microbiota composition (GMC) affects the onset and progression of hepatic fat accumulation. The aim of this study was to investigate in humans whether subjects with high hepatic fat content (HHFC) differ in their GMC from those with low hepatic fat content (LHFC), and whether these differences are associated with body composition, biomarkers and abdominal adipose tissue inflammation. METHODS: Hepatic fat content (HFC) was measured using proton magnetic resonance spectroscopy ((1)H MRS). Fecal GMC was profiled by 16S rRNA fluorescence in situ hybridization and flow cytometry. Adipose tissue gene expression was analyzed using Affymetrix microarrays and quantitative PCR. RESULTS: The HHFC group had unfavorable GMC described by lower amount of Faecalibacterium prausnitzii (FPrau) (p<0.05) and relatively higher Enterobacteria than the LHFC group. Metabolically dysbiotic GMC associated with HOMA-IR and triglycerides (p<0.05 for both). Several inflammation-related adipose tissue genes were differentially expressed and correlated with HFC (p<0.05). In addition, the expression of certain genes correlated with GMC dysbiosis, i.e., low FPrau-to-Bacteroides ratio. CONCLUSIONS: HHFC subjects differ unfavorably in their GMC from LHFC subjects. Adipose tissue inflammation may be an important link between GMC, metabolic disturbances, and hepatic fat accumulation.

Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men--the role of gut microbiota composition: study protocol for the AELC randomized controlled trial.

BACKGROUND: Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects. METHODS/DESIGN: A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50-65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3-5 times/week and 30-60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview. DISCUSSION: Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN42622771.

Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health?

Recently, contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis, and the associated regulatory role of exercise and PGC-1α. We therefore evaluated whether muscle FNDC5 mRNA and serum irisin are exercise responsive and whether PGC-1α expression is associated with FNDC5 expression. The male subjects in the study performed single exercises: (1) 1 h low-intensity aerobic exercise (AE) (middle-aged, n = 17), (2) a heavy-intensity resistance exercise (RE) bout (young n = 10, older n = 11) (27 vs. 62 years), (3) long-term 21 weeks endurance exercise (EE) training alone (twice a week, middle-aged, n = 9), or (4) combined EE and RE training (both twice a week, middle-aged, n = 9). Skeletal muscle mRNA expression was analysed by quantitative PCR and serum irisin by ELISA. No significant changes were observed in skeletal muscle PGC-1α, FNDC5 and serum irisin after AE, EE training or combined EE + RE training. However, a single RE bout increased PGC-1α by 4-fold in young and by 2-fold in older men, while FNDC5 mRNA only increased in young men post-RE, by 1.4-fold. Changes in PGC-1α or serum irisin were not consistently accompanied by changes in FNDC5. In conclusion, for the most part, neither longer-term nor single exercise markedly increases skeletal muscle FNDC5 expression or serum irisin. Therefore their changes in response to exercise are probably random and not consistent excluding the confirmation of any definitive link between exercise and FNDC5 expression and irisin release in humans. Moreover, irisin and FNDC5 were not associated with glucose tolerance and being overweight, or with metabolic disturbances, respectively. Finally, factor(s) other than PGC-1α and transcription may regulate FNDC5 expression.

Bidirectional associations between adiposity and physical activity: a longitudinal study from pre-puberty to early adulthood.

Objective: This study aimed to investigate directional influences in the association between adiposity and physical activity (PA) from pre-puberty to early adulthood. Methods: In the Calex-study, height, weight, body fat and leisure-time physical activity (LTPA) were measured at age11.2-years, 13.2-years and 18.3-years in 396 Finnish girls. Body fat was measured by dual-energy X-ray absorptiometry, calculating fat mass index (FMI) as total fat mass in kilograms divided by height in meters squared. LTPA level was evaluated using a physical activity questionnaire. In the European Youth Heart Study (EYHS), height, weight and habitual PA were measured at age 9.6-years, 15.7-years and 21.8-years in 399 Danish boys and girls. Habitual PA and sedentary behaviour were assessed with an accelerometer. Directional influences of adiposity and PA were examined using a bivariate cross-lagged path panel model. Results: The temporal stability of BMI from pre-puberty to early adulthood was higher than the temporal stability of PA or physical inactivity over the same time period both in girls and boys. In the Calex-study, BMI and FMI at age 11.2-years were both directly associated with LTPA at age 13.2-years (ß = 0.167, p = 0.005 and ß = 0.167, p = 0.005, respectively), whereas FMI at age 13.2-years showed an inverse association with LTPA at age 18.3-years (ß = - 0.187, p = 0.048). However, earlier LTPA level was not associated with subsequent BMI or FMI. In the EYHS, no directional association was found for physical inactivity, light-, moderate-, and vigorous-PA with BMI during the follow-up in girls. In boys, BMI at age 15.7-years was directly associated with moderate PA (ß = 0.301, p = 0.017) at age 21.8-years, while vigorous PA at age 15.7-years showed inverse associations with BMI at age 21.8-years (ß = - 0.185, p = 0.023). Conclusion: Our study indicates that previous fatness level is a much stronger predictor of future fatness than level of leisure-time or habitual physical activity during adolescence. The directional associations between adiposity and physical activity are not clear during adolescence, and may differ between boys and girls depending on pubertal status.

Age But Not Menopausal Status Is Linked to Lower Resting Energy Expenditure.

CONTEXT: It remains uncertain whether aging before late adulthood and menopause are associated with fat-free mass and fat mass-adjusted resting energy expenditure (REEadj). OBJECTIVES: We investigated whether REEadj differs between middle-aged and younger women and between middle-aged women with different menopausal statuses. We repeated the age group comparison between middle-aged mothers and their daughters to partially control for genotype. We also explored whether serum estradiol and FSH concentrations explain REEadj in midlife. METHODS: We divided 120 women, including 16 mother-daughter pairs, into age groups; group I (n = 26) consisted of participants aged 17 to 21, group II (n = 35) of those aged 22 to 38, and group III (n = 59) of those aged 41 to 58 years. The women in group III were further categorized as pre- or perimenopausal (n = 19), postmenopausal (n = 30), or postmenopausal hormone therapy users (n = 10). REE was assessed using indirect calorimetry, body composition using dual-energy X-ray absorptiometry, and hormones using immunoassays. RESULTS: The REEadj of group I was 126 kcal/day [95% confidence interval (CI): 93-160] higher than that of group III, and the REEadj of group II was 88 kcal/day (95% CI: 49-127) higher. Furthermore, daughters had a 100 kcal/day (95% CI: 63-138 kcal/day) higher REEadj than their middle-aged mothers (all P < .001). In group III, REEadj was not lower in postmenopausal women and did not vary by sex hormone concentrations. CONCLUSIONS: We demonstrated that REEadj declines with age in women before late adulthood, also when controlling partially for genetic background, and that menopause may not contribute to this decline.

Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study.

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7-89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

Prolonged breast-feeding protects mothers from later-life obesity and related cardio-metabolic disorders.

OBJECTIVE: To investigate the long-term effects of duration of postpartum lactation on maternal body composition and risk for cardio-metabolic disorders in later life. DESIGN: Retrospective study. Body composition was measured using dual-energy X-ray absorptiometry and serum glucose, insulin and lipids were analysed using enzymatic photometric methods 16-20 years after the last pregnancy. Medical history and lifestyle factors were collected via a self-administered questionnaire. Detailed information regarding weight change patterns during each pregnancy was obtained from personal maternity tracking records. SETTING: City of Jyväskylä and surroundings in Central Finland. SUBJECTS: Two hundred and twelve women (mean age 48, range 36-60 years). RESULTS: At 16-20 years after their last pregnancy, women who had breast-fed for less than 6 months had higher total body fat mass and fat mass percentage, particularly in the android region (46·5 (sd 8·2) %) than mothers who had breast-fed for longer than 6 months (39·0 (sd 10·2) %) or for longer than 10 months (38·4 (sd 10·9) %, P < 0·01). These differences were independent of pre-pregnancy weight and BMI, menopausal status, smoking status, level of education, participation in past and present leisure-time physical activity, and current dietary energy intake. Higher body fat mass was also associated with higher fasting serum glucose concentration and insulin resistance, TAG, LDL cholesterol and total cholesterol concentrations, as well as higher systolic and diastolic blood pressure (P < 0·05 for all). CONCLUSIONS: Short duration of breast-feeding may induce weight retention and fat mass accumulation, resulting in increased risk of cardio-metabolic disorders in later life.

A randomized controlled trial for response of microbiome network to exercise and diet intervention in patients with nonalcoholic fatty liver disease.

Exercise and diet are treatments for nonalcoholic fatty liver disease (NAFLD) and prediabetes, however, how exercise and diet interventions impact gut microbiota in patients is incompletely understood. We previously reported a 8.6-month, four-arm (Aerobic exercise, n = 29; Diet, n = 28; Aerobic exercise + Diet, n = 29; No intervention, n = 29) randomized, singe blinded (for researchers), and controlled intervention in patients with NAFLD and prediabetes to assess the effect of interventions on the primary outcomes of liver fat content and glucose metabolism. Here we report the third primary outcome of the trial-gut microbiota composition-in participants who completed the trial (22 in Aerobic exercise, 22 in Diet, 23 in Aerobic exercise + Diet, 18 in No Intervention). We show that combined aerobic exercise and diet intervention are associated with diversified and stabilized keystone taxa, while exercise and diet interventions alone increase network connectivity and robustness between taxa. No adverse effects were observed with the interventions. In addition, in exploratory ad-hoc analyses we find that not all subjects responded to the intervention in a similar manner, when using differentially altered gut microbe amplicon sequence variants abundance to classify the responders and low/non-responders. A personalized gut microbial network at baseline could predict the individual responses in liver fat to exercise intervention. Our findings suggest an avenue for developing personalized intervention strategies for treatment of NAFLD based on host-gut microbiome ecosystem interactions, however, future studies with large sample size are needed to validate these discoveries. The Trial Registration Number is ISRCTN 42622771.

Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood.

BACKGROUND: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. METHODS: In this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). FINDINGS: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. INTERPRETATION: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. FUNDING: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyv€askyl€a, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001), the Food and Health Bureau of Hong Kong SAR's Health and Medical Research Fund (HMRF grants 15162161 and 07181036) and the CUHK Direct Grants for Research (2016¢033 and 2018¢034), and a postdoctoral fellowship from K. Carole Ellison (to T.W.). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. This work was supported by European Union's Horizon 2020 research and innovation programme LongITools 874739.

Interactive effects of aging and aerobic capacity on energy metabolism-related metabolites of serum, skeletal muscle, and white adipose tissue.

Aerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial ß-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

Effects of exercise and dietary interventions on serum metabolites in men with insomnia symptoms: A 6-month randomized controlled trial.

Accumulating evidence show that exercise and diet interventions are associated with improved sleep quality. Studies investigating the effects of exercise and dieting on circulating metabolomics in people with sleep disorders, particularly insomnia, are scarce. This 6-month randomized study aimed to assess the effects of exercise and dietary interventions on serum metabolites in men with insomnia symptoms. Seventy-two Finnish men (age: 51.6 ±â€¯10.1 years) with chronic insomnia symptoms who were assigned to different intervention groups completed this study (exercise, n = 24; diet, n = 27; and control, n = 21). The Shapiro-Wilk W-test, Levene test, Spearman correlation analysis, and analysis of variance were used for data analysis. We found that exercise and diet intervention were associated with improved sleep quality and with a number of metabolites across different biochemical pathways. Although we could not show causality, our findings provide new insight into the biological mechanisms underlying the health effects of physical activity, diet, and sleep quality. Further investigation is needed to better understand the link among lifestyle, sleep quality, and metabolic health.

Cardiorespiratory Fitness, Physical Activity, and Insulin Resistance in Children.

PURPOSE: Few studies have investigated the independent and joint associations of cardiorespiratory fitness (CRF) and body fat percentage (BF%) with insulin resistance in children. We investigated the independent and combined associations of CRF and BF% with fasting glycemia and insulin resistance and their interactions with physical activity (PA) and sedentary time among 452 children age 6 to 8 yr. METHODS: We assessed CRF with a maximal cycle ergometer exercise test and used allometrically scaled maximal power output (Wmax) for lean body mass (LM) and body mass (BM) as measures of CRF. The BF% and LM were measured by dual-energy X-ray absorptiometry, fasting glycemia by fasting plasma glucose, and insulin resistance by fasting serum insulin and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The PA energy expenditure, moderate-to-vigorous PA (MVPA), and sedentary time were assessed by combined movement and heart rate sensor. RESULTS: Wmax/LM was not associated with glucose (ß = 0.065, 95% confidence interval [CI] = -0.031 to 0.161), insulin (ß = -0.079, 95% CI = -0.172 to 0.015), or HOMA-IR (ß = -0.065, 95% CI = -0.161 to 0.030). Wmax/BM was inversely associated with insulin (ß = -0.289, 95% CI = -0.377 to -0.200) and HOMA-IR (ß = -0.269, 95% CI = -0.359 to -0.180). The BF% was directly associated with insulin (ß = 0.409, 95% CI = 0.325 to 0.494) and HOMA-IR (ß = 0.390, 95% CI = 0.304 to 0.475). Higher Wmax/BM, but not Wmax/LM, was associated with lower insulin and HOMA-IR in children with higher BF%. Children with higher BF% and who had lower levels of MVPA or higher levels of sedentary time had the highest insulin and HOMA-IR. CONCLUSIONS: Children with higher BF% together with less MVPA or higher levels of sedentary time had the highest insulin and HOMA-IR. Cardiorespiratory fitness appropriately controlled for body size and composition using LM was not related to insulin resistance among children.

Branched-Chain and Aromatic Amino Acids Are Associated With Insulin Resistance During Pubertal Development in Girls.

PURPOSE: Cross-sectional studies in children show branched-chain and aromatic amino acids are associated with insulin resistance, but whether these associations persist from childhood to adulthood is not known. This study aimed to assess whether circulating amino acids associate with insulin resistance during pubertal development. METHODS: This was a 7.5-year longitudinal study from childhood to early adulthood. A total of 396 nondiabetic Finnish girls aged 11.2 ± .8 years at baseline participated in the study which was conducted at the Health Science Laboratory, University of Jyväskylä. Serum concentrations of glucose and insulin were determined by enzymatic photometric methods and amino acids by nuclear magnetic resonance spectroscopy. Insulin resistance was determined by the homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: All amino acids were positively associated with HOMA-IR both before and after menarche (p < .05 for all), except for histidine. Branched-chain amino acids and aromatic amino acids showed the strongest associations, the magnitude of correlation coefficients being similar before and after menarche (R2 = .064-.171). After adjusting for body mass index z-score and height, the associations between branched-chain amino acids and aromatic amino acids and HOMA-IR remained significant both before and after menarche. CONCLUSIONS: Branched-chain amino acids and aromatic amino acids associate with insulin resistance during pubertal development, independent of adiposity. Further studies are needed to determine whether changes in amino acid metabolism link pubertal hyperinsulinemia to accelerated physiological growth and/or heightened cardiometabolic risk later in life.

Does sex hormone-binding globulin cause insulin resistance during pubertal growth?

BACKGROUND: The directional influences between serum sex hormone-binding globulin (SHBG), adiposity and insulin resistance during pubertal growth remain unclear. The aim of this study was to investigate bidirectional associations between SHBG and insulin resistance (HOMA-IR) and adiposity from childhood to early adulthood. METHODS: Participants were 396 healthy girls measured at baseline (age 11.2 years) and at 1, 2, 4 and 7.5 years. Serum concentrations of estradiol, testosterone and SHBG were determined by ELISA, glucose and insulin by enzymatic photometry, insulin-like growth factor 1 (IGF-1) by time-resolved fluoroimmunoassays, whole-body fat mass by dual-energy X-ray absorptiometry and HOMA-IR were determined by homeostatic model assessment. The associations were examined using cross-lagged path models. RESULTS: In a cross-lagged path model, SHBG predicted HOMA-IR before menarche ß = -0.320 (95% CI: -0.552 to -0.089), P = 0.007, independent of adiposity and IGF-1. After menarche, no directional effect was found between SHBG and insulin resistance or adiposity. CONCLUSIONS: Our results suggest that in early puberty, decline in SHBG predicts development of insulin resistance, independent of adiposity. However, after menarche, no directional influences between SHBG, adiposity and insulin resistance were found, suggesting that observational associations between SHBG, adiposity and insulin resistance in pubertal children may be subject to confounding. Further research is needed to understand the underlying mechanisms of the associations between SHBG and cardiometabolic risk markers in peripubertal children.

DNA methylation links prenatal smoking exposure to later life health outcomes in offspring.

BACKGROUND: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. METHODS: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. RESULTS: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10-7) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. CONCLUSIONS: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

Timing of Exercise Affects Glycemic Control in Type 2 Diabetes Patients Treated with Metformin.

OBJECTIVE: The purpose of the study was to examine the acute effects of the timing of exercise on the glycemic control during and after exercise in T2D. METHODS: This study included 26 T2D patients (14 women and 12 men) who were treated with metformin. All patients were tested on four occasions: metformin administration alone (Metf), high-intensity interval training (HIIT) performed at 30 minutes (EX30), 60 minutes (EX60), and 90 minutes (EX90) postbreakfast, respectively. Glucose, insulin, and superoxide dismutase (SOD) activity were examined. RESULTS: Glucose decreased significantly after the exercise in EX30, EX60, and EX90. Compared with Metf, the decline in glucose immediately after the exercise was larger in EX30 (-2.58 mmol/L; 95% CI, -3.36 to -1.79 mmol/L; p < 0.001), EX60 (-2.13 mmol/L; 95% CI, -2.91 to -1.34 mmol/L; p < 0.001), and EX90 (-1.87 mmol/L; 95% CI, -2.65 to -1.08 mmol/L; p < 0.001), respectively. Compared with Metf, the decrease in insulin was larger in EX30 and EX60 (both p < 0.001). CONCLUSIONS: Timing of exercise is a factor to consider when prescribing exercise for T2D patients treated with metformin. This trial is registered with ChiCTR-IOR-16008469 on 13 May 2016.