Activation of the UPR sensor ATF6α is regulated by its redox-dependent dimerization and ER retention by ERp18.

SignificanceMembrane and secretory proteins are synthesized in the endoplasmic reticulum (ER). Perturbations to ER function disrupts protein folding, causing misfolded proteins to accumulate, a condition known as ER stress. Cells adapt to stress by activating the unfolded protein response (UPR), which ultimately restores proteostasis. A key player in the UPR response is ATF6α, which requires release from ER retention and modulation of its redox status during activation. Here, we report that ER stress promotes formation of a specific ATF6α dimer, which is preferentially trafficked to the Golgi for processing. We show that ERp18 regulates ATF6α by mitigating its dimerization and trafficking to the Golgi and identify redox-dependent oligomerization of ATF6α as a key mechanism regulating its function during the UPR.

Results from the China 2022 report card on physical activity for children and adolescents.

Background/Objective: Regular physical activity (PA) is beneficial to young people's health and development. In order to provide nationally representative and internationally comparable evidence on youth PA, China has participated in Global Matrix 2.0 and 3.0. The purpose of this study is to report the updated results of China's Report Card on PA for Children and Adolescents. Methods: The grades were assigned by results derived from the PA and Fitness in China--The Youth Study (PAFCTYS), conducted from October to December in 2020. The data from PAFCTYS 2020 included a nationally representative sample of Chinese school-aged children (n = 133,006, boys: 49.6%, aged 9-17 years). Self-report questionnaires were completed by the sampled students, their parents/guardians (n = 133,006), and physical education teachers (n = 1036) from each sampled school respectively. Results: The grades of China 2022 Report Card are Overall PA (C), Organized Sport Participation (F), Active Play (C-), Active Transportation (C), Sedentary behaviors (C), Physical Fitness (INC), Family and Peers (C-), School (D), Community and Environment (D-), and Government (D). Conclusion: Levels of PA among Chinese youth were low and most young people were below the recommended guidelines, although the grade of Overall PA has been improved since the modified benchmark. Prevalence of sedentary behaviors remained high. Interventions and policies at the community and environment level should be encouraged to promote PA and reduce sedentary behaviors. In addition, national policies on young people's PA should be advocated widely to ensure the policies can be transferred into action.

The mammalian cytosolic thioredoxin reductase pathway acts via a membrane protein to reduce ER-localised proteins.

Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfides. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is crucial for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER. These results provide compelling evidence for the crucial role of the cytosol in regulating ER redox homeostasis, ensuring correct protein folding and facilitating the degradation of misfolded ER proteins.

Cytosolic thioredoxin reductase 1 is required for correct disulfide formation in the ER.

Folding of proteins entering the secretory pathway in mammalian cells frequently requires the insertion of disulfide bonds. Disulfide insertion can result in covalent linkages found in the native structure as well as those that are not, so-called non-native disulfides. The pathways for disulfide formation are well characterized, but our understanding of how non-native disulfides are reduced so that the correct or native disulfides can form is poor. Here, we use a novel assay to demonstrate that the reduction in non-native disulfides requires NADPH as the ultimate electron donor, and a robust cytosolic thioredoxin system, driven by thioredoxin reductase 1 (TrxR1 or TXNRD1). Inhibition of this reductive pathway prevents the correct folding and secretion of proteins that are known to form non-native disulfides during their folding. Hence, we have shown for the first time that mammalian cells have a pathway for transferring reducing equivalents from the cytosol to the ER, which is required to ensure correct disulfide formation in proteins entering the secretory pathway.

Effects of interrupting sitting with different activity bouts on postprandial lipemia: A randomized crossover trial.

To determine whether interrupting prolonged sitting with three different activity breaks has both acute and chronic effects on postprandial lipid metabolism immediately after the activity-break period and on the following day, this study is a secondary analysis of an experimental research, which included 16 sedentary healthy adults (7 men, 24 ± 3 years, BMI 22.2 ± 2.3 kg/m2 ) who completed four 26-h laboratory trials. Participants spent 22.5 hours in a whole room calorimeter for testing energy expenditure (EE), including a 9-h activity-break period: (a) 9-h prolonged sitting (SIT); (b) 3 minutes of brisk walking (60% VO2max ) in between every 30-min sitting bout (WALK3), (c) 5 minutes every 45-min (WALK5), and (d) 8 minutes every 60-min (WALK8). Total area under the curve (tAUC) and incremental AUC (iAUC) for 2-h postprandial serum triglyceride (TG) levels and non-esterified fatty acid (NEFA) levels were examined immediately after the 9-h trial (post-dinner) and the next morning (post-breakfast). WALK8 reduced the post-breakfast TG tAUC by 11% (P = .041) relative to SIT, and the effect was attenuated after adjustment for EE. The tAUC and iAUC indicated no significant treatment effects on post-dinner TG and NEFA, and post-breakfast NEFA in any of the activity-break trials. EE was positively associated with the post-breakfast NEFA iAUC (unstandardized ß = 0.17 µmol/L/MJ [0.05-0.28], P = .006). There was a chronic effect of interrupting sitting with short bouts (8 minutes) of brisk walking every 60 minutes on postprandial lipemia the following morning after intervention, and higher activity bout-induced EE may be more effective in sedentary, healthy adults.

Associations between various kinds of parental support and physical activity among children and adolescents in Shanghai, China: gender and age differences.

BACKGROUND: The associations between various kinds of parental support and children and adolescents' physical activity (PA) are inconclusive. This study aimed 1) to examine the associations between various kinds of parental support and children and adolescents' moderate-to-vigorous physical activity (MVPA), and 2) to examine gender and age differences in the association between each specific kind of parental support and MVPA. METHODS: Using a multi-stage stratified and random cluster sampling method, 711 schools in Shanghai were selected (data were collected from October 2014 to February 2015). In total, 61,429 school-aged children (6-18 years old, 50.7% boys) and their parents were included. Self-reported questionnaires were used to measure sociodemographic characteristics, MVPA and various kinds of parental support, including parental encouragement (PAEN), parental involvement (PAIV), parental financial support (PAFS) and, parental modeling (PAMD). Descriptive statistics and Chi-square were used to report the level of MVPA and its difference across various kinds of parental support by gender groups. The logistic regression analysis was used to examine the associations between parental support and MVPA with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Overall, 19.4% of children and adolescents accumulated MVPA at least 60 min/day. Boys were more physically active than girls (21.4% > 17.4%, p <  0.001). According to the observation of OR estimates, girls may be more susceptible to the influences from various kinds of parental support than boys (OR = 1.59, 1.61, 1.27 and 1.63, 95% CI: 1.19-1.73 among girls, and OR = 1.48, 1.60, 1.21, and 1.60, 95% CI: 1.14-1.69 among boys for PAEN, PAIV, PAFS and PAMD respectively). PAMD is the only one supportive kind that was positively associated with MVPA in both genders across all grades (OR = 1.29-2.98, 95% CI: 1.09-4.08 among boys; OR = 1.27-2.64, 95% CI: 1.10-4.10 among girls). CONCLUSIONS: Less than one fifth of children and adolescents accumulated 60 min MVPA per day. Various kinds of parental support have important effects on children and adolescents' MVPA, which varied by gender and grades. PAMD, in particular, should be emphasized more than PAEN, PAIV and PAFS in family-based interventions aiming at increasing PA in the future.

Effect of Vitamin D Supplementation on Body Composition and Physical Fitness in Healthy Adults: A Double-Blind, Randomized Controlled Trial.

INTRODUCTION: This study aimed to clarify whether 1 year of vitamin D3 supplementation has a direct effect on body composition and physical fitness in healthy adults. METHODS: Ninety-five participants randomly received either 420 IU vitamin D3 per day (n = 48) or placebo (n = 47) in a double-blind manner for 1 year. Lean body mass and percentage body fat were determined. Physical fitness including hand grip strength, leg extension power and cardiorespiratory fitness (CRF) were assessed. Serum 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations were assessed using ELISA kits. RESULTS: Serum 25(OH)D and (1,25[OH]2D) concentrations significantly increased by approximately 11.2 ± 9.2 ng/mL (pinteraction <0.001)and 7.0 ± 7.8 pg/mL (pinteraction <0.001) after 1 year of vitamin D3 supplementation respectively. Lean body mass significantly increased from 43.8 ± 9.6 to 44.3 ± 9.8 kg in vitamin D group, while no change was observed in placebo group (from 42.6 ± 8.9 to 42.4± 8.9 kg) after 1 year intervention. Furthermore, no treatment effects on other indicators of body composition and physical fitness were observed. CONCLUSIONS: One year of vitamin D supplementation effectively improves lean body mass, but not muscle strength and CRF in healthy adults.

Methionine sulfoxide reductase B3 requires resolving cysteine residues for full activity and can act as a stereospecific methionine oxidase.

The oxidation of methionine residues in proteins occurs during oxidative stress and can lead to an alteration in protein function. The enzyme methionine sulfoxide reductase (Msr) reverses this modification. Here, we characterise the mammalian enzyme Msr B3. There are two splice variants of this enzyme that differ only in their N-terminal signal sequence, which directs the protein to either the endoplasmic reticulum (ER) or mitochondria. We demonstrate here that the enzyme can complement a bacterial strain, which is dependent on methionine sulfoxide reduction for growth, that the purified recombinant protein is enzymatically active showing stereospecificity towards R-methionine sulfoxide, and identify the active site and two resolving cysteine residues. The enzyme is efficiently recycled by thioredoxin only in the presence of both resolving cysteine residues. These results show that for this isoform of Msrs, the reduction cycle most likely proceeds through a three-step process. This involves an initial sulfenylation of the active site thiol followed by the formation of an intrachain disulfide with a resolving thiol group and completed by the reduction of this disulfide by a thioredoxin-like protein to regenerate the active site thiol. Interestingly, the enzyme can also act as an oxidase catalysing the stereospecific formation of R-methionine sulfoxide. This result has important implications for the role of this enzyme in the reversible modification of ER and mitochondrial proteins.

Gender and age differences in the association between living arrangement and physical activity levels among youth aged 9-19 years in Shanghai, China: a cross-sectional questionnaire study.

BACKGROUND: We examined the correlations between living arrangement and the physical activity (PA) levels of youth aged 9-19 years while accounting for demographic factors such as age, sex, and socioeconomic status in Shanghai, China. METHODS: Cross-sectional analyses of data from the 2014 Physical Activity and Fitness in Shanghai China-The Youth Study was conducted. Participants were 33,213 primary (9-11-year-olds; n = 13,237), junior middle (12-14-year-olds; n = 11,157), and junior high school students (15-19-year-olds; n = 8819). Youth (boys = 49%) and their guardians were randomly sampled from 17 districts in Shanghai, China. Youths' moderate-to-vigorous PA (MVPA) levels, information about living arrangement, and guardians' sociodemographic factors were collected via questionnaires. RESULTS: Only 17.8% of school-aged youths in Shanghai met MVPA recommendations, with significantly more boys (20.6%) meeting recommendations than girls (p < .001). Youths living in rural areas showed an overall significantly higher percentage of meeting MVPA recommendations (20.3%) than those living in urban areas (p < .001). Youths who lived with single parents showed an overall significantly lower percentage of meeting MVPA recommendations (15.3%) than those living with their grandparent(s) or with both parents (p < .001). A logistic regression analysis revealed that, among 9-11-year-olds, children who live with their grandparent(s) were less likely to meet MVPA recommendations than those who lived with both parents (boys: adjusted odds ratio (aOR) = 0.72, 95% confidence interval (CI) = 0.61-0.84; girls: aOR = 0.84, 95%CI = 0.72-0.98). CONCLUSIONS: Type of living arrangement was associated with the PA of youth in Shanghai, with no significant gender difference. Youth aged 9-19 years who lived with single parents had the lowest percentage of meeting MVPA recommendations. The probability of achieving 60 min/day MVPA recommendations was significantly lower among 9-11-year-old children living with their grandparent(s) than children living with both parents; however, no such difference was observed among adolescents. Our findings suggest that living arrangement may be an important consideration for promotion of PA among youth in China.

Physical activity, screen viewing time, and overweight/obesity among Chinese children and adolescents: an update from the 2017 physical activity and fitness in China-the youth study.

BACKGROUND: With increases in inactive lifestyles and mounting pressure for academic excellence in Chinese younger populations, lack of physical activity and increased prevalence of obesity have become a major public health concern in China. The purpose of this study is to provide updated estimates on the prevalence of meeting moderate-vigorous physical activity (MVPA) and screen viewing time guidelines, and overweight and obesity among Chinese school-aged children and adolescents, with a secondary aim examining variations in prevalence by sex, grade groupings, and residential location. METHODS: The study sample came from the 2017 Physical Activity and Fitness in China-The Youth Study, a cross-sectional and national survey of 131,859 students (aged 7 to 19 years) from 986 public schools in China. Measures of MVPA, screen viewing time, and age- and sex-specific overweight and obese body mass index were used to calculate national prevalence estimates of Chinese school-aged children and adolescents. RESULTS: In 2017, 34.1% (95% confidence interval [CI], 34.09-34.11%) of children and adolescents met MVPA guidelines and 65.4% (95% CI, 65.39-65.41%) adhered to screen viewing time guidelines. The prevalence of overweight and obesity was 15.1% (95% CI, 15.09-15.11%) and 10.7% (95% CI, 10.69-10.71%), respectively. Prevalence estimates differed by sex (boys, girls), grade grouping (primary schools, junior middle schools, junior high schools), and residential location (rural, urban). CONCLUSIONS: There remains a low prevalence of meeting MVPA guidelines and high prevalence of overweight and obesity in Chinese school-aged children and adolescents. Future efforts should focus on monitoring the trend of these behavioral and health risk factors to inform school policies and programs aimed at increasing physical activity and reducing and preventing obesity in younger populations in China.

Association of Serum 25-Hydroxyvitamin D Concentrations With Glucose Profiles in Male Collegiate Football Athletes.

Low serum 25-hydroxyvitamin D [25(OH)D] concentrations are associated with a high risk of insulin resistance and Type 2 diabetes mellitus in adults. However, it is unknown whether this is the case for American collegiate football and rugby football athletes. This study investigated the associations between serum 25(OH)D concentrations and glucose profiles in male collegiate football athletes. Thirty-four collegiate athletes (13 American football players and 21 rugby football players) aged 21 years were recruited. Their body fat percent and visceral fat area were measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, respectively. The participants completed an oral glucose tolerance test (75 g glucose) with venous blood samples obtained at time points 0, 30, 60, 90, and 120 min for the determination of plasma glucose and serum insulin concentrations. Fasting serum 25(OH)D concentrations were also measured. The prevalence of vitamin D deficiency and insufficiency was 17.6% and 58.8%, respectively. The serum 25(OH)D concentrations were negatively associated with the increments in the areas under the curve (iAUC) for glucose (r = -.429, p = .011) and were borderline significantly correlated with the Matsuda index (r = -.303, p = .082). No relationships were observed between the serum 25(OH)D concentrations and other glucose profiles. Multiple stepwise regression analysis of glucose iAUC concentrations as the dependent variable indicated that the serum 25(OH)D concentrations, but not body fat indicators, were independently associated with glucose iAUC (ß = -0.390, p = .025). The serum 25(OH)D concentrations were only an independent predictor for glucose iAUC in male collegiate football athletes, suggesting that increased 25(OH)D concentrations would be helpful for maintaining glucose homeostasis.

Ageing affects the association between serum 25- hydroxyvitamin D concentrations and cardiorespiratory fitness in middle-aged and elderly men.

BACKGROUND AND OBJECTIVES: The studies investigated the association between serum 25-hydroxyvitamin D (25(OH)D) concentrations and cardiorespiratory fitness (CRF) are few, and the results are controversial. We aim to evaluate the association of serum 25(OH)D concentrations with CRF in adults, and assess whether the associations vary with ageing. METHODS AND STUDY DESIGN: The study included 78 middle-aged (30-64 years) and 83 elderly (65-79 years) Japanese men. Hand grip strength and leg extension power were measured using hand grip and leg dynamometers, respectively. CRF was measured via a maximal graded exercise test and quantified as the peak oxygen uptake (VO2peak). Fasting serum 25(OH)D concentrations were determined by enzyme-linked immunosorbant assay. RESULTS: Serum 25(OH)D concentrations were positively related to hand grip strength (r=0.331, p<0.001), leg extension power (r=0.353, p<0.001), CRF (r=0.285, p<0.001) in all adults after adjustment for age. Significant interaction between 25(OH)D and age on CRF was observed (p<0.05). Age-related reduction of CRF was prevented in high 25(OH)D group (p<0.05). In the elderly, subjects in high 25(OH)D group had higher CRF compared with those in low group (p<0.05). CONCLUSIONS: We found that serum 25(OH)D concentrations significantly related with leg extension power, hand grip strength and CRF after adjustment for age. The relationship of vitamin D and CRF was affected by ageing. Higher serum 25(OH)D concentrations are a key predictor for CRF in the elderly, but not in middle-aged men.

Co-existence of physical activity and sedentary behavior among children and adolescents in Shanghai, China: do gender and age matter?

BACKGROUND: There is limited evidence for the prevalence of the co-existence of physical activity (PA) and sedentary behavior (SED), and its correlates among children and adolescents. This study has two aims: 1) to investigate the prevalence of PA and SED, and their co-existence, and 2) to examine the associations between PA or SED, or both with gender and age among children and adolescents in Shanghai, China. METHODS: Using a cross-sectional study design (conducted from September to December 2014), 50,090 children and adolescents (10-18 years old, 50.4% boys) were included in this study. A self-reporting questionnaire was used to measure participants' sociodemographic characteristics, PA, and SED. Descriptive statistics were used to describe sample characteristics, the prevalence of PA and SED, and their co-existence. A Generalized Linear Model was conducted to explore the associations between the prevalence of PA and SED, and their co-existence with gender and age separately. RESULTS: Of the children and adolescents studied, only 18.4% met the guidelines for PA, 25.5% met the guidelines for SED, and 5.7% met the guidelines for both. Boys were more physically active (aOR = 1.43, 95% CI: 1.36-1.50), and girls were less sedentary (aOR = 1.29, 95%CI: 1.24-1.34). The prevalence of PA, SED, or both all declined as age increased (p < 0.001). Stratified analysis by gender revealed greater declining trends of meeting the PA or SED guidelines, or both in girls (all p < 0.005). CONCLUSION: Very few children and adolescents showed active lifestyles, and this was significantly related to age. Effective interventions aiming to promote PA and concurrently to limited SED among children and adolescents should be implemented as early as possible.

The Peroxiredoxin Family: An Unfolding Story.

Peroxiredoxins (Prxs) are a large and conserved family of peroxidases that are considered to be the primary cellular guardians against oxidative stress in all living organisms. Prxs share a thioredoxin fold and contain a highly-reactive peroxidatic cysteine in a specialised active-site environment that is able to reduce their peroxide substrates. The minimal functional unit for Prxs are either monomers or dimers, but many dimers assemble into decameric rings. Ring structures can further form a variety of high molecular weight complexes. Many eukaryotic Prxs contain a conserved GGLG and C-terminal YF motif that confer sensitivity to elevated levels of peroxide, leading to hyperoxidation and inactivation. Inactive forms of Prxs can be re-reduced by the enzyme sulfiredoxin, in an ATP-dependent reaction. Cycles of hyperoxidation and reactivation are considered to play an integral role in a variety of H2O2-mediated cell signalling pathways in both stress and non-stress conditions. Prxs are also considered to exhibit chaperone-like properties when cells are under oxidative or thermal stress. The roles of various types of covalent modifications, e.g. acetylation and phosphorylation are also discussed. The ability of Prxs to assemble into ordered arrays such as nanotubes is currently being exploited in nanotechnology.

The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme.

The membrane topology of vitamin K epoxide reductase (VKOR) is controversial with data supporting both a three transmembrane and a four transmembrane model. The positioning of the transmembrane domains and the loops between these domains is critical if we are to understand the mechanism of vitamin K oxidation and its recycling by members of the thioredoxin family of proteins and the mechanism of action of warfarin, an inhibitor of VKOR. Here we show that both mammalian VKOR isoforms adopt the same topology, with the large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). We used a redox sensitive green fluorescent protein (GFP) fused to the N- or C-terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin-like transmembrane protein (TMX) to demonstrate ER localization of the major loop. The topology is identical with the bacterial homologue from Synechococcussp., for which the structure and mechanism of recycling has been characterized. Our results provide a resolution to the membrane topology controversy and support previous results suggesting a role for members of the ER protein disulfide isomerase (PDI) family in recycling VKOR.

Lack of an efficient endoplasmic reticulum-localized recycling system protects peroxiredoxin IV from hyperoxidation.

Typical 2-Cys peroxiredoxins are required to remove hydrogen peroxide from several different cellular compartments. Their activity can be regulated by hyperoxidation and consequent inactivation of the active-site peroxidatic cysteine. Here we developed a simple assay to quantify the hyperoxidation of peroxiredoxins. Hyperoxidation of peroxiredoxins can only occur efficiently in the presence of a recycling system, usually involving thioredoxin and thioredoxin reductase. We demonstrate that there is a marked difference in the sensitivity of the endoplasmic reticulum-localized peroxiredoxin to hyperoxidation compared with either the cytosolic or mitochondrial enzymes. Each enzyme is equally sensitive to hyperoxidation in the presence of a robust recycling system. Our results demonstrate that peroxiredoxin IV recycling in the endoplasmic reticulum is much less efficient than in the cytosol or mitochondria, leading to the protection of peroxiredoxin IV from hyperoxidation.

Accuracy of segmental bioelectrical impedance analysis for predicting body composition in pre- and postmenopausal women.

This study aimed to compare the accuracy for predicting body composition using single-frequent segmental bioelectrical impedance analysis (BIA) between pre- and postmenopausal women. A total f 559 Japanese women aged 30-88yr were divided into 4 groups by questionnaire: natural menopause, pathological menopause, regular menstruation, or irregular menstruation. The measurement values by dual-energy X-ray absorptiometry were used as a reference of the body composition. In terms of the results, regardless of the menopausal status, BIA slightly but significantly overestimated the percentage of body fat (standard error of estimate: 5.3%-6.7%) and the leg lean soft tissue mass (LSTM; 5.1%-6.1%), and underestimated the LSTM in the whole body (6.2%-7.6%) and arm (2.8%-3.7%). The absolute values of the predictive error for leg LSTM were significantly higher in postmenopausal groups than in the premenopausal ones. The corresponding values for the whole body and arm LSTM, and the percentage of body fat were higher in premenopausal groups than in postmenopausal ones. In conclusion, the predictive accuracy of BIA for postmenopausal women is not inferior to that for premenopausal ones, unless we target the leg LSTM.

Polygenic risk for hypertriglyceridemia is attenuated in Japanese men with high fitness levels.

High cardiorespiratory fitness (CRF) is associated with a reduced risk for dyslipidemia; however, blood lipid levels are also affected by individual genetic variations. We performed a cross-sectional study to determine whether CRF modifies polygenic risk for dyslipidemia. Serum levels of triglycerides (TG), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) were measured in 170 Japanese men (age 20-79 yr). CRF was assessed by measuring maximal oxygen uptake (Vo2max), and subjects were divided into low-fitness and high-fitness groups according to the reference Vo2max value for health promotion in Japan. We analyzed 19 single nucleotide polymorphisms (SNPs) associated with TG, LDL-C, or HDL-C levels. Based on these SNPs, we calculated three genetic risk scores (GRSs: TG-GRS, LDL-GRS, and HDL-GRS), and subjects were divided into low, middle, and high groups according to the tertile for each GRS. Serum TG levels of low-fitness individuals were higher in the high and middle TG-GRS groups than in the low TG-GRS group (P < 0.01 and P < 0.05, respectively), whereas no differences were detected in the TG levels of high-fitness individuals among the TG-GRS groups. In contrast, the high LDL-GRS group had higher LDL-C levels than did the low LDL-GRS group, and HDL-C levels were lower in the high HDL-GRS group than in the low HDL-GRS group regardless of the fitness level (P < 0.05). These results suggest that high CRF attenuates polygenic risk for hypertriglyceridemia; however, high CRF may not modify the polygenic risk associated with high LDL-C and low HDL-C levels in Japanese men.

High cardiorespiratory fitness can reduce glycated hemoglobin levels regardless of polygenic risk for Type 2 diabetes mellitus in nondiabetic Japanese men.

High cardiorespiratory fitness (CRF) is associated with a reduced risk of Type 2 diabetes mellitus (T2DM) and improved ß-cell function; genetic factors also determine these risks. This cross-sectional study investigated whether CRF modifies the association of polygenic risk of T2DM with glucose metabolism in nondiabetic Japanese men. Fasting plasma glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured in 174 Japanese men (age: 20-79 yr). ß-Cell function and insulin resistance were evaluated by calculating HOMA-ß and HOMA-IR, respectively. CRF was assessed by measuring maximal oxygen uptake (V̇o2max). Subjects were divided into the low and high CRF groups within each age group according to the median V̇o2max. Eleven single nucleotide polymorphisms (SNPs) associated with T2DM were analyzed and used to calculate genetic risk score (GRS); subjects were divided into the low, middle, and high GRS groups. The high GRS group had higher HbA1c levels than the low GRS group in both the low and high CRF groups (P < 0.05). Furthermore, the individuals with a high GRS had a lower HOMA-ß than those with a low GRS regardless of CRF (P < 0.05). In multiple linear regression analysis, although GRS was a significant predictor of HbA1c (ß = 0.153, P = 0.025), V̇o2max was also associated with HbA1c (ß = -0.240, P = 0.041) independent of GRS. These results suggest that CRF is associated with HbA1c levels independent of GRS derived from T2DM-related SNPs; however, it does not modify the association of GRS with increased HbA1c or impaired ß-cell function.