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Laura A Da Costa,1,2,*Paul Arora,2,3,* Bibiana García-Bailo,1,2 Mohamed Karmali,1,2 Ahmed El-Sohemy,1 Alaa Badawi2 1Department of Nutritional Sciences, University of Toronto; 2Office of Biotechnology and Population Health, Public Health Agency of Canada; 3Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada *These authors contributed equally to this article Introduction: Obesity is associated with a state of chronic inflammation, and increased cardiometabolic disease risk. The present study examined the relationship between body mass index (BMI) and cardiometabolic and inflammatory biomarkers among normal weight, overweight, and obese Canadian adults.Methods: Subjects (n = 1805, aged 18 to 79 years) from the Canadian Health Measures Survey (CHMS) were examined for associations between BMI, cardiometabolic markers (apolipoprotein [Apo] A1, ApoB, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol, total cholesterol/HDL ratio [total:HDL-C ratio], triglycerides, and glycosylated hemoglobin [HbA1c]), inflammatory factors (C-reactive protein [CRP], fibrinogen, and homocysteine), and 25-hydroxyvitamin D [25(OH)D]. Bootstrap weights for variance and sampling weights for point estimates were applied to account for the complex survey design. Linear regression models adjusted for age, sex, physical activity, smoking status, and ethnicity (in addition to season of clinic visit, for vitamin D analyses only) were used to examine the association between cardiometabolic markers, inflammatory factors, and BMI in Canadian adults.Results: All biomarkers were significantly associated with BMI (P ≤ 0.001). ApoA1 (β = −0.31, P < 0.0001), HDL-C (β = −0.61, P < 0.0001), and 25(OH)D (β = −0.25, P < 0.0001) were inversely associated with BMI, while all other biomarkers showed positive linear associations. Distinct patterns of association were noted among normal weight, overweight, and obese groups, excluding CRP which showed a significant positive association with BMI in the overall population (β = 2.80, P < 0.0001) and in the normal weight (β = 3.20, P = 0.02), overweight (β = 3.53, P = 0.002), and obese (β = 2.22, P = 0.0002) groups.Conclusions: There is an apparent profile of cardiometabolic and inflammatory biomarkers that emerges as BMI increases from normal weight to obesity. Understanding these profiles may permit developing an effective approach for early risk prediction for cardiometabolic disease.Keywords: obesity, inflammation, biomarkers, cardiometabolic disease

Cristina Cuda1, Bibiana Garcia-Bailo1,2, Mohamed Karmali1,2, Ahmed El-Sohemy1, Alaa Badawi21Department of Nutritional Sciences, University of Toronto, 2Office of Biotechnology, Genomics and Population Health, Public Health Agency of Canada, Toronto, Ontario, CanadaBackground: Increasing evidence suggests a role for inflammation in the development of type 2 diabetes. Elevated levels of inflammatory cytokines, including interleukin-6, have been associated with insulin resistance, and dietary lipids can increase cytokine production. The objective of this study was to determine whether a single nucleotide polymorphism near the IL6 gene (rs7801406) modifies the relationship between dietary fat and markers of insulin sensitivity.Methods: Subjects were healthy men and women aged 20–29 years from the Toronto Nutrigenomics and Health Study. Dietary intake was estimated using a one-month semiquantitative food frequency questionnaire. Fasting blood samples were taken for genotyping and biomarker measurement.Results: The single nucleotide polymorphism was not associated with any of the measures of insulin sensitivity. However, it modified the relationship between total dietary fat and the homeostasis model assessment of insulin resistance (P = 0.053 for interaction). Total fat intake was positively related to HOMA-IR in individuals homozygous for the G allele (ß = 0.005 ± 0.002, P = 0.03), but not among heterozygotes. There was an inverse relationship between total fat intake and HOMA-IR in individuals who were homozygous for the A allele (β= –0.012 ± 0.006, P = 0.047).Conclusion: These findings suggest that dietary fat influences insulin sensitivity differently depending on genotype.Keywords: interleukin-6, insulin sensitivity, nutrigenomics, dietary fat

Dietary inorganic nitrate lowers blood pressure (BP) in healthy individuals through improved nitric oxide (NO) bioavailability. However, there is limited evidence examining the long-term effects of dietary nitrate for managing hypertension. We aimed to determine whether the sustained intake of dietary nitrate improved BP and cardiovascular disease (CVD) risk factors in individuals with early-stage hypertension. The Dietary Nitrate (NO3) on BP and CVD Risk Factors (DINO3) Trial was a multi-center, double-blinded, parallel, randomized, controlled trial in participants with elevated BP. Participants were supplemented with high-nitrate (HN) (~400 mg nitrate) or low-nitrate (LN) vegetable powder (~50 mg nitrate) on top of their usual diets for 16 weeks. The primary outcome was office systolic BP at 16 weeks. The secondary outcomes were 24 h ambulatory BP, central BP, heart-rate-corrected augmentation index (AIx75), carotid–femoral pulse wave velocity (cf-PWV), lipids, and high-sensitivity C-reactive protein (hs-CRP). Sixty-six participants were randomized at baseline (39M:27F, age: 51.5 ± 10.8 years, BMI:27.9 ± 3.2 kg/m2). In an intention-to-treat analysis, no differences were observed between HN and LN groups in terms of office systolic BP at 16 weeks (3.91 ± 3.52 mmHg, p = 0.27) or secondary outcomes. In this exploratory study, sustained HN vegetable supplementation did not exhibit more favorable vascular effects than LN vegetable supplementation in individuals with elevated BP.

Abstract Background Inflammation and oxidative stress are associated with the development of numerous chronic diseases. Circulating ascorbic acid, α-tocopherol, and 25-hydroxyvitamin D (25(OH)D) may help reduce concentrations of pro-inflammatory cytokines through their antioxidant and anti-inflammatory properties. These micronutrients may act synergistically, and they may have different anti-inflammatory effects, but previous studies have assessed the link between each of these micronutrients and inflammation in isolation without controlling for the other micronutrients. Our objective was to examine the association between circulating concentrations of ascorbic acid, α-tocopherol, and 25(OH) D and a panel of pro-inflammatory cytokines in an ethnically diverse population of young adults. Methods Participants (n = 1,007) from the Toronto Nutrigenomics and Health study provided fasting blood samples for biomarker measurements and were subsequently categorized into tertiles for each micronutrient based on their circulating concentrations. We conducted Pearson’s correlation analyses across all micronutrients and cytokines. The associations between individual micronutrients and cytokines were examined using analysis of covariance with age, sex, waist circumference, ethnicity, physical activity, season of blood collection, total cholesterol, hormonal contraceptive use among women, and the other two micronutrients as covariates. Results We observed weak micronutrient-cytokine correlations, moderate correlations between certain cytokines, and strong correlations between specific cytokines, particularly interleukin 1- receptor antagonist (IL-1RA), interferon-γ (IFN-γ), and platelet-derived growth factor BB (PDGF-bb). After full covariate adjustment, circulating α-tocopherol was inversely associated with IFN-γ and regulated upon activation normal T-cell expressed and secreted (RANTES). We observed an unexpected positive association between ascorbic acid and IFN-γ. 25(OH)D was not associated with altered concentrations of any inflammatory biomarkers. Conclusions These findings suggest that α-tocopherol, but not ascorbic acid or 25(OH)D, is inversely associated with inflammation in healthy young adults.

Abstract Background Type 2 diabetes mellitus (T2DM) has been linked to a state of pre-clinical chronic inflammation resulting from abnormalities in the innate immune pathway. Serum levels of pro-inflammatory cytokines and acute-phase proteins, collectively known as 'inflammatory network', are elevated in the pre-, or early, stages of T2DM and increase with disease progression. Genetic variation can affect the innate immune response to certain environmental factors, and may, therefore, determine an individual's lifetime risk of disease. Methods We conducted a cross-sectional study in 6,720 subjects from the TwinsUK Registry to evaluate the association between 18 single nucleotide polymorphisms (SNPs) in five genes (TLR4, IL1A, IL6, TNFA, and CRP) along the innate immunity-related inflammatory pathway and biomarkers of predisposition to T2DM [fasting insulin and glucose, HDL- and LDL- cholesterols, triglycerides (TGs), amyloid-A, sensitive C-reactive protein (sCRP) and vitamin D binding protein (VDBP) and body mass index (BMI)]. Results Of 18 the SNPs examined for their association with nine metabolic phenotypes of interest, six were significantly associated with five metabolic phenotypes (Bonferroni correction, P ≤ 0.0027). Fasting insulin was associated with SNPs in IL6 and TNFA, serum HDL-C with variants of TNFA and CRP and serum sCRP level with SNPs in CRP. Cross-correlation analysis among the different metabolic factors related to risk of T2DM showed several significant associations. For example, BMI was directly correlated with glucose (r = 0.11), insulin (r = 0.15), sCRP (r = 0.23), LDL-C (r = 0.067) and TGs (r = 0.18) but inversely with HDL-C (r = -0.14). sCRP was also positively correlated (P < 0.0001) with insulin (r = 0.17), amyloid-A (r = 0.39), TGs (r = 0.26), and VDBP (r = 0.36) but inversely with HDL-C (r = -0.12). Conclusion Genetic variants in the innate immunity pathway and its related inflammatory cascade is associated with some metabolic risk factors for T2DM; an observation that may provide a rationale for further studying their role as biomarkers for disease early risk prediction.

Abstract Background This study aimed to investigate whether waist circumference (WC) or body mass index (BMI) is a better predictor of blood lipid concentrations among young men and women from different ethnocultural groups. Methods Participants were 1181 healthy men (n = 358) and women (n = 823) aged 20-29 years taken from the cross-sectional Toronto Nutrigenomics and Health Study. Analyses were conducted separately for men and women, and for Caucasian and East Asian ethnocultural groups. Serum triglycerides (TG) and total to HDL cholesterol ratio (TC:HDL cholesterol) were used as outcomes. Associations between the adiposity and blood lipid measures were examined using partial correlations and odds ratios derived from logistic regression models. Results WC had a stronger association with serum lipid concentrations than BMI. WC was significantly related to TG and TC:HDL cholesterol after adjusting for BMI and covariates among men and women (P ≤ 0.01). However, after adjusting for WC and covariates, BMI was not significantly associated with the two serum lipid measures. WC was a better predictor of TG and TC:HDL among all sex and ethnocultural subgroups except among East Asian women where little difference between the two measures was observed. Conclusions WC is a stronger predictor of cardiometabolic health when compared with BMI among young adults, especially among men.

Abstract Background Mixed CLA isomers variably affect bone resorption in animals and decrease osteoclast formation and activity in murine osteoclasts. These variable effects may be due to the different isomers present in commercial preparations of CLA, and the effects of the predominant individual isomers, 9cis,11trans (9,11) and 10trans,12cis (10,12) CLA are not clear. The objectives of this study were to determine the effects of the individual CLA isomers on osteoclast formation and activity from human CD14+ monocytes, and to determine whether any changes are accompanied by changes in cathepsin K, matrix metalloproteinase-9 (MMP-9), receptor activator of NF-κB (RANK) and tumour necrosis factor alpha (TNFα) gene expression. Osteoclasts were identified as TRAP+ multinucleated cells. Osteoclast activity was quantified by the amount of TRAP in the cultured media. Results At 50 μM, 9,11 CLA inhibited osteoclast formation by ~70%, and both 9,11 and 10,12 CLA decreased osteoclast activity by ~85–90%. Both isomers inhibited cathepsin K (50 μM 9,11 by ~60%; 10,12 by ~50%) and RANK (50 μM 9,11 by ~85%; 50 μM 10,12 by ~65%) expression, but had no effect on MMP-9 or TNFα expression. Conclusion 9,11 CLA inhibits osteoclast formation and activity from human cells, suggesting that this isomer may prevent bone resorption in humans. Although 10,12 CLA did not significantly reduce osteoclast formation, it reduced osteoclast activity and cathepsin K and RANK expression, suggesting that this isomer may also affect bone resorption.

Five years ago, with the editorial board of Frontiers in Nutrition, we took a leap of faith to outline the Goals for Nutrition Science - the way we see it (1). Now, in 2020, we can put ourselves to the test and take a look back. Without a doubt we got it right with several of the key directions. To name a few, Sustainable Development Goals (SDGs) for Food and Nutrition are part of the global public agenda, and the SDGs contribute to the structuring of international science and research. Nutritional Science has become a critical element in strengthening work on the SDGs, and the development of appropriate methodologies is built on the groundwork of acquiring and analyzing big datasets. Investigation of the Human Microbiome is providing novel insight on the interrelationship between nutrition, the immune system and disease. Finally, with an advanced definition of the gut-brain-axis we are getting a glimpse into the potential for Nutrition and Brain Health. Various milestones have been achieved, and any look into the future will have to consider the lessons learned from Covid-19 and the sobering awareness about the frailty of our food systems in ensuring global food security. With a view into the coming 5 years from 2020 to 2025, the editorial board has taken a slightly different approach as compared to the previous Goals article. A mind map has been created to outline the key topics in nutrition science. Not surprisingly, when looking ahead, the majority of scientific investigation required will be in the areas of health and sustainability. Johannes le Coutre, Field Chief Editor, Frontiers in Nutrition.

Five years ago, with the editorial board of Frontiers in Nutrition, we took a leap of faith to outline the Goals for Nutrition Science - the way we see it (1). Now, in 2020, we can put ourselves to the test and take a look back. Without a doubt we got it right with several of the key directions. To name a few, Sustainable Development Goals (SDGs) for Food and Nutrition are part of the global public agenda, and the SDGs contribute to the structuring of international science and research. Nutritional Science has become a critical element in strengthening work on the SDGs, and the development of appropriate methodologies is built on the groundwork of acquiring and analyzing big datasets. Investigation of the Human Microbiome is providing novel insight on the interrelationship between nutrition, the immune system and disease. Finally, with an advanced definition of the gut-brain-axis we are getting a glimpse into the potential for Nutrition and Brain Health. Various milestones have been achieved, and any look into the future will have to consider the lessons learned from Covid-19 and the sobering awareness about the frailty of our food systems in ensuring global food security. With a view into the coming 5 years from 2020 to 2025, the editorial board has taken a slightly different approach as compared to the previous Goals article. A mind map has been created to outline the key topics in nutrition science. Not surprisingly, when looking ahead, the majority of scientific investigation required will be in the areas of health and sustainability. Johannes le Coutre, Field Chief Editor, Frontiers in Nutrition.

Approximately 16% of North American couples are affected by infertility, with 30% of cases being attributable to male factor infertility. The regulation of reproductive hormones via the hypothalamic–pituitary–gonadal axis is important for spermatogenesis and subsequently male fertility. Maintaining iron homeostasis is critical to normal reproductive physiological function. This cross-sectional study’s objective was to determine the association between serum biomarkers of iron and reproductive hormones. Men experiencing infertility (n = 303) were recruited from Mount Sinai Hospital, Toronto. Serum was analyzed for iron and ferritin as biomarkers of iron status and reproductive hormones (follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, and prolactin), which were the primary outcome. Associations were determined using non-parametric Spearman’s rank correlation coefficient, linear regressions, and logistic regressions. A significant independent monotonic inverse relationship between serum iron and prolactin (p = 0.0002) was found. In linear regression analyses, iron was inversely associated with luteinizing hormone (unadjusted p = 0.03, adjusted p = 0.03) and prolactin (unadjusted p = 0.001 and adjusted p = 0.003). Serum ferritin was inversely associated with both gonadotropins, follicle-stimulating hormone (adjusted p = 0.03), and luteinizing hormone (adjusted p = 0.02). These findings suggest that biomarkers of iron are associated with pituitary-produced reproductive hormones, which play a role in the hypothalamic–pituitary–gonadal signaling pathway involved in spermatogenesis, testicular testosterone production, and male fertility.

Dietary inorganic nitrate lowers blood pressure (BP) in healthy individuals through improved nitric oxide (NO) bioavailability. However, there is limited evidence examining the long-term effects of dietary nitrate for managing hypertension. We aimed to determine whether the sustained intake of dietary nitrate improved BP and cardiovascular disease (CVD) risk factors in individuals with early-stage hypertension. The Dietary Nitrate (NO3) on BP and CVD Risk Factors (DINO3) Trial was a multi-center, double-blinded, parallel, randomized, controlled trial in participants with elevated BP. Participants were supplemented with high-nitrate (HN) (~400 mg nitrate) or low-nitrate (LN) vegetable powder (~50 mg nitrate) on top of their usual diets for 16 weeks. The primary outcome was office systolic BP at 16 weeks. The secondary outcomes were 24 h ambulatory BP, central BP, heart-rate-corrected augmentation index (AIx75), carotid–femoral pulse wave velocity (cf-PWV), lipids, and high-sensitivity C-reactive protein (hs-CRP). Sixty-six participants were randomized at baseline (39M:27F, age: 51.5 ± 10.8 years, BMI:27.9 ± 3.2 kg/m2). In an intention-to-treat analysis, no differences were observed between HN and LN groups in terms of office systolic BP at 16 weeks (3.91 ± 3.52 mmHg, p = 0.27) or secondary outcomes. In this exploratory study, sustained HN vegetable supplementation did not exhibit more favorable vascular effects than LN vegetable supplementation in individuals with elevated BP. [ABSTRACT FROM AUTHOR]

Caffeine is commonly used to improve athletic performance across a variety of sports. Previously, the CYP1A2 gene has been shown to modify the effects of caffeine on endurance performance. The effect of caffeine on strength and power activities is unclear and may differ depending on an individual's CYP1A2 genotype. A randomized controlled trial was used to determine whether caffeine impacts strength and power, determined by the handgrip and vertical jump tests, respectively, and whether CYP1A2 genotype modifies any effects. Competitive male athletes (age = 25 ± 4 years) completed vertical jump (n = 97), and handgrip tests (n = 102) under three conditions: 0 (placebo), 2, or 4 mg of caffeine per kilogram of body mass (in milligrams per kilogram). CYP1A2 (rs762551) genotype was determined from saliva samples. No differences between caffeine doses and placebo were observed for strength or power; however, significant Caffeine × Gene interactions were observed for all exercise tests. Individuals with the CC genotype experienced a 12.8% decrease in handgrip strength with 4 mg/kg of caffeine compared with placebo (53 ± 11 kg vs. 61 ± 17 kg, p =.02). No differences were observed in those with the AC or AA genotypes. Despite observing a significant Caffeine × Gene interaction for vertical jump performance, no differences were observed between caffeine doses and placebo for all genotypes. In summary, caffeine (4 mg/kg) worsened handgrip strength performance in those with the CC genotype, but no differences were observed in those with the AC or AA genotypes. Athletes may want to consider their CYP1A2 genotype prior to using caffeine to improve muscle strength. [ABSTRACT FROM AUTHOR]

Past research in rodents suggests that fatty acid (FA) desaturase expression and activity may be modified by vitamin A; however, this has not been investigated in humans. The primary objective of this study was to examine associations between dietary retinoid intakes, plasma retinoid concentrations, and FA desaturase indices in young adults. As a secondary objective, biological sex and estrogen‐containing contraceptive (EC) use were investigated due to prior evidence demonstrating that both can influence plasma retinol concentration and FA desaturase indices. Dietary retinoid intake (food frequency questionnaire), plasma retinoid concentrations (high‐performance liquid chromatography–tandem mass spectrometry), plasma FA (gas chromatography), and FA desaturase indices (product‐to‐precursor ratios) from 945 adults recruited for the cross‐sectional Toronto Nutrigenomics and Health study were analyzed. Participants were stratified into quartiles based on plasma retinol concentration and data analyzed by one‐way analysis of covariance. Dietary retinoid intakes were not associated with the overall n‐3 pathway, overall n‐6 pathway, delta‐5 desaturase, delta‐6 desaturase, or delta‐9 desaturase indices (all r < 0.10, p > 0.05). The overall n‐6 pathway index was significantly higher (p = 0.0004) and the delta‐5 desaturase index was significantly lower (p = 0.0003) in individuals with higher plasma retinol levels; however, these differences were lost when participants were grouped by biological sex and EC use. Although weak relationships were observed between plasma retinol and some FA desaturase indices in the total population, these associations appear to be driven by biological sex and EC usage rather than retinoids. We therefore find little evidence of a relationship between retinoids and FA desaturase indices in young, healthy adults. [ABSTRACT FROM AUTHOR]

Premenstrual symptoms are a cyclically occurring combination of adverse psychological and somatic symptoms that impact the quality of life for most females of childbearing age. Growing evidence suggests that diet may attenuate premenstrual symptoms; however, the relationship between vitamin C and premenstrual symptoms remains unclear. The aim of the research was to determine the association between different measures of vitamin C status and premenstrual symptoms. Females (n = 555) aged 20 to 29 years from the Toronto Nutrigenomics and Health Study completed a General Health and Lifestyle Questionnaire, capturing 15 premenstrual symptoms. Dietary intake was measured using a 196-item Toronto-modified Harvard food frequency questionnaire. Serum ascorbic acid concentrations were measured, and participants were categorized into deficient (<11 µmol/L), suboptimal (11–28 µmol/L), and adequate (>28 µmol/L) ascorbic acid levels. DNA was genotyped for the GSTT1 (Ins/Del) polymorphism. Using logistic regression, odds of experiencing premenstrual symptoms were compared between vitamin C intake levels above and below the recommended daily allowance (75 mg/d) between ascorbic acid levels and between GSTT1 genotypes. Increased vitamin C intake was associated with premenstrual appetite changes (OR, 1.65; 95% CI, 1.01–2.68). Compared to deficient ascorbic acid levels, suboptimal levels were associated with premenstrual appetite changes (OR, 2.59; 95% CI, 1.02–6.58) and bloating/swelling (OR, 3.00; 95% CI, 1.09–8.22). Adequate serum ascorbic acid levels were not associated with premenstrual appetite changes (OR, 1.69; 95% CI, 0.73–3.94) or bloating/swelling (OR, 1.92; 95% CI, 0.79–4.67). Those with the GSTT1 functional variant (Ins*Ins) had an increased risk of premenstrual bloating/swelling (OR, 1.96; 95% CI, 1.10–3.48); however, the interaction between vitamin C intake and GSTT1 was not significant for any premenstrual symptoms. Our findings suggest that indicators of higher vitamin C status are associated with increased premenstrual appetite changes and bloating/swelling. The observed associations with GSTT1 genotype suggest that these observations are not likely due to reverse causation. The results of this study suggest that greater vitamin C intake may exacerbate premenstrual boating and increases of appetite in women. Our discovery that the functional GSTT1 variant linked to higher serum ascorbic acid concentrations are also linked to an increased risk of premenstrual appetite changes suggests that the dietary effects we observed are not due to reverse causation. These findings highlight the importance of personalized, evidence-based guidelines for the management of premenstrual disorders. [ABSTRACT FROM AUTHOR]

Introduction: Infertility affects about 16% of North American couples, with the male factor contributing to ~30% of cases. Reproductive hormones play an integral role in regulating the reproductive system and consequently, fertility. Oxidative stress reduces testosterone synthesis, and reduction in oxidative stress can improve hormone profiles. Ascorbic acid is a potent antioxidant that accounts for up to 65% of seminal antioxidant activity; however, its effects on reproductive hormones in humans are unknown. Methods: The objective was to determine the association between serum ascorbic acid concentrations and male reproductive hormones. We conducted a crosssectional study involving infertile males (n = 302) recruited from Mount Sinai Hospital, Toronto. Serum was analyzed for ascorbic acid, luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), prolactin and estradiol. Statistical analyses included Spearman's rank correlations, linear regressions, logistic regressions, simple slope and Johnson-Neyman procedures. Results: After adjusting for covariates, ascorbic acid was inversely associated with LH (P = 0.01). Ascorbic acid was positively associated with TT only among males over the age of 41.6 years (P = 0.01). Discussion: Our findings show that ascorbic acid is associated with higher testosterone levels and improved androgenic status in infertile males, and some of the effects appear to be age dependent. [ABSTRACT FROM AUTHOR]