Nutritional Aspects to Cardiovascular Diseases and Type 2 Diabetes Mellitus.

PURPOSE OF REVIEW: In this narrative review, we discuss the current evidence related to the role of dietary interventions to prevent and treat type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We also propose alternative therapeutic strategies other than weight loss in this population, namely, improvements in cardiorespiratory fitness and its determinants. RECENT FINDINGS: While weight loss has been consistently associated with the prevention of T2DM and improvements in glycemic control in those with established diseases, its role in preventing and treating CVD is less clear. In fact, in this setting, improvements in diet quality have provided greater benefits, suggesting that this might represent an alternative, or an even more effective strategy than energy-restriction. Improvements in diet quality, with and without caloric restriction have been shown to improve CVD risk and to prevent the development of T2DM in individuals at risk; however, with regard to glycemic control in patients with T2DM, any dietary intervention resulting in significant weight loss may produce clinically meaningful benefits. Finally, dietary interventions with and without energy restriction that can improve cardiorespiratory fitness, even in absence of weight loss in patients with obesity, should be encouraged.

Primary care providers' physical activity counseling and referral practices and barriers for cardiovascular disease prevention.

The US Preventive Services Task Force (USPSTF) recommends offering or referring adults who are overweight or obese and have additional cardiovascular disease (CVD) risk factors to intensive behavioral counseling interventions to promote a healthful diet and physical activity for CVD prevention. This study determined the proportion of primary care providers (PCPs) who discussed physical activity with most of their at-risk patients and referred them to intensive behavioral counseling, and reported barriers to counseling. Our analyses used data from DocStyles 2015, a Web-based panel survey of 1251 PCPs. Overall, 58.6% of PCPs discussed physical activity with most of their at-risk patients. Among these PCPs, the prevalence of components offered ranged from 98.5% encouraging increased physical activity to 13.9% referring to intensive behavioral counseling. Overall, only 8.1% both discussed physical activity with most at-risk patients and referred to intensive behavioral counseling. Barriers related to PCPs' attitudes and beliefs about counseling (e.g., counseling is not effective) were significantly associated with both discussing physical activity with most at-risk patients and referring them to intensive behavioral counseling (adjusted odds ratio, 1.92; 95% confidence interval, 1.15-3.20). System-level barriers (e.g., referral services not available) were not. Just over half of PCPs discussed physical activity with most of their at-risk patients, and few both discussed physical activity and referred patients to intensive behavioral counseling. Overcoming barriers related to attitudes and beliefs about physical activity counseling could help improve low levels of counseling and referrals to intensive behavioral counseling for CVD prevention.

The relationship between body composition and left ventricular performance in women with breast, lymphoma, or sarcoma cancer.

BACKGROUND: To understand how body composition in those with elevated body mass index impacts left ventricular function decline during cancer treatment, we determined the association between baseline body mass index (BMI), intra-abdominal adipose tissue (IAT) and subcutaneous adipose tissue (SAT) with baseline to 3-month left ventricular ejection fraction (LVEF) change among women receiving potentially cardiotoxic chemotherapy for breast cancer, lymphoma, or sarcoma. METHODS: Women underwent potentially cardiotoxic chemotherapy, such as doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab, for treatment of breast cancer, lymphoma, or sarcoma. We obtained magnetic resonance images (MRIs) of body composition and cardiac function prior to treatment, and then a repeat MRI for cardiac function assessment at three months into treatment. Analyses and assessment of abdominal adipose tissue volumes and LVEF outcomes were conducted by independent reviewers blinded to all patient identifiers. A general linear model was created to examine associations between adipose tissue depots, BMI, and 3-month LVEF change. RESULTS: Women (n = 210) aged 56 ± 11 years with breast cancer, lymphoma, and sarcoma were enrolled (n = 195, 14, 1 respectively). Baseline BMI, IAT, and SAT fat were independently associated with 3-month LVEF declines (p = 0.001 to 0.025 for all). After adjusting for baseline cardiovascular disease risk factors, BMI, IAT, and SAT, BMI remained the only variable associated with 3-month LVEF decline (p = 0.047). CONCLUSIONS: These results suggest that factors other than abdominal adipose tissue or traditional cardiovascular risk factors may contribute to 3-month declines in LVEF among women with elevated BMI receiving potentially cardiotoxic chemotherapy. Further investigation should be conducted on psychosocial stress, physical activity, sleep, or diet. TRIAL REGISTRATION: DETECTIV_NCT01719562, WF99112, & WF97415-NCT02791581.

Characterizing substrate utilization during the fasted state using plasma high-resolution metabolomics.

OBJECTIVES: High-resolution metabolomics enables global assessment of metabolites and molecular pathways underlying physiologic processes, including substrate utilization during the fasted state. The clinical index for substrate utilization, respiratory exchange ratio (RER), is measured via indirect calorimetry. The aim of this pilot study was to use metabolomics to identify metabolic pathways and plasma metabolites associated with substrate utilization in healthy, fasted adults. METHODS: This cross-sectional study included 33 adults (mean age 27.7 ± 4.9 y, mean body mass index 24.8 ± 4 kg/m2). Participants underwent indirect calorimetry to determine resting RER after an overnight fast. Untargeted metabolomics was performed on fasted plasma samples using dual-column liquid chromatography and ultra-high-resolution mass spectrometry. Linear regression and pathway enrichment analyses identified pathways and metabolites associated with substrate utilization measured with indirect calorimetry. RESULTS: RER was significantly associated with 1389 metabolites enriched within 13 metabolic pathways (P < 0.05). Lipid-related findings included general pathways, such as fatty acid activation, and specific pathways, such as C21-steroid hormone biosynthesis and metabolism, butyrate metabolism, and carnitine shuttle. Amino acid pathways included those central to metabolism, such as glucogenic amino acids, and pathways needed to maintain reduction-oxidation reactions, such as methionine and cysteine metabolism. Galactose and pyrimidine metabolism were also associated with RER (all P < 0.05). CONCLUSIONS: The fasting plasma metabolome reflects the diverse macronutrient pathways involved in carbohydrate, amino acid, and lipid metabolism during the fasted state in healthy adults. Future studies should consider the utility of metabolomics to profile individual nutrient requirements and compare findings reported here to clinical populations.

Increased adiposity is associated with altered skeletal muscle energetics.

The objective of this pilot study was to characterize relationships between skeletal muscle energy metabolism and body composition in healthy adults with varied amounts and distribution of adipose tissue. In vivo muscle energetics were quantified using dynamic 31P magnetic resonance spectroscopy with knee extension exercise standardized to subject lean body mass. Spearman's correlation analysis examined relationships between muscle metabolism indices and measures of adiposity including body mass index (BMI), total body fat, and quadriceps intermuscular adipose tissue (IMAT). Post hoc partial correlations were examined controlling for additional body composition measures. Kruskal-Wallis tests with Dunn-Sidak post hoc comparisons evaluated group differences in energy metabolism based on body composition profiles (i.e., lean, normal-weight obese, and overweight-obese) and IMAT tertiles. BMI negatively correlated with end-exercise muscle pH after correcting for IMAT and total body fat (r = -0.46, P = 0.034). Total adiposity negatively correlated with maximum oxidative capacity after correcting for IMAT (r = -0.54, P = 0.013). IMAT positively correlated with muscle proton buffering capacity after correcting for total body fat (r = 0.53, P = 0.023). Body composition groups showed differences in end-exercise fall in [PCr] with normalized workload (P = 0.036; post hoc: overweight-obese < lean, P = 0.029) and maximum oxidative capacity (P = 0.021; post hoc: normal-weight obese < lean, P = 0.016). IMAT tertiles showed differences in end-exercise fall in [PCr] with normalized workload (P = 0.035; post hoc: 3rd < 1st, P = 0.047). Taken together, these results support increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.NEW & NOTEWORTHY Skeletal muscle energy production is influenced by both lean body mass and adipose tissue but the effect of their distribution on energy metabolism is unclear. This study examined variations in quadriceps muscle energy metabolism in healthy adults with varied relative amounts of lean and adipose tissue. Results suggest increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.

Quality of dietary macronutrients is associated with glycemic outcomes in adults with cystic fibrosis.

Objective: Poor diet quality contributes to metabolic dysfunction. This study aimed to gain a greater understanding of the relationship between dietary macronutrient quality and glucose homeostasis in adults with cystic fibrosis (CF). Design: This was a cross-sectional study of N = 27 adults with CF with glucose tolerance ranging from normal (n = 9) to prediabetes (n = 6) to being classified as having cystic fibrosis-related diabetes (CFRD, n = 12). Fasted blood was collected for analysis of glucose, insulin, and C-peptide. Insulin resistance was assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA2-IR). Subjects without known CFRD also underwent a 2-h oral glucose tolerance test. Three-day food records were used to assess macronutrient sources. Dietary variables were adjusted for energy intake. Statistical analyses included ANOVA, Spearman correlations, and multiple linear regression. Results: Individuals with CFRD consumed less total fat and monounsaturated fatty acids (MUFA) compared to those with normal glucose tolerance (p < 0.05). In Spearman correlation analyses, dietary glycemic load was inversely associated with C-peptide (rho = -0.28, p = 0.05). Total dietary fat, MUFA, and polyunsaturated fatty acids (PUFA) were positively associated with C-peptide (rho = 0.39-0.41, all p < 0.05). Plant protein intake was inversely related to HOMA2-IR (rho = -0.28, p = 0.048). Associations remained significant after adjustment for age and sex. Discussion: Improvements in diet quality are needed in people with CF. This study suggests that higher unsaturated dietary fat, higher plant protein, and higher carbohydrate quality were associated with better glucose tolerance indicators in adults with CF. Larger, prospective studies in individuals with CF are needed to determine the impact of diet quality on the development of CFRD.

Higher diet quality relates to better cardiac function in cancer survivors: The multi-ethnic study of atherosclerosis.

BACKGROUND: Cancer therapies induce cardiac injury and increase cardiovascular disease (CVD) risk. In non-cancer populations, higher diet quality is associated with protection against CVD, but the relationship between diet and cardiac function in cancer survivors is unknown. METHODS: This cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort included 113 cancer survivors (55 breast, 53 prostate, three lung, and three blood) and 4233 non-cancer controls. Dietary intake was reported via validated food frequency questionnaire. Alternate healthy eating index (AHEI) was calculated as a measure of quality. Cardiac function, determined as left ventricular ejection fraction (LVEF), was assessed by cardiac magnetic resonance. RESULTS: Cancer survivors had a lower LVEF compared to controls (61.3 ± 6.5% v 62.4 ± 6.1%, p = 0.04). In all participants, total fat (ß ± SE: -0.04 ± 0.01, p = 0.004), saturated fat (-0.11 ± 0.03, p < 0.001), and trans-fat (-0.36 ± 0.12, p = 0.002) intake were inversely associated with LVEF while AHEI (0.03 ± 0.01, p < 0.001) was positively associated with LVEF. Among cancer survivors only, sucrose intake was negatively related to LVEF (-0.15 ± 0.06, p = 0.02), and the ratio of unsaturated fat to saturated fat (2.7 ± 1.1, p = 0.01) and fiber intake (0.42 ± 0.14, p = 0.003) were positively related to LVEF. DISCUSSION: In cancer survivors, improved dietary fat and carbohydrate quality (i.e., greater consumption of unsaturated fatty acids and fiber) was associated with favorable cardiac function, while higher sucrose was associated with worse cardiac function. Further research is needed to confirm these findings and test whether changes in the identified dietary factors will modulate cardiac function in cancer survivors.

Physical Activity During Breast Cancer Therapy Associates With Preserved Exercise Capacity and Cardiac Function (WF97415).

Background: Cancer treatment increases cardiovascular disease risk, but physical activity (PA) may prevent cardiovascular disease. Objectives: This study examined whether greater PA was associated with better submaximal exercise capacity and cardiac function during cancer therapy. Methods: Participants included 223 women with stage I to III breast cancer (BC) before and 3 months after undergoing treatment and 126 control participants. Leisure-time PA (LTPA) was reported using the Godin-Shephard LTPA questionnaire. Cardiac function was assessed by cardiac magnetic resonance. Submaximal exercise capacity was determined by 6-minute walk distance. Results: BC participants reported similar baseline LTPA scores (24.7; 95% CI: 21.7-28.0) as control participants (29.4; 95% CI: 25.0-34.2). The BC group declined to 16.9 (95% CI: 14.4-19.6) at 3 months relative to 30.8 (95% CI: 26.2-35.8) in control participants. Among BC participants, more LTPA was related to better exercise capacity (ß ± SE: 7.1 ± 1.6; 95% CI: 4.0-10.1) and left ventricular (LV) circumferential strain (-0.16 ± 0.07; 95% CI: -0.29 to -0.02). Increased LTPA over the 3 months was associated with decreased likelihood of treatment-induced cardiac dysfunction according to LV circumferential strain classifications (OR: 0.98; 95% CI: 0.97-0.998). BC participants reporting insufficient LTPA according to PA guidelines exhibited deteriorations in exercise capacity (adjusted mean difference ± SE: -29 ± 10 m; P = 0.029), LV end-systolic volume (5.8 ± 1.3 mL; P < 0.001), LV ejection fraction (-3.2% ± 0.8%; P = 0.002), and LV circumferential strain (2.5% ± 0.5%; P < 0.001), but BC participants meeting LTPA guidelines did not exhibit these adverse changes. Conclusions: PA declined during BC therapy; however, PA participation was associated with attenuated declines in exercise capacity and cardiac function that are often observed in this population. (Understanding and Predicting Breast Cancer Events After Treatment [WF97415 UPBEAT]; NCT02791581).

Sex differences in the relationships between body composition, fat distribution, and mitochondrial energy metabolism: a pilot study.

BACKGROUND: Adiposity and mitochondrial dysfunction are related factors contributing to metabolic disease development. This pilot study examined whether in vivo and ex vivo indices of mitochondrial metabolism were differentially associated with body composition in males and females. METHODS: Thirty-four participants including 19 females (mean 27 yr) and 15 males (mean 29 yr) had body composition assessed by dual energy x-ray absorptiometry and magnetic resonance (MR) imaging. Monocyte reserve capacity and maximal oxygen consumption rate (OCR) were determined ex vivo using extracellular flux analysis. In vivo quadriceps mitochondrial function was measured using 31P-MR spectroscopy based on post-exercise recovery kinetics (τPCr). The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin levels. Variables were log-transformed, and Pearson correlations and partial correlations were used for analyses. RESULTS: Mitochondrial metabolism was similar between sexes (p > 0.05). In males only, higher fat mass percent (FM%) was correlated with lower reserve capacity (r = - 0.73; p = 0.002) and reduced muscle mitochondrial function (r = 0.58, p = 0.02). Thigh subcutaneous adipose tissue was inversely related to reserve capacity in males (r = - 0.75, p = 0.001), but in females was correlated to higher maximal OCR (r = 0.48, p = 0.046), independent of FM. In females, lean mass was related to greater reserve capacity (r = 0.47, p = 0.04). In all participants, insulin (r = 0.35; p = 0.04) and HOMA-IR (r = 0.34; p = 0.05) were associated with a higher τPCr. CONCLUSIONS: These novel findings demonstrate distinct sex-dependent associations between monocyte and skeletal muscle mitochondrial metabolism with body composition. With further study, increased understanding of these relationships may inform sex-specific interventions to improve mitochondrial function and metabolic health.

Plasma high-resolution metabolomic phenotyping of lean mass in a United States adult cohort.

BACKGROUND: Rapid loss of lean mass during catabolic states is associated with impaired convalescence and increased mortality rates. An understanding of metabolic pathways related to lean mass is needed to enable future interventions designed to combat malnutrition. This study assessed the plasma metabolome in relation to lean mass in clinically stable working adults in a US cohort. METHODS: This cross-sectional study included 180 adults (mean ± SD, aged 49.7 ± 10.0 years; body mass index, 27.3 ± 5.5 kg/m2 ; 64% female [n=116]). Fasting plasma was analyzed using high-resolution metabolomics (HRM) via liquid chromatography/mass spectrometry. Lean mass was assessed by dual-energy x-ray absorptiometry and expressed as lean mass index (LMI, lean mass kg/height m2 ). Multiple linear regression, metabolic pathway enrichment, and module analyses were used to characterize systemic metabolism associated with LMI. RESULTS: Of 5360 metabolites used in analyses, 593 were related to LMI, either upregulated or downregulated (P < .05). These were enriched within 11 metabolic pathways, including branched-chain amino acid degradation, metabolism of alanine and aspartate and other amino acids, butyrate, purines, and niacin metabolism. Module analysis revealed central associations between LMI and L-glutamate, L-leucine/L-isoleucine, L-valine, L-phenylalanine, L-methionine, and L-aspartate, among other validated metabolites. CONCLUSION: These novel plasma HRM data demonstrate the wide-reaching associations of lean mass with systemic metabolism in a single snapshot. Such data may inform targeted nutrition support interventions designed to mitigate loss of lean mass and promote regaining skeletal muscle mass and function after illness or injury.

Relationships between plasma apelin and adiponectin with normal weight obesity, body composition, and cardiorespiratory fitness in working adults.

BACKGROUND: A significant proportion of adults have normal weight obesity (NWO), defined as a normal body mass index (BMI) but disproportionately high body fat percentage. Individuals with NWO may have increased risk of cardiometabolic disorders and lower exercise tolerance, but it is unclear if this obesity phenotype is linked with dysregulated production of adipokines or myokines such as adiponectin and apelin, respectively. METHODS: This cross-sectional, secondary analysis included 177 working adults (mean age 49.6 ± 9.9 yrs, 64% female). Plasma high-molecular weight adiponectin and apelin levels were measured by ELISA. Body composition and fat distribution were assessed using dual energy X-ray absorptiometry. Exercise tolerance (VO2 maximum) was determined by treadmill testing. NWO was defined as a BMI <25 kg/m2 and body fat >30% for women or >23% for men. Participants were categorized as lean, NWO, or overweight-obese. RESULTS: A total of 14.7% of subjects were categorized as lean, 23.7% as having NWO, and 61.6% as having overweight-obesity. Plasma adiponectin levels were elevated in the overweight-obesity group (P < 0.05) compared to the lean and NWO groups, which did not differ from each other (P > 0.05). Adiponectin concentrations were inversely associated with BMI, fat mass, fat mass percent, visceral fat, and trunk to leg fat ratio and positively associated with leg fat mass (all P < 0.001). Plasma apelin levels were similar between the three body composition groups (P < 0.05) and were not significantly associated with any body composition indices. Apelin concentrations were inversely related to VO2 maximum (ß = -0.03 ± 0.01, p = 0.002). CONCLUSION: Plasma adiponectin and apelin levels did not distinguish between lean and NWO groups. Positive relationships with leg fat mass and adiponectin suggest the importance of assessing body composition and fat distribution when studying adipokines and cardiometabolic disorders. Further investigations are needed to understand relationships between exercise, body composition, and apelin secretion.

Plasma high-resolution metabolomics identifies linoleic acid and linked metabolic pathways associated with bone mineral density.

BACKGROUND & AIMS: There is a considerable degree of variation in bone mineral density (BMD) within populations. Use of plasma metabolomics may provide insight into established and novel determinants of BMD variance, such as nutrition and gut microbiome composition, to inform future prevention and treatment strategies for loss of BMD. Using high-resolution metabolomics (HRM), we examined low-molecular weight plasma metabolites and nutrition-related metabolic pathways associated with BMD. METHODS: This cross-sectional study included 179 adults (mean age 49.5 ± 10.3 yr, 64% female). Fasting plasma was analyzed using ultra-high-resolution mass spectrometry with liquid chromatography. Whole body and spine BMD were assessed by dual energy X-ray absorptiometry and expressed as BMD (g/cm2) or Z-scores. Multiple linear regression, pathway enrichment, and module analyses were used to determine key plasma metabolic features associated with bone density. RESULTS: Of 10,210 total detected metabolic features, whole body BMD Z-score was associated with 710 metabolites, which were significantly enriched in seven metabolic pathways, including linoleic acid, fatty acid activation and biosynthesis, and glycerophospholipid metabolism. Spine BMD was associated with 970 metabolites, significantly enriched in pro-inflammatory pathways involved in prostaglandin formation and linoleic acid metabolism. In module analyses, tryptophan- and polyamine-derived metabolites formed a network that was significantly associated with spine BMD, supporting a link with the gut microbiome. CONCLUSIONS: Plasma HRM provides comprehensive information relevant to nutrition and components of the microbiome that influence bone health. This data supports pro-inflammatory fatty acids and the gut microbiome as novel regulators of postnatal bone remodeling.

Microbial metabolite delta-valerobetaine is a diet-dependent obesogen.

Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome. However, the causality of changes in the microbiome-host interaction affecting energy metabolism remains controversial. Here, we show the microbiome-derived metabolite δ-valerobetaine (VB) is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans. VB is absent in germ-free mice and their mitochondria but present in ex-germ-free conventionalized mice and their mitochondria. Mechanistic studies in vivo and in vitro show VB is produced by diverse bacterial species and inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine and mitochondrial long-chain acyl-coenzyme As. VB administration to germ-free and conventional mice increases visceral fat mass and exacerbates hepatic steatosis with a western diet but not control diet. Thus, VB provides a molecular target to understand and potentially manage microbiome-host symbiosis or dysbiosis in diet-dependent obesity.

Physical Fitness but Not Diet Quality Distinguishes Lean and Normal Weight Obese Adults.

BACKGROUND: Individuals with normal weight obesity (NWO) have increased cardiometabolic disease and mortality risk, but factors contributing to NWO development are unknown. OBJECTIVE: The objective of this study was to determine whether diet quality scores and physical fitness levels differed between adults classified as lean, NWO, and overweight-obese. Secondary objectives of the study were to compare clinical biomarkers and food groups and macronutrient intakes between the three groups, and to test for associations between body composition components with diet quality scores and physical fitness levels. DESIGN: This is a secondary data analysis from a cross-sectional study that included metropolitan university and health care system employees. Body composition was measured by dual energy x-ray absorptiometry. Individuals with a body mass index <25 kg/m2 and body fat >23% for men and >30% for women were classified as having NWO. Alternate Healthy Eating Index, Dietary Approaches to Stop Hypertension score, and Mediterranean Diet Score were calculated from Block food frequency questionnaires. Physical fitness was assessed by measuring maximal oxygen uptake (VO2 maximum) during treadmill testing. PARTICIPANTS/SETTING: This study included 693 adults (65% women, mean age 48.9 ± 11.5 years) enrolled between 2007 and 2013 in Atlanta, GA. MAIN OUTCOME MEASURES: The main outcome measures were Alternate Healthy Eating Index, Dietary Approaches to Stop Hypertension, and Mediterranean Diet Score diet quality scores and maximal oxygen uptake. STATISTICAL ANALYSES: Multiple linear regression analyses with post hoc comparisons were used to investigate group differences in fitness, diet quality, and biomarkers. Regression analyses were also used to examine relationships between diet quality scores and fitness with body composition. RESULTS: VO2 maximum was significantly lower in the NWO compared with the lean group (36.2 ± 0.8 mL/min/kg vs 40.2 ± 1.0 mL/min/kg; P < 0.05). Individuals with NWO reported similar diet quality to lean individuals and more favorable Alternate Healthy Eating Index and Dietary Approaches to Stop Hypertension scores than individuals with overweight-obesity (P < 0.05). Diet quality scores and physical fitness levels were inversely associated with percent body fat and visceral adipose tissue (P < 0.05), regardless of weight status. Individuals with NWO exhibited higher fasting blood insulin concentrations, insulin resistance, low-density lipoprotein cholesterol, and triglyceride levels, and significantly lower high-density lipoprotein cholesterol levels than lean individuals (P < 0.05). CONCLUSIONS: Physical fitness was significantly decreased in individuals with NWO compared with lean individuals. Higher diet quality was associated with decreased total and visceral fat but did not distinguish individuals with NWO from lean individuals.

Metabolomic Associations with Serum Bone Turnover Markers.

Bone is a dynamic tissue that is in a constant state of remodeling. Bone turnover markers (BTMs), procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX), provide sensitive measures of bone formation and resorption, respectively. This study used ultra-high-resolution metabolomics (HRM) to determine plasma metabolic pathways and targeted metabolites related to the markers of bone resorption and formation in adults. This cross-sectional clinical study included 34 adults (19 females, mean 27.8 years), without reported illnesses, recruited from a US metropolitan area. Serum BTM levels were quantified by an ELISA. Plasma HRM utilized dual-column liquid chromatography and mass spectrometry to identify metabolites and metabolic pathways associated with BTMs. Metabolites significantly associated with P1NP (p < 0.05) were significantly enriched in pathways linked to the TCA cycle, pyruvate metabolism, and metabolism of B vitamins important for energy production (e.g., niacin, thiamin). Other nutrition-related metabolic pathways associated with P1NP were amino acid (proline, arginine, glutamate) and vitamin C metabolism, which are important for collagen formation. Metabolites associated with CTX levels (p < 0.05) were enriched within lipid and fatty acid beta-oxidation metabolic pathways, as well as fat-soluble micronutrient pathways including, vitamin D metabolism, vitamin E metabolism, and bile acid biosynthesis. P1NP and CTX were significantly related to microbiome-related metabolites (p < 0.05). Macronutrient-related pathways including lipid, carbohydrate, and amino acid metabolism, as well as several gut microbiome-derived metabolites were significantly related to BTMs. Future research should compare metabolism BTMs relationships reported here to aging and clinical populations to inform targeted therapeutic interventions.

Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than visceral and abdominal subcutaneous fat in youth.

INTRODUCTION: Body fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat distribution. RESEARCH DESIGN AND METHODS: This was a cross-sectional sub-study of 283 children/adolescents (7-19 years) from the Yale Pediatric NAFLD Cohort. Untargeted, high-resolution metabolomics (HRM) was performed on plasma and combined with existing clinical variables including hepatic and abdominal fat measured by MRI. Integrative network analysis was coupled with pathway enrichment analysis and multivariable linear regression (MLR) to examine which metabolites and clinical variables associated with each fat depot. RESULTS: The data divided into four communities of correlated variables (|r|>0.15, p<0.05) after integrative network analysis. In the largest community, hepatic fat was associated with eight clinical biomarkers, including measures of insulin resistance and dyslipidemia, and 878 metabolite features that were enriched predominantly in amino acid (AA) and lipid pathways in pathway enrichment analysis (p<0.05). Key metabolites associated with hepatic fat included branched-chain AAs (valine and isoleucine/leucine), aromatic AAs (tyrosine and tryptophan), serine, glycine, alanine, and pyruvate, as well as several acylcarnitines and glycerophospholipids (all q<0.05 in MLR adjusted for covariates). The other communities detected in integrative network analysis consisted of abdominal visceral, superficial subcutaneous, and deep subcutaneous fats, but no clinical variables, fewer metabolite features (280, 312, and 74, respectively), and limited findings in pathway analysis. CONCLUSIONS: These data-driven findings show a stronger association of hepatic fat with key CMD risk factors compared with abdominal fats. The molecular network identified using HRM that associated with hepatic fat provides insight into potential mechanisms underlying the hepatic fat-insulin resistance interface in youth.

Plasma High-Resolution Metabolomics Differentiates Adults with Normal Weight Obesity from Lean Individuals.

OBJECTIVE: This study explored underlying metabolism-related dysfunction by examining metabolomic profiles in adults categorized as lean, as having normal weight obesity (NWO), or as having overweight/obesity. METHODS: Participants (N = 179) had fasting plasma analyzed by liquid chromatography and high-resolution mass spectrometry for high-resolution metabolomics. Body composition was assessed by dual-energy x-ray absorptiometry. NWO was defined as BMI < 25 and body fat > 30% for women and > 23% for men. Differentiating metabolomic features were determined by using linear regression models and likelihood ratio tests with false discovery rate correction. Mummichog was used for pathway and network analyses. RESULTS: A total of 222 metabolites significantly differed between the groups at a false discovery rate of q = 0.2. Linoleic acid, ß-alanine, histidine, and aspartate/asparagine metabolism pathways were significantly enriched (all P < 0.01) by metabolites that were similarly upregulated in the NWO and overweight/obesity groups compared with the lean group. A module analysis linked branched-chain amino acids and amino acid metabolites as elevated in the NWO and overweight/obesity groups compared with the lean group (all P < 0.05). CONCLUSIONS: Metabolomic profiles of individuals with NWO reflected similar metabolic disruption as those of individuals with overweight/obesity. High-resolution metabolomics may help identify people at risk for developing obesity-related disease, despite normal BMI.

Visceral adipose tissue is associated with poor diet quality and higher fasting glucose in adults with cystic fibrosis.

BACKGROUND: Body fat distribution and diet quality influence clinical outcomes in general populations but are understudied in individuals with cystic fibrosis (CF). The aim of this pilot study was to assess body fat distribution and diet quality in relation to fasting glucose and lung function in adults with CF. METHODS: Subjects were 24 adults (ages 18-50) with CF and 25 age-matched controls. The Healthy Eating Index 2015 (HEI-2015) was calculated from 3-day food records and data were adjusted per 1000 kcal. Whole and regional body composition, including visceral adipose tissue (VAT), was assessed by dual energy X-ray absorptiometry. RESULTS: Subjects with CF reported more added sugar intake [26.1 (IQR 18.1) vs. 12.9 (12.5) g/1000 kcal, p < 0.001] and had lower HEI-2015 scores [48.3 (IQR 9.9) vs. 63.9 (27.3), p < 0.001] compared to controls. There were no differences in BMI, total body fat, or lean body mass (LBM) between subjects with CF and controls (p > 0.05 for all), although subjects with CF had higher VAT than control subjects [0.3 (IQR 0.3) vs 0.1 (0.3) kg, p = 0.02]. Among subjects with CF, VAT was positively associated with added sugar intake (p < 0.001) and fasting blood glucose (p = 0.04). Lung function was positively associated with BMI (p = 0.005) and LBM (p = 0.03) but not with adiposity indicators. CONCLUSIONS: These novel data link body fat distribution with diet quality and fasting glucose levels in adults with CF, whereas LBM was associated with lung function. This study highlights the importance of increasing diet quality and assessing body composition and fat distribution in the CF population.

Cardiometabolic Risk Reduction Through Recreational Group Sport Interventions in Adults: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the pooled effects of community-based, recreational-level group sports on cardiometabolic risk factors and fitness parameters among adults. PARTICIPANTS AND METHODS: We systematically searched PubMed, EMBASE, PsychINFO, CINAHL, and Web of Science electronic databases for English-language articles reporting the effectiveness of recreational-level group sports published between January 1, 1965, and January 17, 2017. We extracted baseline and end of intervention means for cardiometabolic and fitness parameters. Random- or fixed-effects meta-analyses were used to obtain pooled before and after change in outcome means within intervention participants and between groups. RESULTS: From 2491 screened titles, 23 publications were included (902 participants; mean ± SD age, 46.6±11.7 years), comprising 21 soccer and 2 rugby interventions. Intervention participants achieved larger improvements (mean [95% CI]) compared with control subjects in weight (-1.44 kg [-1.79 to -1.08 kg]), body mass index (-0.88 kg/m2 [-1.73 to -0.03 kg/m2]), waist circumference (-0.77 cm [-1.21 to -0.33 cm]), body fat (-1.8% [-3.12% to -0.49%]), total cholesterol level (-0.33 mmol/L [-0.53 to -0.13 mmol/L]), low-density lipoprotein cholesterol level (-0.35 mmol/L [-0.54 to -0.15 mmol/L]), systolic blood pressure (-5.71 mm Hg [-7.98 to -3.44 mm Hg]), diastolic blood pressure (-3.36 mm Hg [-4.93 to -1.78 mm Hg]), maximum oxygen consumption (3.93 mL/min per kg [2.96-4.91 mL/min]), and resting heart rate (-5.51 beats/min [-7.37 to -3.66 beats/min]). Most studies (16) were classified as high quality, and we found no evidence of publication bias. CONCLUSION: We found significant cardiometabolic and fitness improvements following group sport participation, primarily recreational soccer. These findings suggest that group sport interventions are promising strategies for reducing cardiometabolic risk in adults.