Joyce C McCann’s research while affiliated with Children's Hospital Oakland Research Institute and other places

[This corrects the article DOI: 10.1371/journal.pone.0240437.].

Background Poor diets contribute to metabolic complications of obesity, insulin resistance and dyslipidemia. Metabolomic biomarkers may serve as early nutrition-sensitive health indicators. This family-based lifestyle change program compared metabolic outcomes in an intervention group (INT) that consumed 2 nutrient bars daily for 2-months and a control group (CONT). Methods Overweight, predominantly minority and female adolescent (Teen)/parent adult caretaker (PAC) family units were recruited from a pediatric obesity clinic. CONT (8 Teen, 8 PAC) and INT (10 Teen, 10 PAC) groups randomized to nutrient bar supplementation attended weekly classes that included group nutrition counseling and supervised exercise. Pre-post physical and behavioral parameters, fasting traditional biomarkers, plasma sphingolipids and amino acid metabolites were measured. Results In the full cohort, a baseline sphingolipid ceramide principal component composite score correlated with adiponectin, triglycerides, triglyceride-rich very low density lipoproteins, and atherogenic small low density lipoprotein (LDL) sublasses. Inverse associations were seen between a sphingomyelin composite score and C-reactive protein, a dihydroceramide composite score and diastolic blood pressure, and the final principal component that included glutathionone with fasting insulin and the homeostatic model of insulin resistance. In CONT, plasma ceramides, sphinganine, sphingosine and amino acid metabolites increased, presumably due to increased physical activity. Nutrient bar supplementation (INT) blunted this rise and significantly decreased ureagenic, aromatic and gluconeogenic amino acid metabolites. Metabolomic changes were positively correlated with improvements in clinical biomarkers of dyslipidemia. Conclusion Nutrient bar supplementation with increased physical activity in obese Teens and PAC elicits favorable metabolomic changes that correlate with improved dyslipidemia. The trial from which the analyses reported upon herein was part of a series of nutrient bar clinical trials registered at clinicaltrials.gov as NCT02239198.

Asthma in the obese is often severe, difficult to treat, and characterized by less eosinophilic inflammation than asthma in the nonobese. Obesity-associated metabolic dysregulation may be a causal factor. We previously reported that a nutrient- and fiber-dense bar [Children’s Hospital Oakland Research Institute (CHORI)-bar], which was designed to fill gaps in poor diets, improved metabolism in healthy overweight/obese (OW/OB) adults. In this pilot trial, OW/OB adolescents with poorly controlled asthma were randomized to weekly nutrition/exercise classes with or without twice-daily CHORI-bar consumption. Intent-to-treat analysis did not indicate CHORI-bar–specific effects. However, restricting the analysis to participants with acceptable compliance and a relatively low fraction of exhaled nitric oxide (FENO; <50/ ppb, a surrogate for noneosinophilic asthma; study participants: CHORI-bar, n = 16; controls, n = 15) indicated that CHORI-bar–specific, significant improvements in lung function (forced vital capacity, percent-predicted forced expiratory volume in 1 s, and percent-predicted forced expiratory flow between 25 and 75% of forced vital capacity), primarily in participants with low chronic inflammation (high-sensitivity C-reactive protein <1.5 mg/L). (We previously observed that chronic inflammation blunted CHORI-bar–induced metabolic improvements in healthy OW/OB adults.) Lung function improvement occurred without weight loss and was independent of improvements in metabolic and anthropometric end points and questionnaire-based measures of asthma control and quality of life. This study suggests that a nutritional intervention can improve lung function in OW/OB adolescents with asthma and relatively low FENO without requiring major changes in dietary habits, lifestyle, or weight loss and that this effect is blunted by chronic inflammation.

This study determined if twice-daily consumption of a nutrient-dense bar intended to fill gaps in Western diets, without other dietary/lifestyle requirements, favorably shifted metabolic/anthropometric indicators of dysregulation in a healthy direction. Three 8-wk clinical trials in 43 healthy lean and overweight/obese (OW/OB) adults, who served as their own controls, were pooled for analysis. In less inflamed OW/OB [high-sensitivity C-reactive protein (hsCRP) <1.5], statistically significant decreases occurred in weight (-1.1 ± 0.5 kg), waist circumference (-3.1 ± 1.4 cm), diastolic blood pressure (-4.1 ± 1.6 mmHg), heart rate [HR; -4.0 ± 1.7 beats per minute (bpm)], triglycerides (-72 ± 38.2 mg/dl), insulin resistance (homeostatic model of insulin resistance) (-0.72 ± 0.3), and insulin (-2.8 ± 1.3 mU/L); an increase in HDL-2b (+303 ± 116 nM) and realignment of LDL lipid subfractions toward a less atherogenic profile [decreased small LDL IIIb (-44 ± 23.5 nM), LDL IIIa (-99 ± 43.7 nM), and increased large LDL I (+66 ± 28.0 nM)]. In the more inflamed OW/OB (hsCRP >1.5), inflammation was reduced at 2 wk (-0.66 mg/L), and HR at 8 wk (-3.4 ± 1.3 bpm). The large HDL subfraction (10.5-14.5 nm) increased at 8 wk (+346 ± 126 nM). Metabolic improvements were also observed in lean participants. Thus, favorable changes in measures of cardiovascular health, insulin resistance, inflammation, and obesity were initiated within 8 wk in the OW/OB by replacing deficiencies in Western diets without requiring other dietary or lifestyle modifications; chronic inflammation blunted most improvements.-McCann, J. C., Shigenaga, M. K., Mietus-Snyder, M. L., Lal, A., Suh, J. H., Krauss, R. M., Gildengorin, G. L., Goldrich, A. M., Block, D. S., Shenvi, S. V., McHugh, T. H., Olson, D. A., Ames, B. N. A multicomponent nutrient bar promotes weight loss and improves dyslipidemia and insulin resistance in the overweight/obese: chronic inflammation blunts these improvements.

Objective: To determine whether twice daily intake of a low-calorie (110 kcal), high-fiber, fruit and dark chocolate based nutrient-dense bar with supplemental vitamins/minerals, β-glucan, and docosahexaenoic acid might serve as an effective adjunct to lifestyle counseling for weight management in an inner city population. Methods: 18 overweight, predominantly female adolescent/parent guardian dyads and 2 triads (21 adults, 22 teens, randomized as 12 intervention (INT, with bars), 8 control (C) family units were recruited from a pediatric obesity clinic. The cohort was 48.7% Nonhispanic Black, 34.1% Hispanic, and 17.0% Caucasian. Two adults dropped out. The remaining 41 subjects participated in six identical weekly exercise and nutrition sessions by group. Full assessment of physical (BMI, blood pressure), behavioral (diet, activity), metabolic (cardiovascular and diabetes risk biomarkers), and metabolomic status was conducted at baseline and end-of-study. Results: There was excellent attendance in both INT and C groups with all family units participating in more than 80% of group sessions and 100% of baseline and follow-up assessment visits. Compliance with nutrition bar intake was 86 ± 11% and 87 ± 14% among INT group adults and teens respectively. There was considerable obesity, hypertension, dyslipidemia, inflammation, and insulin resistance in all subjects and baseline diets were universally poor. Self-report activity increased and dietary habits improved in both INT and C groups, adults and teens, most notably decreased saturated fat and total carbohydrates (especially added sugars). Weight was stable, even in the INT group despite the addition of 220 additional kcal in two daily nutrition bars. In paired analyses, systolic blood pressure (SBP) improved significantly in INT teens (-6.7 ± 9.2 mm Hg, p = 0.02), and worsened in C teens (+6.3 ± 7.7 mm Hg, p = 0.04); p = 0.002 for unpaired comparison by teen group. Plasma homocysteine levels and two amino acids, citrulline and sarcosine, implicated in the arginine-urea cycle pathway fell in both INT parents and teens, but not in controls. The drop in citrulline was more significant in INT teens ( p = 0.005) than in adults ( p = 0.047). In a diet-induced obesity mouse model, elevated plasma citrulline has been associated with cardiometabolic complications attributed to decreased systemic arginine bioavailability that may affect capacity to produce nitric oxide. The observed metabolomic changes are consistent with more efficient mitochondrial processing and may relate to the systolic BP improvement observed in teens. Conclusions: A nutritional supplement bar may be a valuable adjunct for weight management, resulting in early favorable metabolomic changes.

Dietary intake modulates disease risk, but little is known how components within food mixtures affect pathophysiology. A low-calorie, high-fiber, fruit-based nutrient-dense bar of defined composition (e.g., vitamins and minerals, fruit polyphenolics, β-glucan, docosahexaenoic acid) appropriate for deconstruction and mechanistic studies is described and evaluated in a pilot trial. The bar was developed in collaboration with the U.S. Department of Agriculture. Changes in cardiovascular disease and diabetes risk biomarkers were measured after 2 wk twice-daily consumption of the bar, and compared against baseline controls in 25 healthy adults. Plasma HDL-cholesterol (HDL-c) increased 6.2% (P=0.001), due primarily to a 28% increase in large HDL (HDL-L; P<0.0001). Total plasma homocysteine (Hcy) decreased 19% (P=0.017), and glutathione (GSH) increased 20% (P=0.011). The changes in HDL and Hcy are in the direction associated with decreased risk of cardiovascular disease and cognitive decline; increased GSH reflects improved antioxidant defense. Changes in biomarkers linked to insulin resistance and inflammation were not observed. A defined food-based supplement can, within 2 wk, positively impact metabolic biomarkers linked to disease risk. These results lay the groundwork for mechanistic/deconstruction experiments to identify critical bar components and putative synergistic combinations responsible for observed effects.

Achieving recommended dietary intakes of vitamins and minerals, fiber, and other health-promoting small molecules, such as fruit polyphenolics and essential fatty acids, is difficult, even for healthy adults consuming generally good diets. We assessed the hypothesis that short term consumption of a comprehensive nutrition bar can favorably impact metabolic biomarkers linked to future disease risk. Methods: An approximately 100 kcal nutrition bar containing a vitamin, mineral, and docosahexaenoic acid (DHA)-fortified polyphenolic-rich whole food matrix composed of fruit, walnuts, and dark chocolate blended with insoluble and soluble fiber was developed. Pooled results are presented from 3 pilot trials in which 25 generally healthy adults (15 F, 10 M) were enrolled in 2-wk interventions to study the effect of twice-daily consumption of the bar on plasma lipoprotein subfractions (ion mobility analysis), and redox status (thiol amino acids) in addition to conventional biomarkers associated with dyslipidemia, insulin resistance, and inflammation. All variables were continuous, and paired t-tests were used to test for significant change between baseline and follow-up measures. Results: Mean HDL cholesterol increased by 6.6 + 9.7% ( p = 0.001), predominantly due to a rise in the large buoyant HDL2b subclass which rose from 1665.9 ± 1017.7 to 2089.4 ± 1197.6 nmol/L ( p < 0.0001; 28% increase). Plasma triglyceride and LDL cholesterol levels did not change significantly but there was a trend towards increased LDL peak particle diameter (p = 0.086). Mean plasma homocysteine decreased from 12.6 ± 6.4 to 10.2 ± 3.7 µM (p=0.006, 19.2% decline). Measures of insulin resistance and inflammation did not change. Weight remained stable despite intake of 200 additional daily calories. Participants reported a significant decrease in hunger on an analog scale and compensatory decreased intake of other foods. Summary: Twice daily consumption of a low-calorie complete nutritional supplement increases satiety and large HDL particle concentrations within 2 weeks without weight gain.

The triage theory proposes that modest deficiency of any vitamin or mineral (V/M) could increase age-related diseases. V/M-dependent proteins required for short-term survival and/or reproduction (i.e., "essential") are predicted to be protected on V/M deficiency over other "nonessential" V/M-dependent proteins needed only for long-term health. The result is accumulation of insidious damage, increasing disease risk. We successfully tested the theory against published evidence on vitamin K. Here, we review about half of the 25 known mammalian selenoproteins; all of those with mouse knockout or human mutant phenotypes that could be used as criteria for a classification of essential or nonessential. Five selenoproteins (Gpx4, Txnrd1, Txnrd2, Dio3, and Sepp1) were classified as essential and 7 (Gpx1, Gpx 2, Gpx 3, Dio1, Dio2, Msrb1, and SelN) nonessential. On modest selenium (Se) deficiency, nonessential selenoprotein activities and concentrations are preferentially lost, with one exception (Dio1 in the thyroid, which we predict is conditionally essential). Mechanisms include the requirement of a special form of tRNA sensitive to Se deficiency for translation of nonessential selenoprotein mRNAs except Dio1. The same set of age-related diseases and conditions, including cancer, heart disease, and immune dysfunction, are prospectively associated with modest Se deficiency and also with genetic dysfunction of nonessential selenoproteins, suggesting that Se deficiency could be a causal factor, a possibility strengthened by mechanistic evidence. Modest Se deficiency is common in many parts of the world; optimal intake could prevent future disease.