Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity.

Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

Effect of metformin and lifestyle intervention on adipokines and hormones in breast cancer survivors: a pooled analysis from two randomized controlled trials.

PURPOSE: We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS: Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS: Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p < 0.01) and HOMA-IR (- 0.48 vs - 0.25; p = 0.03), and an increase in SHBG (2.80 vs 1.45 nmol/L; p < 0.01). Excluding women taking aromatase inhibitors, metformin (n = 84) compared to placebo (n = 99) decreased estradiol (- 4 vs 0 pmol/L; p < 0.01), estrone (- 8 vs 2 pmol/L; p < 0.01) and testosterone (- 0.1 vs 0 nmol/L-; p = 0.02). LSI favorably affected adiponectin (0.45 vs - 0.06 ug/mL; p < 0.01), leptin (- 10.5 vs - 4.4 ng/mL; p < 0.01), HOMA-IR (- 0.6 vs 0.2; p = 0.03), and SHBG (2.7 vs 1.1 nMol/L; p = 0.04) compared to controls. The strongest impact was observed combining metformin with LSI on adipokines, CRP, SHBG, and estrogens. CONCLUSIONS: Supportive healthy lifestyle programs combined with metformin to achieve maximal risk reduction among BC cancer survivors are recommended, especially for those with obesity in menopause.

Exploring the impact of environmental exposure changes on metabolic biomarkers: A 6-month GPS-GIS study among women with overweight or obesity.

BACKGROUND: Little is known about the impact of environmental exposure change on metabolic biomarkers associated with cancer risk. Furthermore, this limited epidemiological evidence on metabolic biomarkers focused on residential exposure, without considering the activity space which can be done by modelling dynamic exposures. In this longitudinal study, we aimed to investigate the impact of environmental exposures change on metabolic biomarkers using GPS-GIS based measurements. METHODS: Among two weight loss interventions, the Reach for Health and the MENU studies, which included ∼460 women at risk of breast cancer or breast cancer survivors residing in Southern California, three metabolic biomarkers (insulin resistance, fasting glucose, and C-reactive protein) were assessed. Dynamic GPS-GIS based exposure to green spaces, recreation, walkability, NO2, and PM2.5 were calculated at baseline and 6 months follow-up using time-weighted spatial averaging. Generalized estimating equations models were used to examine the relationship between changes in environmental exposures and biomarker levels over time. RESULTS: Overall, six-month environmental exposure change was not associated with metabolic biomarkers change. Stratified analyses by level of environmental exposures at baseline revealed that reduced NO2 and PM2.5 exposure was associated with reduced fasting glucose concentration among women living in a healthier environment at baseline (ß -0.010, 95%CI -0.025, 0.005; ß -0.019, 95%CI -0.034, -0.003, respectively). Women living in poor environmental conditions at baseline and exposed to greener environments had decreased C-reactive protein concentrations (ß -1.001, 95%CI -1.888, -0.131). CONCLUSIONS: The impact of environmental exposure changes on metabolic biomarkers over time may be modified by baseline exposure conditions.

Arriba por la Vida Estudio: a randomized controlled trial promoting standing behavior to reduce sitting time among postmenopausal Latinas.

Postmenopausal Hispanic/Latina (N = 254) women with a body mass index (BMI) ≥ 25 kg/m2 were randomized to an intervention to reduce sitting time or a comparison condition for 12 weeks. The standing intervention group received three in-person health-counseling sessions, one home visit, and up to eight motivational interviewing calls. The heart healthy lifestyle comparison group (C) received an equal number of contact hours to discuss healthy aging. The primary outcome was 12-week change in sitting time measured via thigh-worn activPAL. Group differences in outcomes were analyzed using linear mixed-effects models. Participants had a mean age of 65 (6.5) years, preferred Spanish language (89%), BMI of 32.4 (4.8) kg/m2, and sat for an average of 540 (86) minutes/day. Significant between-group differences were observed in reductions of sitting time across the 12-week period [Mdifference (SE): C - 7.5 (9.1), SI - 71.0 (9.8), p < 0.01]. Results demonstrate that coaching models to reduce sitting are feasible and effective.

Variable Eating Patterns: A Potential Novel Risk Factor for Systemic Inflammation in Women.

BACKGROUND: The timing and regularity of eating patterns could play a role in systemic inflammation, as circadian clocks responsible for daily rhythms of inflammatory signaling are entrained by food intake. PURPOSE: To evaluate associations of intra-weekly and weekday-weekend differences in eating timing patterns with high-sensitivity C-reactive protein (hsCRP). METHODS: A community-based sample of 103 U.S. women from the American Heart Association Go Red for Women Strategically Focused Research Network completed a meal-timing questionnaire and provided a blood sample for measurement of hsCRP. Differences in weekday versus weekend eating start time, eating end time, and nightly fasting duration were calculated as eating jetlag metrics. Intra-weekly variability in eating timing patterns was defined by the standard deviation (SD) of these variables. Multivariable linear regression models were used to evaluate cross-sectional associations of eating timing variability metrics with hsCRP. RESULTS: Each additional 30-min difference in weekday-weekend eating end time was related to 13% higher hsCRP (p = .023). Similarly, every 30-min increase in eating end time SD, reflecting greater variability in timing of last eating occasion, was associated with 29% higher hsCRP. Per 1-hr weekday-weekend difference in nightly fasting duration, there was a 45% elevation in hsCRP (p = .003). Every 30-min increase in nightly fasting duration SD, representing greater variability in span of the daily fasting/eating periods, was associated with 46% higher hsCRP. CONCLUSIONS: Variable eating timing patterns were associated with higher hsCRP. Intervention studies are needed to determine whether stabilizing the timing of eating occasions may represent a novel strategy to reduce chronic inflammation.

Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials.

BACKGROUND: Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment. METHODS: Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC-QTOF-MS metabolomics, targeted LC-MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment. RESULTS: Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism. CONCLUSIONS: Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.

Air pollution and metabolic disorders: Dynamic versus static measures of exposure among Hispanics/Latinos and non-Hispanics.

INTRODUCTION: Exposure to air pollution disproportionately affects racial/ethnic minorities that could contribute to health inequalities including metabolic disorders. However, most existing studies used a static assessment of air pollution exposure (mostly using the residential address) and do not account for activity space when modelling exposure to air pollution. The aim of this study is to understand how exposure to air pollution impacts metabolic disorders biomarkers, how this effect differs according to ethnicity, and for the first time compare these findings with two methods of exposure assessment: dynamic and static measures. METHODS: Among the Community of Mine study, a cross-sectional study conducted in San Diego County, insulin resistance, diabetes, hypertension, obesity, dyslipidemia, and metabolic syndrome (MetS) were assessed. Exposure to air pollution (PM2.5, NO2, traffic) was calculated using static measures around the home, and dynamic measures of mobility derived from Global Positioning Systems (GPS) traces using kernel density estimators to account for exposure variability across space and time. Associations of air pollution with metabolic disorders were quantified using generalized estimating equation models to account for the clustered nature of the data. RESULTS: Among 552 participants (mean age 58.7 years, 42% Hispanic/Latino), Hispanics/Latinos had a higher exposure to PM2.5 compared to non-Hispanics using static measures. In contrast, Hispanics/Latinos had less exposure to PM2.5 using dynamic measures. For all participants, higher dynamic exposure to PM2.5 and NO2 was associated with increased insulin resistance and cholesterol levels, and increased risk of obesity, dyslipidemia and MetS (RR 1.17, 95% CI: 1.07-1.28; RR 1.21, 95% CI: 1.12-1.30, respectively). The association between dynamic PM2.5 exposure and MetS differed by Hispanic/Latino ethnicity. CONCLUSION: These results highlight the importance of considering people's daily mobility in assessing the impact of air pollution on health.

Recent advances and health implications of dietary fasting regimens on the gut microbiome.

Calorie restriction is a primary dietary intervention demonstrated over many decades in cellular and animal models to modulate aging pathways, positively affect age-associated diseases and, in clinical studies, to promote beneficial health outcomes. Because long-term compliance with daily calorie restriction has proven problematic in humans several intermittent fasting regimens, including alternate day fasting and time-restricted feeding, have evolved revealing similar clinical benefits as calorie restriction. Despite significant research on the cellular and physiological mechanisms contributing to, and responsible for, these observed benefits, relatively little research has investigated the impact of these various fasting protocols on the gut microbiome (GM). Reduced external nutrient supply to the gut may beneficially alter the composition and function of a "fed" gut microflora. Indeed, the prevalent, obesogenic Western diet can promote deleterious changes in the GM, signaling intermediates involved in lipid and glucose metabolism, and immune responses in the gastrointestinal tract. This review describes recent preclinical and clinical effects of varying fasting regimens on GM composition and associated physiology. Although the number of preclinical and clinical interventions are limited, significant data thus far suggest fasting interventions impact GM composition and physiology. However, there are considerable heterogeneities of study design, methodological considerations, and practical implications. Ongoing research on the health impact of fasting regimens on GM modulation is warranted.

Diurnal patterns of sedentary behavior and changes in physical function over time among older women: a prospective cohort study.

BACKGROUND: Sedentary behavior (SB) is linked to negative health outcomes in older adults. Most studies use summary values, e.g., total sedentary minutes/day. Diurnal timing of SB accumulation may further elucidate SB-health associations. METHODS: Six thousand two hundred four US women (mean age = 79 ± 7; 50% White, 34% African-American) wore accelerometers for 7-days at baseline, yielding 41,356 person-days with > 600 min/day of data. Annual follow-up assessments of health, including physical functioning, were collected from participants for 6 years. A novel two-phase clustering procedure discriminated participants' diurnal SB patterns: phase I grouped day-level SB trajectories using longitudinal k-means; phase II determined diurnal SB patterns based on proportion of phase I trajectories using hierarchical clustering. Mixed models tested associations between SB patterns and longitudinal physical functioning, adjusted for covariates including total sedentary time. Effect modification by moderate-vigorous-physical activity (MVPA) was tested. RESULTS: Four diurnal SB patterns were identified: p1 = high-SB-throughout-the-day; p2 = moderate-SB-with-lower-morning-SB; p3 = moderate-SB-with-higher-morning-SB; p4 = low-SB-throughout-the-day. High MVPA mitigated physical functioning decline and correlated with better baseline and 6-year trajectory of physical functioning across patterns. In low MVPA, p2 had worse 6-year physical functioning decline compared to p1 and p4. In high MVPA, p2 had similar 6-year physical functioning decline compared to p1, p3, and p4. CONCLUSIONS: In a large cohort of older women, diurnal SB patterns were associated with rates of physical functioning decline, independent of total sedentary time. In particular, we identified a specific diurnal SB subtype defined by less SB earlier and more SB later in the day, which had the steepest decline in physical functioning among participants with low baseline MVPA. Thus, diurnal timing of SB, complementary to total sedentary time and MVPA, may offer additional insights into associations between SB and physical health, and provide physicians with early warning of patients at high-risk of physical function decline.

Protocol for a cross sectional study of cancer risk, environmental exposures and lifestyle behaviors in a diverse community sample: the Community of Mine study.

BACKGROUND: Physical inactivity and unhealthy diet are modifiable behaviors that lead to several cancers. Biologically, these behaviors are linked to cancer through obesity-related insulin resistance, inflammation, and oxidative stress. Individual strategies to change physical activity and diet are often short lived with limited effects. Interventions are expected to be more successful when guided by multi-level frameworks that include environmental components for supporting lifestyle changes. Understanding the role of environment in the pathways between behavior and cancer can help identify what environmental conditions are needed for individual behavioral change approaches to be successful, and better recognize how environments may be fueling underlying racial and ethnic cancer disparities. METHODS: This cross-sectional study was designed to select participants (n = 602 adults, 40% Hispanic, in San Diego County) from a range of neighborhoods ensuring environmental variability in walkability and food access. Biomarkers measuring cancer risk were measured with fasting blood draw including insulin resistance (fasting plasma insulin and glucose levels), systemic inflammation (levels of CRP), and oxidative stress measured from urine samples. Objective physical activity, sedentary behavior, and sleep were measured by participants wearing a GT3X+ ActiGraph on the hip and wrist. Objective measures of locations were obtained through participants wearing a Qstarz Global Positioning System (GPS) device on the waist. Dietary measures were based on a 24-h food recall collected on two days (weekday and weekend). Environmental exposure will be calculated using static measures around the home and work, and dynamic measures of mobility derived from GPS traces. Associations of environment with physical activity, obesity, diet, and biomarkers will be measured using generalized estimating equation models. DISCUSSION: Our study is the largest study of objectively measured physical activity, dietary behaviors, environmental context/exposure, and cancer-related biomarkers in a Hispanic population. It is the first to perform high quality measures of physical activity, sedentary behavior, sleep, diet and locations in which these behaviors occur in relation to cancer-associated biomarkers including insulin resistance, inflammation, impaired lipid metabolism, and oxidative stress. Results will add to the evidence-base of how behaviors and the built environment interact to influence biomarkers that increase cancer risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT02094170 , 03/21/2014.

AIBP protects against metabolic abnormalities and atherosclerosis.

Apolipoprotein A-I binding protein (AIBP) has been shown to augment cholesterol efflux from endothelial cells and macrophages. In zebrafish and mice, AIBP-mediated regulation of cholesterol levels in the plasma membrane of endothelial cells controls angiogenesis. The goal of this work was to evaluate metabolic changes and atherosclerosis in AIBP loss-of-function and gain-of-function animal studies. Here, we show that Apoa1bp-/-Ldlr-/- mice fed a high-cholesterol, high-fat diet had exacerbated weight gain, liver steatosis, glucose intolerance, hypercholesterolemia, hypertriglyceridemia, and larger atherosclerotic lesions compared with Ldlr-/- mice. Feeding Apoa1bp-/-Ldlr-/- mice a high-cholesterol, normal-fat diet did not result in significant differences in lipid levels or size of atherosclerotic lesions from Ldlr-/- mice. Conversely, adeno-associated virus-mediated overexpression of AIBP reduced hyperlipidemia and atherosclerosis in high-cholesterol, high-fat diet-fed Ldlr-/- mice. Injections of recombinant AIBP reduced aortic inflammation in Ldlr-/- mice fed a short high-cholesterol, high-fat diet. Conditional overexpression of AIBP in zebrafish also reduced diet-induced vascular lipid accumulation. In experiments with isolated macrophages, AIBP facilitated cholesterol efflux to HDL, reduced lipid rafts content, and inhibited inflammatory responses to lipopolysaccharide.jlr Our data demonstrate that AIBP confers protection against diet-induced metabolic abnormalities and atherosclerosis.

Randomized controlled trial of increasing physical activity on objectively measured and self-reported cognitive functioning among breast cancer survivors: The memory & motion study.

BACKGROUND: Increasing physical activity can improve cognition in healthy and cognitively impaired adults; however, the benefits for cancer survivors are unknown. The current study examined a 12-week physical activity intervention, compared with a control condition, on objective and self-reported cognition among breast cancer survivors. METHODS: Sedentary breast cancer survivors were randomized to an exercise arm (n = 43) or a control arm (n = 44). At baseline and at 12 weeks, objective cognition was measured with the National Institutes of Health Cognitive Toolbox, and self-reported cognition using the Patient-Reported Outcomes Measurement Information System scales. Linear mixed-effects regression models tested intervention effects for changes in cognition scores. RESULTS: On average, participants (n = 87) were aged 57 years (standard deviation, 10.4 years) and were 2.5 years (standard deviation, 1.3 years) post surgery. Scores on the Oral Symbol Digit subscale (a measure of processing speed) evidenced differential improvement in the exercise arm versus the control arm (b = 2.01; P < .05). The between-group differences in improvement on self-reported cognition were not statistically significant but were suggestive of potential group differences. Time since surgery moderated the correlation, and participants who were ≤2 years post surgery had a significantly greater improvement in Oral Symbol Digit score (exercise vs control (b = 4.00; P < .01), but no significant improvement was observed in patients who were >2 years postsurgery (b = -1.19; P = .40). A significant dose response was observed with greater increased physical activity associated with objective and self-reported cognition in the exercise arm. CONCLUSIONS: The exercise intervention significantly improved processing speed, but only among those who had been diagnosed with breast cancer within the past 2 years. Slowed processing speed can have substantial implications for independent functioning, supporting the potential importance of early implementation of an exercise intervention among patients with breast cancer. Cancer 2018;124:192-202. © 2017 American Cancer Society.

Metabolic Effects of Intermittent Fasting.

The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.

Impact of Intermittent Fasting and/or Caloric Restriction on Aging-Related Outcomes in Adults: A Scoping Review of Randomized Controlled Trials.

Intermittent fasting (IF) and caloric restriction (CR) are dietary strategies to prevent and attenuate obesity associated with conditions and aging-related outcomes. This scoping review examined the cardiometabolic, cancer, and neurocognitive outcome differences between IF and CR interventions among adults. We applied a systematic approach to scope published randomized controlled trials (databases: PubMed, CINAHL Plus, PsychInfo, Scopus, and Google Scholar) from inception through August 2023. The initial search provided 389 unique articles which were critically appraised. Thirty articles met the eligibility criteria for inclusion: 12 were IF, 10 were CR, and 8 were combined IF and CR interventions. IF and CR were associated with weight loss; however, IF studies tended to report greater adherence compared with CR. Overall, IF and CR were equivalently effective across cardiometabolic, cancer, and neurocognitive outcomes. Our findings suggest that IF has health benefits in a variety of conditions and may be better accepted and tolerated than CR, but more comparative research is required.

Differences in metabolic biomarkers in people with schizophrenia who are of Mexican descent compared to non-Hispanic whites.

Metabolic dysfunction is highly prevalent and contributes to premature mortality among people with schizophrenia (PwS), especially in Hispanic/Latino/a/x/e PwS, compared to non-Hispanic White (NHW) PwS. This study evaluated the relative contributions of Mexican descent and schizophrenia diagnosis to metabolic biomarker levels. This cross-sectional study included 115 PwS and 102 non-psychiatric comparison (NC) participants - English-speakers aged 26-66 years, 27% Mexican descent, and 52% women across both groups. Assessments included evaluations of BMI, psychopathology, and fasting metabolic biomarkers. We used ANOVA analyses to compare metabolic outcomes between diagnostic and ethnic subgroups, linear regression models to examine associations between Mexican descent and metabolic outcomes, and Spearman's correlations to examine relationships between metabolic outcomes and illness-related variables in PwS. Mexican PwS had higher hemoglobin A1c levels, insulin resistance, and body mass index than NHW PwS. Mexican descent was associated with higher hemoglobin A1c levels, insulin resistance, body mass index, and leptin levels, controlling for age, sex, depression, education, and smoking. Among Mexican PwS, worse negative symptoms were associated with greater insulin resistance. These findings support the possibility of ethnicity-based differences in metabolic dysregulation, though further investigation is warranted to create targeted health interventions for Hispanic PwS.

Design and Rationale of Prolonged Nightly Fasting for Multiple Myeloma Prevention (PROFAST): Protocol for a Randomized Controlled Pilot Trial.

BACKGROUND: Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy. OBJECTIVE: We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM). METHODS: Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibility is assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast. RESULTS: The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025. CONCLUSIONS: PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51368.

Gut microbiome remodeling and metabolomic profile improves in response to protein pacing with intermittent fasting versus continuous caloric restriction.

The gut microbiome (GM) modulates body weight/composition and gastrointestinal functioning; therefore, approaches targeting resident gut microbes have attracted considerable interest. Intermittent fasting (IF) and protein pacing (P) regimens are effective in facilitating weight loss (WL) and enhancing body composition. However, the interrelationships between IF- and P-induced WL and the GM are unknown. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks. Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P (p < 0.05), whereas metabolites associated with a longevity-related metabolic pathway increase with CR (p < 0.05). Differences indicate GM and metabolomic factors play a role in WL maintenance and body composition. This novel work provides insight into the GM and metabolomic profile of participants following an IF-P or CR diet and highlights important differences in microbial assembly associated with WL and body composition responsiveness. These data may inform future GM-focused precision nutrition recommendations using larger sample sizes of longer duration. Trial registration, March 6, 2020 (ClinicalTrials.gov as NCT04327141), based on a previous randomized intervention trial.

The 2011-2016 Transdisciplinary Research on Energetics and Cancer (TREC) initiative: rationale and design.

PURPOSE: Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms. METHODS: The National Cancer Institute developed an innovative concept to establish a center grant mechanism in nutrition, energetics, and physical activity, referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the centers. RESULTS: Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes three animal studies, three cohort studies, four randomized clinical trials, one cross-sectional study, and two modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality. CONCLUSION: The NIH Science of Team Science group will evaluate the value added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk of cancer as well as cancer survivors.

Gut microbiome diversity, variability, and latent community types compared with shifts in body weight during the freshman year of college in dormitory-housed adolescents.

Significant human gut microbiome changes during adolescence suggest that microbial community evolution occurs throughout important developmental periods including the transition to college, a typical life phase of weight gain. In this observational longitudinal study of 139 college freshmen living in on-campus dormitories, we tracked changes in the gut microbiome via 16S amplicon sequencing and body weight across a single academic year. Participants were grouped by weight change categories of gain (WG), loss (WL), and maintenance (WM). Upon assessment of the community structure, unweighted and weighted UniFrac metrics revealed significant shifts with substantial variation explained by individual effects within weight change categories. Genera that positively contributed to these associations with weight change included Bacteroides, Blautia, and Bifidobacterium in WG participants and Prevotella and Faecalibacterium in WL and WM participants. Moreover, the Prevotella/Bacteroides ratio was significantly different by weight change category, with WL participants displaying an increased ratio. Importantly, these genera did not display co-dominance nor ease of transition between Prevotella- and Bacteroides-dominated states. We further assessed the overall taxonomic variation, noting the increased stability of the WL compared to the WG microbiome. Finally, we found 30 latent community structures within the microbiome with significant associations with waist circumference, sleep, and dietary factors, with alcohol consumption chief among them. Our findings highlight the high level of individual variation and the importance of initial gut microbiome community structure in college students during a period of major lifestyle changes. Further work is needed to confirm these findings and explore mechanistic relationships between gut microbes and weight change in free-living individuals.

The freshman year of college is a transitional period that may provide insights into the relationship between the gut microbiome and body weight regulation due to the lifestyle changes that increase vulnerability to weight change. During this critical period many of the lifestyle factors that influence body weight formalize and have important bearing on health outcomes throughout an individual's life. In this college-aged population, shifts in community structure and variability of gut microbes were different by weight change trajectory. Genera that underpinned these shifts such as Bacteroides, Blautia, Bifidobacterium, Prevotella, and Faecalibacterium displayed varying degrees of inter-individual variability and, in some instances, resistance to alternative states. Accounting for these considerations in the context of body weight control in adolescents may prove useful for improving target outcomes in an intervention setting.