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BackgroundObesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated.Subjects/methodsWe fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma.ResultsWe found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss.ConclusionsThese results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight.

Obesity and inflammation are both risk factors for a variety of cancers, including breast cancer in postmenopausal women. Intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of breast cancer, and also reduces obesity-associated inflammation and insulin resistance, but whether the two effects are related is currently unknown. We tested this hypothesis in a postmenopausal breast cancer model using ovariectomized, immune-competent female mice orthotopically injected with Py230 mammary tumor cells. Obesity, whether triggered genetically or by high-fat diet (HFD) feeding, increased inflammation in the mammary fat pad and promoted mammary tumorigenesis. The presence of tumor cells in the mammary fat pad further enhanced the local inflammatory milieu. Tumor necrosis factor-alpha (TNF-α) was the most highly upregulated cytokine in the obese mammary fat pad, and we observed that TNF-α dose-dependently stimulated Py230 cell growth in vitro. An ω-3 PUFA-enriched HFD (referred to as fish oil diet, FOD) reduced inflammation in the obese mammary fat pad in the absence of tumor cells and inhibited Py230 tumor growth in vivo. Although some anti-inflammatory effects of ω-3 PUFAs were previously shown to be mediated by the G-protein-coupled receptor 120 (GPR120), the FOD reduced Py230 tumor burden in GPR120-deficient mice to a similar degree as observed in wild-type mice, indicating that the effect of FOD to reduce tumor growth does not require GPR120 in the host mouse. Instead, in vitro studies demonstrated that ω-3 PUFAs act directly on tumor cells to activate c-Jun N-terminal kinase, inhibit proliferation and induce apoptosis. Our results show that obesity promotes mammary tumor progression in this model of postmenopausal breast cancer and that ω-3 PUFAs, independent of GPR120, inhibit mammary tumor progression in obese mice.

Background: Sedentary behavior has been identified as a significant risk factor for Metabolic Syndrome (MetS). However, it is unclear if the sedentary pattern measurement approach (posture vs. movement) impacts observed associations or if associations differ for Hispanic/Latino communities, who have higher risk of MetS., Methods: Participants from the Community of Mine (CoM) study (N = 602) wore hip-based accelerometers for 14 days and completed MetS-associated biomarker assessment (triglycerides, blood pressure, fasting glucose, HDL cholesterol, waist circumference). Sedentary patterns were classified using both cutpoints (movement-based) and the Convolutional Neural Network Hip Accelerometer Posture (CHAP) algorithm (posture-based). We used logistic regression to estimate associations between MetS with sedentary patterns overall and stratified by Hispanic/Latino ethnicity., Results: CHAP and cutpoint sedentary patterns were consistently associated with MetS. When controlling for total sedentary time and moderate to vigorous physical activity, only CHAP-measured median sedentary bout duration (OR = 1.15, CI: 1.04, 1.28) was significant. In stratified analysis, CHAP-measured median bout duration and time spent in sedentary bouts ≥ 30 min were each associated with increased odds of MetS, but the respective associations were stronger for Hispanic/Latino ethnicity (OR = 1.71 and 1.48; CI = 1.28-2.31 and 1.12-1.98) than for non-Hispanic/Latino ethnicity (OR = 1.43 and 1.40; CI = 1.10-1.87 and 1.06-1.87)., Conclusions: The way sedentary patterns are measured can impact the strength and precision of associations with MetS. These differences may be larger in Hispanic/Latino ethnic groups and warrants further research to inform sedentary behavioral interventions in these populations., (© 2024. The Author(s).)

Introduction: Growing evidence exists that greenspace exposure can reduce metabolic syndrome risk, a growing public health concern with well-documented inequities across population subgroups. We capitalize on the use of g-computation to simulate the influence of multiple possible interventions on residential greenspace on nine metabolic biomarkers and metabolic syndrome in adults (N = 555) from the 2014-2017 Community of Mine Study living in San Diego County, California., Methods: Normalized difference vegetation index (NDVI) exposure from 2017 was averaged across a 400-m buffer around the participants' residential addresses. Participants' fasting plasma glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations, systolic and diastolic blood pressure, hemoglobin A1c (%), waist circumference, and metabolic syndrome were assessed as outcomes of interest. Using parametric g-computation, we calculated risk differences for participants being exposed to each decile of the participant NDVI distribution compared to minimum NDVI. Differential health impacts from NDVI exposure by sex, ethnicity, income, and age were examined., Results: We found that a hypothetical increase in NDVI exposure led to a decrease in hemoglobin A1c (%), glucose, and high-density lipoprotein cholesterol concentrations, an increase in fasting total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations, and minimal changes to systolic and diastolic blood pressure, waist circumference, and metabolic syndrome. The impact of NDVI changes was greater in women, Hispanic individuals, and those under 65 years old., Conclusions: G-computation helps to simulate the potential health benefits of differential NDVI exposure and identifies which subpopulations can benefit most from targeted interventions aimed at minimizing health disparities., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Chrononutrition is a rapidly evolving field of nutritional epidemiology that addresses the complex relationship between temporal eating patterns, circadian rhythms, and metabolic health, but most prior research has focused on the cardiometabolic consequences of time-restricted feeding and intermittent fasting. The purpose of this topical review is to summarize epidemiological evidence from observational and intervention studies regarding the role of chrononutrition metrics related to eating timing and regularity in cardiometabolic health preservation and cardiovascular disease prevention. Observational studies are limited due to the lack of time-stamped diet data in most population-based studies. Findings from cohort studies generally indicate that breakfast skipping or the later timing of the first eating occasion, a later lunch and dinner, and a greater proportion of caloric intake consumed in the evening are associated with adverse cardiometabolic outcomes, including higher risk for coronary heart disease, hypertension, type 2 diabetes, obesity, dyslipidemia, and systemic inflammation. Randomized controlled trials are also limited, as most in the field of chrononutrition focus on the cardiometabolic consequences of time-restricted feeding. Overall, interventions that shift eating timing patterns to earlier in the day and that restrict evening caloric intake tend to have protective effects on cardiometabolic health, but small sample sizes and short follow-up are notable limitations. Innovation in dietary assessment approaches, to develop low-cost validated tools with acceptable participant burden that reliably capture chrononutrition metrics, is needed for advancing observational evidence. Culturally responsive pragmatic intervention studies with sufficiently large and representative samples are needed to understand the impact of fixed and earlier eating timing schedules on cardiometabolic health. Additional research is warranted to understand the modifiable determinants of temporal eating patterns, to investigate the role of chrononutrition in the context of other dimensions of diet (quantity, quality, and food and nutrition security) in achieving cardiometabolic health equity, and to elucidate underlying physiological mechanisms.

Postmenopausal Hispanic/Latina (N = 254) women with a body mass index (BMI) ≥ 25 kg/m 2 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/m 2 , 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 [M difference (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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

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/m 2 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., (©David J Lee, Elizabeth K O'Donnell, Noopur Raje, Cristina Panaroni, Robert Redd, Jennifer Ligibel, Dorothy D Sears, Omar Nadeem, Irene M Ghobrial, Catherine R Marinac. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.03.2024.)

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, NO 2 , 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 (β -0.010, 95%CI -0.025, 0.005; β -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 (β -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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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.

Physical activity (PA) is significantly associated with many health outcomes. The wide usage of wearable accelerometer-based activity trackers in recent years has provided a unique opportunity for in-depth research on PA and its relations with health outcomes and interventions. Past analysis of activity tracker data relies heavily on aggregating minute-level PA records into day-level summary statistics in which important information of PA temporal/diurnal patterns is lost. In this paper we propose a novel functional data analysis approach based on Riemann manifolds for modeling PA and its longitudinal changes. We model smoothed minute-level PA of a day as one-dimensional Riemann manifolds and longitudinal changes in PA in different visits as deformations between manifolds. The variability in changes of PA among a cohort of subjects is characterized via variability in the deformation. Functional principal component analysis is further adopted to model the deformations, and PC scores are used as a proxy in modeling the relation between changes in PA and health outcomes and/or interventions. We conduct comprehensive analyses on data from two clinical trials: Reach for Health (RfH) and Metabolism, Exercise and Nutrition at UCSD (MENU), focusing on the effect of interventions on longitudinal changes in PA patterns and how different modes of changes in PA influence weight loss, respectively. The proposed approach reveals unique modes of changes, including overall enhanced PA, boosted morning PA, and shifts of active hours specific to each study cohort. The results bring new insights into the study of longitudinal changes in PA and health and have the potential to facilitate designing of effective health interventions and guidelines.

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.

Study Objectives: Examining multiple dimensions of sleep health may better capture associations between sleep and health risks, including cardiometabolic disease (CMD). Hispanics have elevated risk for inadequate sleep and CMD biomarkers. Few studies have explored whether associations between sleep and CMD differ by Hispanic ethnicity., Methods: Leveraging data from the Community of Mine (CoM) study, a cross-sectional investigation of 602 ethnically diverse participants, we derived accelerometer-measured sleep duration and efficiency, and self-reported sleep quality. Accelerometer-measured sleep exposures were analyzed both as continuous and categorical variables. Multivariate and quantile regression models were used to assess associations between sleep and CMD biomarkers (insulin resistance, systolic blood pressure, and low-density-lipoprotein cholesterol), controlling for age, sex, ethnicity, education, smoking status, and body mass index. We examined the potential effect modification of Hispanic ethnicity., Results: We observed mixed results based on CMD biomarkers and sleep exposure. Increased sleep duration was significantly related to low-density lipoprotein cholesterol in adjusted models (estimate = 0.06; 95% CI: 0.02, 0.11). Poor sleep efficiency was associated with greater insulin resistance in the adjusted quantile (estimate = 0.20; 95% CI: 0.04, 0.36) model at the 90th percentile. Self-reported sleep quality was not associated with CMD outcomes. There was no evidence of effect modification by Hispanic ethnicity., Conclusions: In this cohort, sleep health measures were found to have mixed and at times opposing effects on CMD outcomes. These effects did not demonstrate an interaction with Hispanic ethnicity., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Objectives: Weight gain and unfavorable body composition are prevalent among midlife/older women throughout menopause. These shifts may negatively impact health, well-being, and longevity. Efforts to attenuate weight and body composition changes are traditionally driven by manipulation of diet and/or exercise; however, sustained results are limited, possibly because the full spectrum of biobehavioral systems is not addressed by diet and exercise alone. We propose a biobehavioral model detailing mechanisms of body composition decline among perimenopausal women and the associated components of Meditative Movement (ie, tai chi, qigong, yoga) that address each of these factors., Methods: Based on our previous work and extensive review of the literature, we developed a multifactorial and multidimensional biobehavioral model including factors that most directly relate to body composition among perimenopausal women: 1) psychological (ie, stress and mood, mindfulness and self-compassion, body awareness), 2) behavioral (ie, sleep, physical activity, eating behaviors), and 3) physiological (ie, cortisol, estrogen). Relationships between each factor, Meditative Movement practice components, and predicted effects on body composition were explored in detail., Results: Our model describes select psychological, behavioral, and physiological factors, and potential mechanistic pathways of Meditative Movement practice driving improved changes in body composition and weight outcomes for perimenopausal women., Conclusions: The proposed model details a novel, evidence-supported means to reduce the risk of deleterious shifts in body composition throughout perimenopause and menopause thereafter. We suggest that these changes may occur directly and/or indirectly through psychological, behavioral, and physiological mechanisms that facilitate the desired changes in body composition., Competing Interests: Financial disclosure/conflicts of interest: K.G. receives ongoing institutional funding from the National Institute for Health and Care Research, the Medical Research Council/Economic Social Research Council/UK Research and Innovation, and the National Institutes of Health. She also received a past grant from Juvenile Diabetes Research Foundation. The other authors have nothing to disclose., (Copyright © 2023 by The Menopause Society.)

Background: Prolonged bouts of sedentary time, independent from the time spent in engaging in physical activity, significantly increases cardiometabolic risk. Nonetheless, the modern workforce spends large, uninterrupted portions of the day seated at a desk. Previous research suggests-via improved cardiometabolic biomarkers-that this risk might be attenuated by simply disrupting sedentary time with brief breaks of standing or moving. However, this evidence is derived from acute, highly controlled laboratory experiments and thus has low external validity., Objective: This study aims to investigate if similar or prolonged cardiometabolic changes are observed after a prolonged (2-week) practice of increased brief standing and moving behaviors in real-world office settings., Methods: This randomized crossover trial, called the WorkWell Study, will compare the efficacy of two 2-week pilot intervention conditions designed to interrupt sitting time in sedentary office workers (N=15) to a control condition. The intervention conditions use a novel smartphone app to deliver real-time prompts to increase standing (STAND) or moving (MOVE) by an additional 6 minutes each hour during work. Our primary aim is to assess intervention-associated improvements to daily postprandial glucose using continuous glucose monitors. Our secondary aim is to determine whether the interventions successfully evoke substantive positional changes and light-intensity physical activity (LPA). Other outcomes include the feasibility and acceptability of the intervention conditions, fasting blood glucose concentration, femoral artery flow-mediated dilation (f-FMD), and systolic and diastolic blood pressure., Results: The trial is ongoing at the time of submission., Conclusions: This study is a novel, randomized crossover trial designed to extend a laboratory-based controlled study design into the free-living environment. By using digital health technologies to monitor and prompt participants in real time, we will be able to rigorously test the effects of breaking up sedentary behavior over a longer period of time than is seen in traditional laboratory-based studies. Our innovative approach will leverage the strengths of highly controlled laboratory and free-living experiments to achieve maximal internal and external validity. The research team's multidisciplinary expertise allows for a broad range of biological measures to be sampled, providing robust results that will extend knowledge of both the acute and chronic real-life effects of increased standing and LPA in sedentary office workers. The WorkWell Study uses a rigorous transdisciplinary protocol that will contribute to a more comprehensive picture of the beneficial effects of breaking up sitting behavior., Trial Registration: ClinicalTrials.gov NCT04269070; https://clinicaltrials.gov/study/NCT04269070., International Registered Report Identifier (irrid): DERR1-10.2196/45133., (©Shannon L Wilson, Rachel Crosley-Lyons, Jordan Junk, Kristina Hasanaj, Miranda L Larouche, Kevin Hollingshead, Haiwei Gu, Corrie Whisner, Dorothy D Sears, Matthew P Buman. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 23.08.2023.)

Adipocyte dysregulation is one mechanism linking overweight and breast cancer recurrence. Exercise and weight loss are associated with a decreased risk of breast cancer recurrence in breast cancer survivors with overweight or obesity, which may be mediated through reduced leptin levels, increased adiponectin levels, and an elevated adiponectin to leptin (A:L) ratio. The four-arm randomized controlled WISER Survivor trial examined the 12-month intervention effects of exercise, weight loss, and the combination of exercise and weight loss on adipokine levels among breast cancer survivors ( n = 339) with overweight or obesity. Compared with Control, the Combination of Exercise and Weight Loss decreased leptin levels (-35.9%; 95% CI: -46.8%, -25.0%) and increased A:L ratio (11.6%; 95% CI: 5.6%, 17.6%) but did not change adiponectin levels (4.1%; 95% CI: -3.1%, 11.2%). Compared with Control, Weight Loss Alone decreased leptin levels (-35.6%; 95% CI: -46.6%, -24.5%) and increased A:L ratio (10.6%; 95% CI: 4.7%, 16.5%) but did not change adiponectin levels (0.9%; 95% CI: -6.0%, 7.9%). Compared with Control, Exercise Alone did not change leptin levels, adiponectin levels, or A:L ratio. In analyses that consolidated intervention groups, compared with Control, weight loss of ≥5% decreased leptin levels ( p trend < 0.01) and increased A:L ratio ( p trend < 0.01) but did not alter adiponectin levels ( p trend = 0.53). Weight loss, with or without exercise, was associated with decreased leptin levels in breast cancer survivors with overweight or obesity. Improvements in the adipokine secretion profile (A:L ratio) were primarily driven by a weight loss-induced change in leptin levels.

Accelerometers are widely used for tracking human movement and provide minute-level (or even 30 Hz level) physical activity (PA) records for detailed analysis. Instead of using day-level summary statistics to assess these densely sampled inputs, we implement functional principal component analysis (FPCA) approaches to study the temporal patterns of PA data from 245 overweight/obese women at three visits over a 1-year period. We apply longitudinal FPCA to decompose PA inputs, incorporating subject-specific variability, and then test the association between these patterns and obesity-related health outcomes by multiple mixed effect regression models. With the proposed methods, the longitudinal patterns in both densely sampled inputs and scalar outcomes are investigated and connected. The results show that the health outcomes are strongly associated with PA variation, in both subject and visit-level. In addition, we reveal that timing of PA during the day can impact changes in outcomes, a finding that would not be possible with day-level PA summaries. Thus, our findings imply that the use of longitudinal FPCA can elucidate temporal patterns of multiple levels of PA inputs. Furthermore, the exploration of the relationship between PA patterns and health outcomes can be useful for establishing weight-loss guidelines.

Obesity is associated with chronic inflammation that may contribute to T2D among youth. We examined the association between inflammatory biomarkers and insulin sensitivity and β-cell function and response to lifestyle intervention among Latino youth with obesity. Latino youth (n = 64) were randomized to six months of lifestyle intervention (INT, n = 40) or usual care (UC, n = 24). INT included nutrition education and physical activity. UC involved meeting with a pediatric endocrinologist and registered dietitian to discuss healthy lifestyles. At baseline, multiple linear regression assessed fasting serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), high-molecular weight adiponectin (HMW Adpn), IL-10, IL-1 receptor antagonist (IL-1ra) as predictors of insulin sensitivity (whole-body insulin sensitivity index, WBISI) and β-cell function (oral disposition index, oDI). Changes in outcomes between groups were assessed using covariance pattern models. At baseline, MCP-1 (β ± SE, -0.12 ± 0.05, p = 0.027) and IL-1ra (-0.03 ± 0.01, p = 0.005) were negatively associated with WBISI. Treatment effects were not observed for inflammatory markers. WBISI was significantly increased among both INT (from 1.8 ± 0.2 to 2.6 ± 0.4, p = 0.005) and UC (from 1.6 ± 0.2 to 2.8 ± 0.5, p = 0.002) with no significant differences between the groups. Obesity-related inflammatory mediators were associated with T2D risk factors but were unaffected by lifestyle intervention among Latino youth.

Intermittent fasting entails restricting food intake during specific times of day, days of the week, religious practice, or surrounding clinically important events. Herein, the metabolic and circadian rhythm mechanisms underlying the proposed benefits of intermittent fasting for the cancer population are described. We summarize epidemiological, preclinical, and clinical studies in cancer published between January 2020 and August 2022 and propose avenues for future research. An outstanding concern regarding the use of intermittent fasting among cancer patients is that fasting often results in caloric restriction, which can put patients already prone to malnutrition, cachexia, or sarcopenia at risk. Although clinical trials do not yet provide sufficient data to support the general use of intermittent fasting in clinical practice, this summary may be useful for patients, caregivers, and clinicians who are exploring intermittent fasting as part of their cancer journey for clinical outcomes and symptom management., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations., Methods: In a four-arm randomized controlled trial, 318 breast cancer survivors with overweight or obesity were randomized to exercise alone, weight loss alone, exercise plus weight loss, or control for 12 months. Inflammation outcomes included C-reactive protein (CRP), serum amyloid A (SAA), intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1)., Results: Compared with control, exercise alone increased ICAM-1 (9.3%; 95% confidence interval [CI] = 1.6-16.9) and VCAM-1 (8.6%; 95% CI = 2.6-14.5) but did not change CRP or SAA. Compared with control, weight loss alone reduced CRP (-35.2%; 95% CI = -49.9 to -20.7), and SAA (-25.6%; 95% CI = -39.8 to -11.9) but did not change ICAM-1 or VCAM-1. Compared with control, exercise plus weight loss reduced CRP (-44.1%; 95% CI = -57.1 to -31.1) and SAA (-26.6%; 95% CI = -40.5 to -12.6) but did not change ICAM-1 or VCAM-1. Among 194 participants with elevated CRP at baseline (e.g., >3 mg·L -1 ), compared with control, weight loss alone (0.17; 95% CI = 0.04-0.30) and exercise plus weight loss (0.31; 95% CI = 0.16-0.46) increased the probability of achieving normal CRP at month 12. In analyses that consolidated randomized groups, body weight and adiposity reductions, but not change in fitness level, correlated with decreased CRP, SAA, and ICAM-1 levels., Conclusions: In breast cancer survivors with overweight or obesity, weight loss or exercise plus weight loss reduced measures of inflammation that are associated with breast cancer recurrence and cardiovascular death., (Copyright © 2022 by the American College of Sports Medicine.)

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., (© Society of Behavioral Medicine 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022. The Author(s).)

Accumulating evidence links cardiometabolic health with social and environmental neighborhood exposures, which may contribute to health inequities. We examined whether environmental characteristics were individually or jointly associated with insulin resistance, hypertension, obesity, type 2 diabetes, and metabolic syndrome in San Diego County, CA. As part of the Community of Mine Study, cardiometabolic outcomes of insulin resistance, hypertension, BMI, diabetes, and metabolic syndrome were collected in 570 participants. Seven census tract level characteristics of participants' residential environment were assessed and grouped as follows: economic, education, health care access, neighborhood conditions, social environment, transportation, and clean environment. Generalized estimating equation models were performed, to take into account the clustered nature of the data and to estimate β or relative risk (RR) and 95 % confidence intervals (CIs) between each of the seven environmental characteristics and cardiometabolic outcomes. Quantile g-computation was used to examine the association between the joint effect of a simultaneous increase in all environmental characteristics and cardiometabolic outcomes. Among 570 participants (mean age 58.8 ± 11 years), environmental economic, educational and health characteristics were individually associated with insulin resistance, diabetes, obesity, and metabolic syndrome. In the mixture analyses, a joint quartile increase in all environmental characteristics (i.e., improvement) was associated with decreasing insulin resistance (β, 95 %CI: -0.09, -0.18-0.01)), risk of diabetes (RR, 95 %CI: 0.59, 0.36-0.98) and obesity (RR, 95 %CI: 0.81, 0.64-1.02). Environmental characteristics synergistically contribute to cardiometabolic health and independent analysis of these determinants may not fully capture the potential health impact of social and environmental determinants of health., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Individual sleep dimensions have been linked to cardiovascular disease (CVD) risk and cardiometabolic health (CMH), but sleep health is multifaceted. We investigated associations of a multidimensional sleep health (MDSH) score, enabling the assessment of sleep health gradients, with CVD and CMH. Participants were 4555 adults aged ≥20 years from the 2017-2018 National Health and Nutrition Examination Survey. A MDSH score, capturing poor, moderate, and ideal sleep was computed from self-reported sleep duration, sleep regularity, difficulty falling asleep, symptoms of sleep disorders, and daytime sleepiness. Survey-weighted multivariable linear and logistic models examined associations of MDSH with CVD and CMH. Ideal and moderate vs. poor MDSH were related to lower odds of hypertension (62% and 41%), obesity (73% and 56%), and central adiposity (68% and 55%), respectively; a statistically significant linear trend was observed across gradients of MDSH ( p -trend < 0.001). Ideal vs. moderate/poor MDSH was associated with 32% and 40% lower odds of prevalent CVD and type 2 diabetes, respectively. More favorable MDSH was associated with lower blood pressure, BMI, waist circumference, and fasting glucose. In sex-stratified analyses, ideal vs. moderate/poor MDSH was associated with lower CVD odds and blood pressure in women only. The MDSH framework may be more than just the sum of its parts and could better capture information regarding CVD risk.

Introduction : Children and adolescents with cancer report increased fatigue and decreased physical activity, introducing risk factors for chronic disease and suppressed quality of life. Research suggests an inverse relationship between fatigue and physical activity, but the biological explanation is not well understood. The purpose of this study was to 1) explore metabolites associated with fatigue or physical activity and 2) to identify any shared metabolomic elements. Methods: Children, ages 8-17 years, attending a pediatric oncology summer camp provided Patient-Reported Outcome Measurement System® (PROMIS) Pediatric Fatigue assessments, physical activity data (steps/day), and urine samples pre- and post-camp. Differences in PROMIS Pediatric Fatigue scores and average daily steps were calculated using paired t-tests. Liquid chromatography-tandem mass spectrometry was conducted using a targeted metabolomic approach. Results: Thirty-two enrolled children had complete data. Fatigue scores decreased (pre-camp 45.1; post-camp 42.1; p = 0.04) while steps-per-day increased (pre-camp 6699; post-camp 16,021; p < 0.001). Twenty-seven metabolites significantly differentiated (false discovery rate <0.20) between low, medium, or high physical activity, while 8 metabolites discriminated between high and low fatigue. Indole-3-lactic acid, a tryptophan metabolite, was significantly associated with both physical activity and fatigue. Conclusion: This study provides evidence of metabolome associations with fatigue and physical activity in children with cancer. Overlapping metabolomic elements provide evidence of biological inter-connectivity and suggest areas for future research. Given the known evidence regarding the benefits of physical activity, and the potential interaction with fatigue, nurses should routinely assess patient reports of these elements and provide patient/family education related to fatigue management and physical activity goals.

Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in β-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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 (PM 2.5 , NO 2 , 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 PM 2.5 compared to non-Hispanics using static measures. In contrast, Hispanics/Latinos had less exposure to PM 2.5 using dynamic measures. For all participants, higher dynamic exposure to PM 2.5 and NO 2 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 PM 2.5 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The evidence linking sugar-sweetened beverage (SSB) intake and mortality risk is conflicting, and associations between various SSB subtypes and mortality remain unclear., Objective: To examine the association between baseline SSB intake, subtypes of SSB intake, and mortality risk in women., Design: Prospective cohort study., Participants/setting: Participants of the California Teachers Study (n = 100,314; median age = 53 years) free of cardiovascular disease, cancer, and diabetes at baseline (1995-1996) were followed from 1995 to 2015. Baseline SSB intake was defined as caloric soft drinks (regular soft drinks, not diet soda), sweetened bottled waters or teas, and fruit drinks; and was derived from a self-administered food frequency questionnaire., Main Outcome Measure: Mortality was ascertained via annual linkage with state- and nationwide mortality records and the National Death Index over 20 years., Statistical Analysis: Multivariable-adjusted Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% CIs for assessing associations between SSB intake and mortality. Rare/never consumers were the comparator group., Results: There were a total of 14,143 deaths over 20 years (30.5% from cardiovascular disease; 29.2% from cancer). In women who consumed ≥ 7 servings/week of SSBs at baseline (4% of participants), the multivariable-adjusted HRs were not significant for all-cause, cardiovascular disease-specific, or cancer-specific mortality. Consuming ≥ 7 servings/week of baseline caloric soft drink was associated with a higher risk of all-cause (HR = 1.26, 95% CI 1.10 to 1.46; P for trend = 0.02) and cancer-specific (HR = 1.33, 95% CI 1.08 to 1.63; P for trend = 0.08) mortality. In secondary analyses, consuming ≥ 1.5 c/day of baseline SSBs was associated with all-cause mortality (HR = 1.12, 95% CI 1.02 to 1.24; P for trend = 0.01)., Conclusions: Although the baseline frequency of total SSB intake was not significantly associated with mortality, consuming ≥ 7 servings/week of caloric soft drinks was associated with higher risk of all-cause and cancer-specific mortality. Findings support public health efforts to reduce caloric soft drink consumption., (Copyright © 2022 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Various microbial products leaked from gut lumen exacerbate tissue inflammation and metabolic disorders in obesity. Vsig4+ macrophages are key players preventing infiltration of bacteria and their products into host tissues. However, roles of islet Vsig4+ macrophages in the communication between microbiota and β cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in β cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into β cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into β cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in β cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in β cells and subsequently obesity-associated islet abnormalities., (© 2022. The Author(s).)

Metformin and weight loss relationships with epigenetic age measures-biological aging biomarkers-remain understudied. We performed a post-hoc analysis of a randomized controlled trial among overweight/obese breast cancer survivors (N = 192) assigned to metformin, placebo, weight loss with metformin, or weight loss with placebo interventions for 6 months. Epigenetic age was correlated with chronological age (r = 0.20-0.86; P < 0.005). However, no significant epigenetic aging associations were observed by intervention arms. Consistent with published reports in non-cancer patients, 6 months of metformin therapy may be inadequate to observe expected epigenetic age deceleration. Longer duration studies are needed to better characterize these relationships.Trial Registration: Registry Name: ClincialTrials.Gov.Registration Number: NCT01302379.Date of Registration: February 2011.URL: https://clinicaltrials.gov/ct2/show/NCT01302379., (© 2021. The Author(s).)

Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses.

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Background Sleep variability and social jetlag are associated with adverse cardiometabolic outcomes via circadian disruption. Variable eating patterns also lead to circadian disruption, but associations with cardiometabolic health are unknown. Methods and Results Women (n=115, mean age: 33±12 years) completed a 1-week food record using the Automated Self-Administered 24-Hour Dietary Assessment Tool at baseline and 1 year. Timing of first and last eating occasions, nightly fasting duration, and %kcal consumed after 5 pm (%kcal 5 pm) and 8 pm (%kcal 8 pm) were estimated. Day-to-day eating variability was assessed from the SD of these variables. Eating jetlag was defined as weekday-weekend differences in these metrics. Multivariable-adjusted linear models examined cross-sectional and longitudinal associations of day-to-day variability and eating jetlag metrics with cardiometabolic risk. Greater jetlag in eating start time, nightly fasting duration, and %kcal 8 pm related to higher body mass index and waist circumference at baseline ( P <0.05). In longitudinal analyses, a 10% increase in %kcal 8 pm SD predicted increased body mass index (β, 0.52; 95% CI, 0.23-0.81) and waist circumference (β, 1.73; 95% CI, 0.58-2.87); greater %kcal 8 pm weekday-weekend differences predicted higher body mass index (β, 0.25; 95% CI, 0.07-0.43). Every 30-minute increase in nightly fasting duration SD predicted increased diastolic blood pressure (β, 0.95; 95% CI, 0.40-1.50); an equivalent increase in nightly fasting duration weekday-weekend differences predicted higher systolic blood pressure (β, 0.58; 95% CI, 0.11-1.05) and diastolic blood pressure (β, 0.45; 95% CI, 0.10-0.80). Per 10% increase in %kcal 5 pm SD, there were 2.98 mm Hg (95% CI, 0.04-5.92) and 2.37mm Hg (95% CI, 0.19-4.55) increases in systolic blood pressure and diastolic blood pressure; greater %kcal 5 pm weekday-weekend differences predicted increased systolic blood pressure (β, 1.83; 95% CI, 0.30-3.36). For hemoglobin A1c, every 30-minute increase in eating start and end time SD and 10% increase in %kcal 5 pm SD predicted 0.09% (95% CI, 0.03-0.15), 0.06% (95% CI, 0.001-0.12), and 0.23% (95% CI, 0.07-0.39) increases, respectively. Conclusions Variable eating patterns predicted increased blood pressure and adiposity and worse glycemic control. Findings warrant confirmation in population-based cohorts and intervention studies.

Obesity-associated breast cancer recurrence is mechanistically linked with elevated insulin levels and insulin resistance. Exercise and weight loss are associated with decreased breast cancer recurrence, which may be mediated through reduced insulin levels and improved insulin sensitivity. This is a secondary analysis of the WISER Survivor clinical trial examining the relative effect of exercise, weight loss and combined exercise and weight loss interventions on insulin and insulin resistance. The weight loss and combined intervention groups showed significant reductions in levels of: insulin, C-peptide, homeostatic model assessment 2 (HOMA2) insulin resistance (IR), and HOMA2 beta-cell function (β) compared to the control group. Independent of intervention group, weight loss of ≥10% was associated with decreased levels of insulin, C-peptide, and HOMA2-IR compared to 0-5% weight loss. Further, the combination of exercise and weight loss was particularly important for breast cancer survivors with clinically abnormal levels of C-peptide.

Time spent sitting is positively correlated with endothelial dysfunction and cardiovascular disease risk. The underlying molecular mechanisms are unknown. MicroRNAs contained in extracellular vesicles (EVs) reflect cell/tissue status and mediate intercellular communication. We explored the association between sitting patterns and microRNAs isolated from endothelial cell (EC)-derived EVs. Using extant actigraphy based sitting behavior data on a cohort of 518 postmenopausal overweight/obese women, we grouped the woman as Interrupted Sitters (IS; N = 18) or Super Sitters (SS; N = 53) if they were in the shortest or longest sitting pattern quartile, respectively. The cargo microRNA in EC-EVs from the IS and SS women were compared. MicroRNA data were weighted by age, physical functioning, MVPA, device wear days, device wear time, waist circumference, and body mass index. Screening of CVD-related microRNAs demonstrated that miR-199a-5p, let-7d-5p, miR-140-5p, miR-142-3p, miR-133b level were significantly elevated in SS compared to IS groups. Group differences in let-7d-5p, miR-133b, and miR-142-3p were validated in expanded groups. Pathway enrichment analyses show that mucin-type O-glycan biosynthesis and cardiomyocyte adrenergic signaling (P < 0.001) are downstream of the three validated microRNAs. This proof-of-concept study supports the possibility that CVD-related microRNAs in EC-EVs may be molecular transducers of sitting pattern-associated CVD risk in overweight postmenopausal women.

Background: Many older adults spend the majority of their waking hours sitting, which increases their risk of chronic diseases. Given the challenges that many older adults face when engaging in moderate-to-vigorous physical activity, understanding the health benefits of decreasing sitting time and increasing the number of sit-to-stand transitions is needed to address this growing public health concern., Objective: The aim of this 3-arm randomized controlled trial is to investigate how changes in sitting time and brief sit-to-stand transitions impact biomarkers of healthy aging and physical, emotional, and cognitive functioning compared with a healthy attention control arm., Methods: Sedentary and postmenopausal women (N=405) will be recruited and randomly assigned to 1 of the 3 study conditions for 3 months: healthy living attention control (Healthy Living), reduce sitting time (Reduce Sitting), and increase sit-to-stand transitions (Increase Transitions). Assessments conducted at baseline and 3 months included fasting blood draw, blood pressure, anthropometric measurements, physical functioning, cognitive testing, and 7 days of a thigh-worn accelerometer (activPAL) and a hip-worn accelerometer (ActiGraph). Blood-based biomarkers of healthy aging included those associated with glycemic control (glycated hemoglobin, fasting plasma insulin and glucose, and homeostatic model assessment of insulin resistance)., Results: Recruitment began in May 2018. The intervention is ongoing, with data collection expected to continue through the end of 2022., Conclusions: The Rise for Health study is designed to test whether 2 different approaches to interrupting sitting time can improve healthy aging in postmenopausal women. Results from this study may inform the development of sedentary behavior guidelines and interventions to reduce sitting time in older adults., Trial Registration: ClinicalTrials.gov NCT03473145; https://clinicaltrials.gov/ct2/show/NCT03473145., International Registered Report Identifier (irrid): DERR1-10.2196/28684., (©Sheri J Hartman, Lindsay W Dillon, Andrea Z LaCroix, Loki Natarajan, Dorothy D Sears, Neville Owen, David W Dunstan, James F Sallis, Simon Schenk, Matthew Allison, Michelle Takemoto, Alexandra M Herweck, Bao Nguyen, Dori E Rosenberg. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.05.2021.)

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.

Active travel (AT) provides an opportunity to alleviate the physical inactivity and climate crises contributing to the global chronic disease burden, including cardiovascular diseases (CVD). Though AT shows promising links to reduced CVD risk, prior studies relied on self-reported AT assessment. In the present study, device-measured and self-reported AT were compared across population subgroups and relationships with CVD risk biomarkers were evaluated for both measures. The study recruited an ethnically diverse sample (N = 602, mean age 59 years, 42% Hispanic/Latino ethnicity) from neighborhoods that varied by walkability and food access. AT was assessed using concurrently collected accelerometer and GPS data and self-report data from a validated survey. Relationships with body mass index (BMI), triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure (BP), and moderate-to-vigorous physical activity (MVPA) were modeled using multivariable linear regression. Devices captured more AT than did self-report. We found differences in AT measures by population subgroups, including race, ethnicity, education, income, vehicle access, and walkability. Men had more accelerometer-measured MVPA, though women self-reported more daily minutes. Both device and survey AT measures were positively associated with total accelerometer-measured MVPA, though the relationship was stronger with device-measured AT. Device-measured AT was associated with lower BMI. No other CVD risk biomarker was associated with either AT measure. No effect modification by Hispanic/Latino ethnicity was detected. Further studies with device-based measures are warranted to better understand the relationship between AT and cardiovascular health.

Introduction: Difficulties with cognition are extremely common among breast cancer survivors and can significantly impact quality of life, daily functioning, and ability to return to work. One promising intervention is increasing physical activity, as it has been effective in improving cognition in non-cancer populations. Few physical activity intervention trials with cognition outcomes have included cancer survivors. This project builds upon our previous work indicating that increased physical activity can improve objectively measured processing speed and self-reported cognition among breast cancer survivors., Methods: The I Can! study will examine whether a physical activity intervention improves cognition among 250 post-treatment breast cancer survivors (Stages I-III, <5 years post-treatment) who are reporting cognitive difficulties. This 2-arm randomized controlled trial comparing a 6-month physical activity intervention (Exercise Group) to a health & wellness attention-comparison condition (Health & Wellness Group) will examine intervention effects on cognition (at 3 and 6 months) and maintenance of effects at 12 months. The primary aim is to investigate the impact of exercise on objectively measured processing speed and self-reported cognition. Secondary aims are to investigate maintenance of cognitive changes and examine candidate biological mechanisms and psychological mediators., Conclusion: The I Can! study will contribute to the scientific, public health, and survivorship intervention literature by providing new information on the impact of physical activity for cognitive impairment in breast cancer survivors. Findings from this study will inform guidelines for physical activity to improve the lives of millions of breast cancer survivors., (Copyright © 2021. Published by Elsevier Inc.)

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.

Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.

Nightly fasting duration (NFD) and eating timing and frequency may influence cardiometabolic health via their impact on circadian rhythms, which are entrained by food intake, but observational studies are limited. This 1-year prospective study of 116 US women (33 ± 12y, 45% Hispanic) investigated associations of habitual NFD and eating timing and frequency with cardiovascular health (CVH; American Heart Association Life's Simple 7 score) and cardiometabolic risk factors. NFD, eating timing and frequency, and nighttime eating levels were evaluated from 1-week electronic food records completed at baseline and 1 y. In multivariable-adjusted linear regression models, longer NFD was associated with poorer CVH (β = -0.22, p = 0.016 and β = -0.22, p = 0.050) and higher diastolic blood pressure (DBP) (β = 1.08, p < 0.01 and β = 1.74, p < 0.01) in cross-sectional and prospective analyses, respectively. Later timing of the first eating occasion at baseline was associated with poorer CVH (β = -0.20, p = 0.013) and higher DBP (β = 1.18, p < 0.01) and fasting glucose (β = 1.43, p = 0.045) at 1 y. After adjustment for baseline outcomes, longer NFD and later eating times were also associated with higher waist circumference (β = 0.35, p = 0.021 and β = 0.27, p < 0.01, respectively). Eating frequency was inversely related to DBP in cross-sectional (β = -1.94, p = 0.033) and prospective analyses (β = -3.37, p < 0.01). In cross-sectional analyses of baseline data and prospective analyses, a higher percentage of daily calories consumed at the largest evening meal was associated with higher DBP (β = 1.69, p = 0.046 and β = 2.32, p = 0.029, respectively). Findings suggest that frequent and earlier eating may lower cardiometabolic risk, while longer NFD may have adverse effects. Results warrant confirmation in larger multi-ethnic cohort studies with longer follow-up periods.

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.