Improvements In Metabolic Health Research Articles

Crithmum maritimum Extract Restores Lipid Homeostasis and Metabolic Profile of Liver Cancer Cells to a Normal Phenotype.

Hepatocellular carcinoma (HCC) is an alarming epidemiological clinical problem worldwide. Pharmacological approaches currently available do not provide adequate responses due to poor effectiveness, high toxicity, and serious side effects. Our previous studies have shown that the wild edible plant Crithmum maritimum L. inhibits the growth of liver cancer cells and promotes liver cell differentiation by reducing lactic acid fermentation (Warburg effect). Here, we aimed to further characterise the effects of C. maritimum on lipid metabolism and markers of cellular metabolic health, such as AMP-activated protein kinase (AMPK), Sirtuin 1 (SIRT1), and Sirtuin 3 (SIRT3), as well as the insulin signalling pathway. To better mimic the biological spectrum of HCC, we employed four HCC cell lines with different degrees of tumorigenicity and lactic acid fermentation/Warburg phenotype. Lipid accumulation was assessed by Oil Red O (ORO) staining, while gene expression was measured by real-time quantitative PCR (RT-qPCR). The activation of AMPK and insulin signalling pathways was determined by Western blotting. Results indicate that C. maritimum prevents lipid accumulation, downregulates lipid and cholesterol biosynthesis, and modulates markers of metabolic health, such as AMPK, SIRT1 and SIRT3. This modulation is different amongst HCC cell lines, revealing an important functional versatility of C. maritimum. Taken together, our findings corroborate the importance of C. maritimum as a valuable nutraceutical, reinforcing its role for the improvement of metabolic health.

Abstract PS07-08: Bazedoxifene plus conjugated estrogen reduces mammary proliferation markers and improves adipocyte size, gut microbiome, and metabolic health: Findings from a preclinical model of obesity and breast cancer risk

Abstract Background: Many women at high risk for breast cancer will not take tamoxifen or aromatase inhibitors for cancer prevention due to concern of side effects including hot flashes. Further, tamoxifen has detrimental metabolic effects in some overweight/obese women. Duavee®, a tissue-selective complex of bazedoxifene + conjugated estrogen, is FDA-approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects and potential for breast cancer risk reduction. In a single arm clinical trial, BZA+CE reduced Ki-67 and mammographic density (PMID: 31420361), and this combination is currently being assessed further in a Phase IIB trial of postmenopausal high risk women with vasomotor symptoms. Here, we examined the modifying effects of obesity on response to BZA+CE in a rodent model of obesity and breast cancer risk. Methods: Rats received carcinogen at 7-weeks of age to induce mammary tumors and were fed a high-fat diet (46% kcal fat) to promote obesity. Lean and obese rat were selected based on adiposity at 16 weeks. Separate cohorts of lean and obese ovary-intact or ovariectomized (OVX) rats were randomized to a daily dose of BZA+CE or placebo control for 8 weeks. We assessed tumor development throughout the study and end of study RNA from mammary glands was analysed by gene expression microarray (Affymetrix). We also analyzed body weight/composition, markers of metabolic health (circulating glucose, insulin, adiponectin), as well as changes in the gut microbiome (metagenomic sequencing on DNA isolated from baseline and end-of-study fecal samples) in response to BZA+CE. Results: BZA+CE improved metabolic health in both ovary intact and OVX rats, including reduced body weight and % body fat, particularly in the visceral regions. These effects were greater in obese rats compared to lean. BZA+CE reduced the number of large adipocytes and increased small (insulin sensitive) adipocytes in the mammary adipose, indicating benefical changes in local tumor microenvironment. We found no evidence that Duavee® promoted tumor development or growth in ovary-intact or OVX’d rats. Gene set enrichment analysis (GSEA) of microarray data showed enrichment of cell proliferation pathways in MG from obese rats and these same pathways were downregulated with BZA+CE, consistent with anti-cancer effects. Analysis of the microbiome found that BZA+CE increased proportional abudance of Odoribacter laneus in the gut, regardless of lean/obese or intact/OVX status. Previous studies have demonstrated that this bacterim improves glucose control and reduces inflammatory cytokines when administered to obese mice, suggesting a possible mechanistic link in this study. Conclusions: Unlike traditional SERMs that can have negative metabolic effects, BZA+CE improved whole body and mammary gland metabolic health and reduced expression of cell proliferation pathways, particularly in obese rats. Prelminary data suggest that changes in the gut microbiome could contribute, at least in part, to these effects. Together this supports BZA+CE (Duavee) as an agent with potential beneficial effects on breast cancer risk reduction and improvements in metabolic health in women with obesity. Further analyses will guide assessment of outcomes in an ongoing parallel clinical study in postmenopausal women at high risk for breast cancer. Citation Format: Katherine L. Cook, Ramsey Jenshcke, Karen Corleto, Carol Fabian, Stephen Hursting, Bruce Kimler, Danilo Landrock, Erin Giles. Bazedoxifene plus conjugated estrogen reduces mammary proliferation markers and improves adipocyte size, gut microbiome, and metabolic health: Findings from a preclinical model of obesity and breast cancer risk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-08.

A retrospective and explorative analysis of dietary and behavioural factors on weight loss and well-being following a 12-week lifestyle education program promoting anti-inflammatory dietary principles

It is estimated that one-quarter of the world’s population has Metabolic Syndrome (MS)(1), a key driver of growth in healthcare expenditure. Traditional approaches to treating MS through the application of standard dietary recommendations and caloric restriction have had limited success. More recent evidence suggests that novel, anti-inflammatory approaches such as replacing refined carbohydrates and ultra-processed food with unprocessed or minimally processed, lower carbohydrate foods and adapting meal timing and frequency may be more effective(2). The aim of the study was twofold: 1) To determine the effectiveness of anti-inflammatory dietary strategies for long-term weight loss and improvement in metabolic health and 2) To examine the relationships between eating behaviours and long-term weight loss. Twelve-month audit data from a UK based 12-week lifestyle program that focuses the principles of consuming an anti-inflammatory diet was analysed using repeated-measures ANOVA to examine the effects of the program on changes in weight and waist circumference. A quantitative, survey-based research design was used to retrospectively identify relationships between eating behaviours and both anti-inflammatory and pro-inflammatory dietary patterns. Multivariate regression using stepwise method was used to examine differences in weight change based on eating patterns and behaviours. Six hundred and forty-two (N = 642) participants (age = 50.4 ± 12.5 years, female 63.6%, weight = 96.1 kg ± 22.1, BMI 35.2 kg/m2 ± 7.5) demonstrated a weight loss average of 4.49 kg ± 3.78 post-lifestyle program (12 weeks). Survey respondents (N = 64) reported a maximum long term weight loss of 13.9 kg ± 11.9. Weight loss and percentage weight loss after the program was significantly predicted by daily consumption of sweet drinks and grain-based foods. The model predicted one unit increase in daily serving consumption of these foods resulted in less weight lost [2.3 kg (4.5%)]. Seventy one percent of survey respondents had maintained most or all their weight loss for more than 6 months. The model predicted change in consumption of grain-based foods, TFEQ-emotional eating score, consumption of savoury ultra-processed foods, and following an alternative dietary approach after the program were statistically significant in predicting weight loss maintenance (R2 = 0.803, F(4, 20) = 20.376, p < 0.001). The preliminary findings suggest that anti-inflammatory dietary approaches are effective and sustainable for weight loss. Eating behaviour may both support and hinder long term changes in eating patterns and whilst there are significant relationships between eating behaviour and eating patterns, the extent to which dietary patterns drive eating behaviour remains unclear.

Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial

The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy. More recently, this treatment has shown promise in the treatment of psychiatric illness. We conducted a 4–month pilot study to investigate the effects of a KD on individuals with schizophrenia or bipolar disorder with existing metabolic abnormalities. Twenty–three participants were enrolled in a single–arm trial. Results showcased improvements in metabolic health, with no participants meeting metabolic syndrome criteria by study conclusion. Adherent individuals experienced significant reduction in weight (12 %), BMI (12 %), waist circumference (13 %), and visceral adipose tissue (36 %). Observed biomarker enhancements in this population include a 27 % decrease in HOMA–IR, and a 25 % drop in triglyceride levels. In psychiatric measurements, participants with schizophrenia showed a 32 % reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31 %, and the proportion of participants that started with elevated symptomatology improved at least 1–point on CGI (79 %). Psychiatric outcomes across the cohort encompassed increased life satisfaction (17 %) and enhanced sleep quality (19 %). This pilot trial underscores the potential advantages of adjunctive ketogenic dietary treatment in individuals grappling with serious mental illness.

Associations of cholecystectomy with metabolic health changes and incident cardiovascular disease: a retrospective cohort study

Although some studies conducted about the risk of cholecystectomy and cardiovascular disease, there was a limit to explaining the relationship. We investigated the short-term and long-term relationship between cholecystectomy and cardiovascular disease, and evidence using the elements of the metabolic index as an intermediate step. It was a retrospective cohort study and we used the National Health Insurance Service database of South Korea between 2002 and 2015. Finally, 5,210 patients who underwent cholecystectomy and 49,457 at 1:10 age and gender-matched controls of subjects were collected. The main results was estimated by Multivariate Cox proportional hazard regression to calculate the hazard ratio (HR) with 95% confidence interval (CI) for risk of cardiovascular disease after cholecystectomy. Regarding short-term effects of cholecystectomy, increased risk of cardiovascular disease (aHR 1.35, 95% CI 1.15–1.58) and coronary heart disease (aHR 1.77, 95% CI 1.44–2.16) were similarly seen within 2 years of surgery. When analyzing the change in metabolic risk factors, cholecystectomy was associated with a change in systolic blood pressure (adjusted mean [aMean]: 1.51, 95% CI: [− 1.50 to − 4.51]), total cholesterol (aMean − 14.14, [− 20.33 to 7.95]) and body mass index (aMean − 0.13, [− 0.37 to 0.11]). Cholecystectomy patients had elevated risk of cardiovascular disease in the short-term, possibly due to the characteristics of the patient before surgery. The association of cholecystectomy and cardiovascular disease has decreased after 2 years in patients who underwent cholecystectomy, suggesting that because of improvement of metabolic health, cholecystectomy-associated elevation of cardiovascular disease risk may be ameliorated 2 years after cholecystectomy.

Adipocyte Glucocorticoid Receptor Activation With High Glucocorticoid Doses Impairs Healthy Adipose Tissue Expansion by Repressing Angiogenesis.

In Human, glucocorticoids (GC) are commonly prescribed because of their anti-inflammatory and immunosuppressive properties. However, high doses of GC often lead to adverse side effects including diabetes and lipodystrophy. We recently reported that adipocyte glucocorticoid receptor (GR)-deficient (AdipoGR-KO) mice under corticosterone (CORT) treatment exhibited a massive adipose tissue (AT) expansion associated with a paradoxical improvement of metabolic health compared to control mice. However, whether GR may control adipose development remains unclear. Here, we show a specific induction of the hypoxiainducible factor HIF-1α and the pro-angiogenic Vascular Endothelial Growth Factor-A expression in GR-deficient adipocytes of AdipoGR-KO mice as compared to control mice, together with an increased adipose vascular network, as assessed by 3D-analysis imaging. GR activation reduced HIF-1α recruitment on Vegfa promoter resulting from Hif-1α downregulation at the transcriptional and post-translational levels. Importantly, in CORT-treated AdipoGR-KO mice, the blockade of VEGFA by a soluble decoy receptor prevented AT expansion and the healthy metabolic phenotype. Finally, in subcutaneous AT from Cushing patients, higher VEGFA expression was associated with a better metabolic profile. Collectively, these results highlight that adipocyte GR negatively controls AT expansion and metabolic health through the down-regulation of the major angiogenic effector VEGFA and inhibiting vascular network development. (LIPOCUSH, NCT01688349).

Achieving Normoglycemia With Tirzepatide: Analysis of SURPASS 1-4 Trials.

Tirzepatide is a novel single-molecule glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, which demonstrated unprecedented improvements in glycemic control and body weight reduction, in the SURPASS phase 3 program. In this exploratory analysis, we aimed to characterize tirzepatide-treated participants who achieved HbA1c <5.7% and evaluate changes in clinical markers associated with long-term cardiometabolic health. Baseline characteristics and change from baseline to week 40 for several efficacy and safety parameters were analyzed according to HbA1c attainment category (<5.7%, 5.7-6.5%, and >6.5%) using descriptive statistics in participants taking ≥75% of treatment doses, without rescue medication, in the SURPASS 1-4 trials (N = 3,229). Logistic regression models with tirzepatide doses adjusted as a covariate were used to obtain odds ratios and assess the impact of patient characteristics achieving an HbA1c <5.7%. Tirzepatide-treated participants who achieved HbA1c <5.7% were slightly younger, with a shorter duration of diabetes and lower HbA1c value at baseline compared with those who did not achieve HbA1c <5.7%. In addition, they showed greater improvements in HbA1c, body weight, waist circumference, blood pressure, liver enzymes, and lipid parameters without increasing hypoglycemia risk. Normoglycemia was unprecedently achieved in a significant proportion of participants in the SURPASS clinical program, without increasing hypoglycemia risk, and was associated with an overall improvement in metabolic health.

62-LB: Sleep Improves over Five Years of Very Low Carbohydrate Nutrition Therapy for Prediabetes Delivered by Continuous Remote Care

Background: People with prediabetes are more likely to suffer from poor sleep, and sleep characteristics are correlated with metabolic markers such as glycemia and weight. We previously reported 1-yr improvements in sleep and metabolic health among people with prediabetes participating in a very low carb intervention including nutritional ketosis delivered via continuous remote care. Improvements in metabolic health were also observed out to 5 yrs. Given the relationships between sleep and metabolic health, in this analysis we explored whether sleep characteristics that improved at 1 yr were also improved at 5 yrs. Methods: Adults with prediabetes initially enrolled in a 2-yr single-arm trial were offered to continue for 3 more yrs of prospective follow-up. Of the 72 participants completing 2 yrs, 58 (81%) of participants consented to the extension and 45 (78%) were retained at 5 yrs. Baseline characteristics of those who extended include: 83% female, mean age= 53 yrs, mean HbA1c = 5.9%, and mean BMI= 39. Sleep was assessed with the Pittsburgh Sleep Quality Index at baseline, 3 mos, 1 yr, 2 yrs, 3.5 yrs, and 5 yrs. Among all extending participants, we explored changes over time in Global Sleep, Sleep Quality, Sleep Disturbances, and Daytime Dysfunction using 4 linear mixed effects models (intent-to-treat analyses) controlling for age, gender, and race. Results: The overall effect of time was significant for all sleep measures, such that sleep improved over time (ps &amp;lt;0.02). From baseline to 5 yrs, sleep score improvements ranged from 21-28% (ps &amp;lt;0.02). Conclusions: Participants in a virtual nutrition therapy intervention focused on nutritional ketosis reported long-term improvements in sleep out to 5 yrs concurrent with sustained metabolic health improvements. This provides additional evidence that this intervention benefits overall health. Additional research is needed to better understand what drove perceptions of sleep improvement. Disclosure R. N. Adams: Employee; Virta Health Corp. S. J. Athinarayanan: Employee; Virta Health Corp. B. M. Volk: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. S. D. Phinney: Stock/Shareholder; Virta Health Corp. Board Member; Virta Health Corp. Employee; Virta Health Corp. J. Volek: Stock/Shareholder; Virta Health Corp. A. L. McKenzie: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp.

Chronic voluntary wheel running exercise ameliorates metabolic dysfunction via PGC-1α expression independently of FNDC5/irisin pathway in high fat diet-induced obese mice

Exercise is an effective intervention to ameliorate metabolic diseases including obesity and insulin resistance, but the mechanisms involved in the metabolic amelioration have not yet been fully elucidated. This study aimed to determine whether AMPK–SIRT1–PGC-1α–FNDC5/Irisin-UCP1 expression is activated and whether metabolic dysfunction is ameliorated by chronic voluntary wheel running (VWR) in high-fat diet (HFD) induced obese mice. C57BL6J mice were randomly assigned into three groups at the age of 7 weeks for 10 weeks: normal chow diet (CON) group, HFD group, and HFD + VWR group. Chronic VWR ameliorates metabolic parameters and leads to increases in the expression of PGC-1α in the gastrocnemius muscle in HFD-induced obese mice. In contrast, the expression of AMPKα, SIRT1, and FNDC5, or circulating irisin levels did not lead to alteration. Improvement of metabolic health was partly mediated via PGC-1α expression by chronic VWR, but not FNDC5/Irisin pathway in HFD-induced obese mice.

Investigating the change in gene expression profile of blood mononuclear cells post-laparoscopic sleeve gastrectomy in Chinese obese patients.

Laparoscopic sleeve gastrectomy (LSG) is a sustainable technique that effectively treats morbid obesity. However, the molecular mechanisms underlying the improvement of metabolic health following this process warrants more investigation. This study investigates LSG-related molecules and uses bulk RNA-sequencing high-throughput analysis to unravel their regulatory mechanisms. Peripheral blood mononuclear cells (PBMC) were collected from ten obese patients with BMI ≥ 32.5 kg/m2 in the Department of General Surgery of Kunming First People's Hospital. After LSG, patients were followed up for one month, and blood samples were retaken. Blood samples from ten patients before and after LSG and bulk RNA-Seq data were analyzed in this study. LSG-associated gene expression was detected by weighted gene coexpression network analysis (WGCNA) and differential analysis. Subsequently, essential signature genes were identified using logistic least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) were utilized to reveal the potential functions of the target genes. Furthermore, the Pearson correlation of signature genes with leptin and lipocalin was also explored. Finally, we constructed a robust endogenous RNA (ceRNA) network based on miRWalk and starBase databases. We identified 18 overlapping genes from 91 hub genes, and 165 differentially expressed mRNAs (DE-mRNA), which were revealed to be significantly associated with immune cells, immune response, inflammatory response, lipid storage, and localization upon functional enrichment analysis. Three signature genes, IRF1, NFKBIA, and YRDC, were identified from the 18 overlapping genes by LASSO and SVM-REF algorithms. The logistic regression model based on the three signature genes highlighted how robustly they discriminated between samples. ssGSEA indicated these genes to be involved in lipid metabolism and degradation pathways. Moreover, leptin levels were significantly reduced in patients undergoing LSG, and NFKBIA significantly negatively correlated with leptin. Finally, we identified how the long non-coding RNA (lncRNA) ATP2B1-AS1 regulated the expression of the signature genes by competitively binding to six microRNAs (miRNAs), which were hsa-miR-6509-5p, hsa-miR-330-5P, hsa-miR-154-5P, hsa-miR-145-5P, hsa-miR4726-5P and hsa-miR-134-5P. This study identified three critical regulatory genes significantly differentiated between patients before and after LSG treatment and highlighted their potentially crucial role after bariatric surgery. This provides novel insights to increase our understanding of the underlying mechanisms of weight loss and associated metabolic improvement after bariatric surgery.

Abstract P649: Juvenile Exercise Delays Frailty and Promotes Metabolic Health in Aged Mice

Introduction: Physical exercise is well-recognized for its beneficial effects on health. Acute or short-term effects of exercise have been extensively studied; however, it remains unclear whether exercise in juvenile has sustained beneficial effects until old age. Hypothesis: We hypothesized that juvenile exercise would delay frailty and promote metabolic health in aged mice. Methods: Male and female mice were divided into sedentary and exercise groups, and each group contains 50 mice. Mice in exercise group started swimming at 1 month of age and stopped at 4 month of age (1.5 hour per day and 5 days per week). No exercise intervention was conducted in other time. The general health, cardiac function, metabolism and other parameters were examined in aged mice. Transcriptional profiling of various tissues and organs was performed to obtain insight into mechanisms that how juvenile exercise affects aged mice. Results: Juvenile exercise mice showed significant reduction in frailty and improvement in metabolic health compared with sedentary controls. Both male and female juvenile exercise mice were scored lower in frailty at the age of 24 months. Juvenile exercise improved the integument and physical/musculoskeletal status of male mice. For females, juvenile exercise reduced frailty in all aspects. Female juvenile exercise mice weighted more than sedentary mice at 24 months old but male groups showed no difference. The cardiac function, food consumption, grip strength and rotarod running time between two groups also presented no difference at 24 months. Juvenile exercise mice showed improved flexibility in substrate usage at the age of 24 months under fasting condition. Aged mice in exercise group showed significant higher energy expenditure, fat and carbohydrate oxidation than their controls. KEGG overrepresentation analysis for the differentially expressed genes demonstrated that pathways altered by juvenile exercise were most related to metabolism, especially lipid metabolism. Conclusions: These results demonstrate that regular and moderate physical exercise in juvenile age extends health span in mice, highlighting the sustained beneficial effects of juvenile exercise.

Evidence of Use of Whole-Body Vibration in Individuals with Metabolic Syndrome: A Systematic Review and Meta-Analysis

(1) Background: Metabolic syndrome (MSy) is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increase the risk of cardiovascular disease. This systematic review with meta-analysis was conducted to assess the effects of whole-body vibration exercise (WBVE) in metabolic syndrome (MSy) individuals. (2) Methods: An electronic search in Pubmed, Embase, Scopus, Web of Science, ScienceDirect, PEDro, and CINAHL databases in December 2022 was performed. Data regarding the included studies were extracted. The level of evidence, the methodological quality, and the risk of bias of each selected publication were individually evaluated. (3) Results: Eight studies were included in the systematic review and four studies in the meta-analysis, with a mean methodological quality score on the Physiotherapy Evidence Database (PEDro scale) of 5.6, considered "fair" quality. The qualitative results suggested positive effects of the systemic vibration therapy in relevant outcomes, such as quality of life, functionality, pain level, trunk flexibility, cardiovascular responses (blood pressure and heart rate), neuromuscular activation, range of motion of the knees, rating of perceived exertion, and body composition. The quantitative results, with weighted mean differences, standard mean differences, and 95% confidence intervals (CIs), were calculated. Conclusions: WBVE may be an alternative capable of interfering with physical-mainly for flexibility with weighted mean differences (1.70; 95% CI 0.15, 3.25; n = 39)-functional, psychosocial, neuromuscular, emotional parameters, and consequently contribute to improvements in metabolic health and reduce the cardiovascular risk factor in MSy individuals. Nevertheless, further additional studies are required to understand the long-term effects of WBVE on MSy and its complications in a better way. Protocol study registration was as follows: PROSPERO (CRD 42020187319).

Associations between Timing and Duration of Eating and Glucose Metabolism: A Nationally Representative Study in the U.S.

Diabetes is highly prevalent and is associated with dietary behaviors. Time-restricted eating, which consolidates caloric intake to a shortened eating duration, has demonstrated improvement in metabolic health. Timing of eating could also impact metabolism. Our objective was to examine whether the timing of eating was associated with metabolic health independently of eating duration. Data (n = 7619) are from four cycles (2005-2012) of the National Health and Nutrition Examination Survey (NHANES), a nationally representative U.S. survey that included surveys, physical examinations, and dietary recalls. The primary exposures are eating duration and eating start time estimated from two non-consecutive dietary recalls. Primary outcomes were fasting glucose and estimated insulin resistance using the homeostatic model assessment method (HOMA-IR). The mean (95% CI) eating duration was 12.0 h (11.9-12.0) and the mean (95% CI) start time was 8:21 (8:15-8:26). Earlier eating start time was significantly associated with lower fasting glucose and estimated insulin resistance but eating interval duration was not. Every hour later that eating commenced was associated with approximately 0.6% higher glucose level and 3% higher HOMA-IR (both p < 0.001). In this cross-sectional study, earlier eating start time was associated with more favorable metabolic measures, indicating that meal timing is another important characteristic of dietary patterns that may influence metabolism.

Synbiotics as potent functional food: recent updates on therapeutic potential and mechanistic insight.

Synbiotics are the specific mixtures of prebiotics with probiotics intended to give health benefits to the host by stabilizing and supporting the gut microbiota.The prebiotic substance used in the synbiotics selectively favors the growth and metaboliteproduction of probiotics. Gut microbiome dysbiosis may lead to generation and progression of various chronic diseases. Synbiotics act synergistically to modulate the gut ecosystem for improvement of metabolic health of the host. Probiotics have been found promising against various diseases being safer, effective, as an alternative or combinatorial therapy. Specific combinations of probiotics with suitable prebiotic substrateassynbiotics, may be the more effective therapeutic agents that can provide all benefits of probiotics as well as prebiotics. Though, effective combinations, dosage, mechanism of action, safety, cost effectiveness and other clinical investigations are required to be established along with other relevant aspects. Synbiotics have the potential to be functional food of importance in future. Present review summarizes the mechanistic overview of synbiotics related to gut microbiota, therapeutic potential and promising health benefits for human illnesses according to the available literature. In present scenario, synbiotics are more promising future alternatives as therapeutics to maintain healthy microbiota inside the host gut which directly affects the onset or development ofrelated disorders or diseases.

Calorie restriction causes multiple beneficial metabolic adaptations linearly related with the degree of weight loss in non-obese individuals: Results of CALERIE, a multicenter randomised controlled trial

BACKGROUND &amp; AIMS: Understanding the temporal association and relative power of anthropometric, body composition and energy metabolism measurements of calorie restriction (CR) in predicting metabolic and hormonal adaptations is important, given the clinical and public health implications of excess weight and adiposity. METHODS: Anthropometric (body weight, BMI, waist circumference), body composition (body fat and lean mass by DXA), energy metabolism (leptin and total daily energy intake by doubly labelled water [DLW]) markers and an extensive assessment of cardiometabolic, inflammatory and hormonal risk factors were obtained in 191, 21–50 year old non-obese (BMI 22·0–27·9 kg/m2) women and men, who participated in the 2-yr CALERIE randomized clinical trial. Pairwise correlations for each adiposity and energy metabolism measure were calculated against each other and against each metabolic parameter. In addition, spline and linear regression models were developed to determine a threshold effect of adiposity and energy metabolism measures to trigger changes in metabolic parameters. RESULTS: Among the progressively more sophisticated measures of adiposity, body weight is the variable that is most strongly correlated with cardiometabolic and inflammatory outcomes during CR-induced weight loss in young and middle-aged non-obese men and women. Waist circumference and DXA body fat are not superior to body weight or BMI in detecting these biological modifications. We did not find a specific threshold in weight loss to be exceeded for changes in metabolic and inflammatory adaptations to occur. Even small reductions in body weight cause a significant decline in serum T3 levels, a predictor of post-CR weight regain. CONCLUSIONS: Calorie restriction with adequate nutrition causes multiple beneficial cardiometabolic and hormonal adaptations that are linearly related with the degree of weight loss in non-obese individuals. Once a baseline has been established, tracking changes in body weight is sufficient to monitor improvements in metabolic health.

A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www. gov (NCT02991209) and ended June 2019. Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n=35, 51%) or placebo (n=34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.

A Changed Gut Microbiota Diversity Is Associated With Metabolic Improvements After Duodenal Mucosal Resurfacing With Glucagon-Like-Peptide-1 Receptor Agonist in Type 2 Diabetes in a Pilot Study.

The gut microbiota influences and interacts with the host metabolism through effects on nutrient metabolism and digestion. Duodenal Mucosal Resurfacing (DMR) is a novel endoscopic procedure involving duodenal mucosal ablation by the use of hydrothermal energy. DMR, when combined with a glucagon-like peptide-1 receptor agonist (GLP-1RA), resulted in discontinuation of exogenous insulin treatment in 69% of patients with insulin dependent type 2 diabetes mellitus (T2DM) in the INSPIRE study. These patients also experienced improved glycaemic control and metabolic health. We thus investigated if these clinical effects were associated with a change in gut microbiota alpha and beta diversity. Faecal samples from the 16 patients were obtained for Illumina shotgun sequencing at baseline and 3 months after DMR. We assessed alpha and beta diversity of the gut microbiota in these samples and analysed its correlations with changes in HbA1c, body weight, and liver MRI proton density fat fraction (PDFF). HbA1c correlated negatively with alpha diversity (p=0.011, rho: -0.62) whereas changes in PDFF correlated significantly with beta diversity (p=0.036, rho: 0.55) 3 months after initiation of the combined intervention. These correlations with metabolic parameters were observed despite finding no change in gut microbiota diversity at 3 months post DMR. The correlation between gut microbiota richness (alpha diversity) and HbA1c as well as the change in PDFF and changed microbiota composition (beta diversity) suggests that changed gut microbiota diversity is associated with metabolic improvements after DMR in combination with glucagon-like-peptide-1 receptor agonist in type 2 diabetes. Larger controlled studies are however needed to find causal links between DMR with GLP-1RA, the gut microbiota, and improvements in metabolic health.

3-LB: A Free-Living Walking-Based Exercise Programme Improves HbA1c in Individuals with Obesity, with Additional Benefits of Nutritional Status on Metabolic Health

Background: Regular exercise improves insulin resistance and glycaemic control, but ‘real world’ programmes are not universally effective. Laboratory studies show that post-breakfast exercise improves postprandial glucose excursions with subsequent meals while pre-breakfast exercise augments whole-body fat oxidation. Whether these acute effects translate to greater changes in metabolic health with exercise training is not clear. Aim: To investigate if exercise before/after breakfast leads to differential improvements in metabolic health and/or postprandial glycaemic response. Methods: Thirty-four people with obesity (43±12 y, BMI 35.1±5.1 kg/m2) undertook a 12-week walking-based programme, with two continuous and two interval sessions each week (for 30-60 min, at 50% HRmax vs. alternating 3 min at 85% HRmax and 3 min 50% HRmax respectively) . Participants exercised before (FAST) or after (FED) breakfast (n=17 per group) . Body composition, HbA1c, blood lipids and liver transaminases (ALT/AST) were assessed pre- and post-intervention. Postprandial glucose responses were assessed in week 1 and 12 using flash glucose monitoring. Results: Adherence (FAST: 93%, FED: 95%) and compliance (FAST: 85%, FED: 88%) was high in both groups. Body mass, BMI, waist-to-hip ratio and HbA1c decreased similarly between groups (all P &amp;gt;0.001, HbA1c P=0.01) . However, ALT decreased after FAST (-16%; P=0.001) , but not FED training (-2%; P=0.720) . In week 1, continuous exercise lowered postprandial responses to lunch (FAST; P=0.064) and dinner (FED; P=0.047) versus interval exercise. In week 12, the postprandial glucose responses to lunch and dinner after interval exercise were lower compared to week 1 (P=0.008) . Conclusions: Free living exercise, pre- or post-breakfast improved body composition, glycaemic control and enhanced the postprandial-lowering effect of interval exercise but pre-breakfast exercise had a greater impact on liver biochemistry. Exercise, pre-breakfast, may be advantageous for people with obesity and fatty liver. Disclosure J. S. Barrett: None. S. O. Shepherd: None. A. Wagenmakers: None. D. Cuthbertson: Other Relationship; AstraZeneca, Novo Nordisk. J. Strauss: None.

Species- and strain-level assessment using rrn long-amplicons suggests donor’s influence on gut microbial transference via fecal transplants in metabolic syndrome subjects

ABSTRACT Fecal microbiota transplantation (FMT) is currently used for treating Clostridium difficile infection and explored for other clinical applications in experimental trials. However, the effectiveness of this therapy could vary, and partly depend on the donor’s bacterial species engraftment, whose evaluation is challenging because there are no cost-effective strategies for accurately tracking the microbe transference. In this regard, the precise identification of bacterial species inhabiting the human gut is essential to define their role in human health unambiguously. We used Nanopore-based device to sequence bacterial rrn operons (16S-ITS-23S) and to reveal species-level abundance changes in the human gut microbiota of a FMT trial. By assessing the donor and recipient microbiota before and after FMT, we further evaluated whether this molecular approach reveals strain-level genetic variation to demonstrate microbe transfer and engraftment. Strict control over sequencing data quality and major microbiota covariates was critical for accurately estimating the changes in gut microbial species abundance in the recipients after FMT. We detected strain-level variation via single-nucleotide variants (SNVs) at rrn regions in a species-specific manner. We showed that it was possible to explore successfully the donor-bacterial strain (e.g., Parabacteroides merdae) engraftment in recipients of the FMT by assessing the nucleotide frequencies at rrn-associated SNVs. Our findings indicate that the engraftment of donors’ microbiota is to some extent correlated with the improvement of metabolic health in recipients and that parameters such as the baseline gut microbiota configuration, sex, and age of donors should be considered to ensure the success of FMT in humans. The study was prospectively registered at the Dutch Trial registry – NTR4488 (https://www.trialregister.nl/trial/4488).

Vitamin D Levels as an Important Predictor for Type 2 Diabetes Mellitus and Weight Regain Post-Sleeve Gastrectomy.

Weight Loss Surgery (WLS), including sleeve-gastrectomy (SG), results in significant weight loss and improved metabolic health in severe obesity (BMI ≥ 35 kg/m2). Previous studies suggest post-operative health benefits are impacted by nutrient deficiencies, such as Vitamin D (25(OH)D) deficiency, while it is currently unknown whether nutrient levels may actually predict post-surgery outcomes. As such, this study investigated whether 25(OH)D levels could predict metabolic improvements in patients who underwent SG. Patients with severe obesity (n = 309; 75% female) undergoing SG participated in this ethics-approved, non-randomized retrospective cohort study. Anthropometry, clinical data, 25(OH)D levels and serum markers were collected at baseline, 6-, 12- and 18-months post-surgery. SG surgery resulted in significant improvements in metabolic health at 6- and 12-months post-surgery compared with baseline, as expected. Patients with higher baseline 25(OH)D had significantly lower HbA1c levels post-surgery (p < 0.01) and better post-surgical T2DM outcomes, including reduced weight regain (p < 0.05). Further analysis revealed that baseline 25(OH)D could predict HbA1c levels, weight regain and T2DM remission one-year post-surgery, accounting for 7.5% of HbA1c divergence (p < 0.01). These data highlight that higher circulating 25(OH)D levels are associated with significant metabolic health improvements post-surgery, notably, that such baseline levels are able to predict those who attain T2DM remission. This highlights the importance of 25(OH)D as a predictive biomarker of post-surgery benefits.