Dietary Weight Loss Intervention Research Articles

Trem2 deficiency attenuates breast cancer tumor growth in lean, but not obese or weight loss, mice and is associated with alterations of clonal T cell populations.

Obesity is an established risk factor for breast cancer development and worsened prognosis; however, the mechanisms for this association - and the potential benefits of weight loss - have not been fully explored. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression. An emerging therapeutic target for cancer is TREM2, a transmembrane receptor of the immunoglobulin superfamily that is expressed on macrophages in adipose tissue and tumors. We utilized genetic loss of function (Trem2 +,+ and Trem2 -/-) models and dietary (lean, obese, and weight loss) intervention approaches to examine impacts on postmenopausal breast cancer. Remarkably, Trem2 deficiency ameliorated tumor growth in lean, but not obese or weight loss mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed that tumors of lean Trem2 -/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied with increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, an immune checkpoint study demonstrated that αPD-1 therapy restricted tumor growth in lean and weight loss, but not obese mice. We conclude that weight history is relevant when considering potential efficacy of TREM2 inhibition in postmenopausal breast cancer. This work reveals immunological interactions between tumors and surrounding adipose tissue, highlighting significant differences under obese and weight loss conditions.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic β-cells. To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm2, 13.4 cm2 and 23.45 cm2, respectively, especially in group C (p <0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p <0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p <0.05), and the changes in SOD and MDA in group B and group C were more significant (p <0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p <0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p <0.05) and HOMA-IR index (r=0.422; p <0.01); SOD positively correlated with LMI/FFMI (r=0.195; p <0.05), negatively correlated with HOMA-IR index (r=-0.433; p <0.01). All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage.

Exploring Experiences of People With Knee Osteoarthritis Who Received a Physiotherapist-Delivered Dietary Weight Loss and Exercise Intervention: A Mixed Methods Study.

Explore the experiences of people with knee osteoarthritis (OA) who received a very low energy diet (VLED) and exercise program from a physiotherapist. Mixed methods study involving questionnaires (n = 42) and semistructured interviews (n = 22) with randomized control trial participants with knee OA who had received a 6-month physiotherapist-delivered VLED weight loss and exercise intervention. Questionnaires measured participant satisfaction and perceptions about physiotherapist's skills/knowledge in delivery of the dietary intervention (measured on 5-7 point Likert scales). Interviews explored participant's experiences and were analyzed based on the principles of reflexive thematic analysis. Questionnaire response: 90%. Participants were satisfied with the program (95%), confident their physiotherapist had the required skills (84%) and knowledge (79%) to deliver the dietary intervention, felt comfortable talking to the physiotherapist about weight (74%), and would recommend others see a physiotherapist for the intervention they undertook (71%). The following four themes were developed from the interviews: (1) one-stop-shop of exercise and diet; (2) physiotherapist-delivered weight loss works (unsure initially; successfully lost weight); (3) physiotherapists knowledge and skills (exercise is forte; most thought physiotherapists had the necessary weight loss skills/knowledge, but some disagreed); and (4) physiotherapists have a role in weight loss (physiotherapists are intelligent, credible, and trustworthy; specific training in weight loss necessary). This study provides, to our knowledge, the first documented perspectives from people with OA who have received a physiotherapist-delivered weight loss intervention. Findings suggest physiotherapists may have a role in delivering a protocolized dietary intervention for some people with knee OA with overweight and obesity.

Obesity-related neuropathy: the new epidemic.

To examine the evidence evaluating the association between obesity and neuropathy as well as potential interventions. Although diabetes has long been associated with neuropathy, additional metabolic syndrome components, including obesity, are increasingly linked to neuropathy development, regardless of glycemic status. Preclinical rodent models as well as clinical studies are shedding light on the mechanisms of obesity-related neuropathy as well as challenges associated with slowing progression. Dietary and surgical weight loss and exercise interventions are promising, but more data is needed. High-fat-diet rodent models have shown that obesity-related neuropathy is a product of excess glucose and lipid accumulation leading to inflammation and cell death. Clinical studies consistently demonstrate obesity is independently associated with neuropathy; therefore, likely a causal risk factor. Dietary weight loss improves neuropathy symptoms but not examination scores. Bariatric surgery and exercise are promising interventions, but larger, more rigorous studies are needed. Further research is also needed to determine the utility of weight loss medications and ideal timing for obesity interventions to prevent neuropathy.

The effects of resistance exercise on cardiometabolic health and body composition in obese or overweight individuals undergoing dietary weight loss interventions: A systematic review and meta-analysis

Obesity prevalence has tripled in over the past 35 years and has detrimental effects on physical and psychological health(1). Weight loss via dietary intervention is a mainstay for the treatment of obesity and reduces body fat(2), but also results in loss of lean tissue(3). A potential solution to mitigate the loss of lean tissue, and thus enhance the benefits of weight loss, is resistance exercise. The aim of the current systematic review was to examine the impact of resistance exercise on body weight/composition and markers of cardiometabolic health, as well as physical function, in people living with overweight or obesity undergoing dietary weight loss interventions.A search was performed in PubMed, Embase, CINAHL, SCOPUS, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) based on the set inclusion and exclusion criteria. Systematic searches yielded N=5147 studies of which n=27 were relevant for inclusion after screening for eligibility. We included randomised controlled clinical trials of adult participants (18-65 years of age) with body mass index (BMI) ≥ 25kg/m2) that compared dietary weight loss interventions including resistance exercise with 1) dietary weight loss interventions including other non-resistance exercise and/or 2) dietary weight loss interventions without any exercise. Resistance exercise was classed as any form of resistance or muscle strengthening exercise (e.g. gym or home- based, supervised or non-supervised, used equipment or body weight only). Key data were extracted, risk of bias was assessed using the Cochrane risk of bias tool, and the quality of evidence assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Meta-analysis was performed including only studies that compared dietary weight loss plus resistance exercise interventions to diet-only (i.e. not including any other exercise) weight loss interventions to explore differences in body weight/composition and cardiometabolic health changes between diet plus resistance exercise and diet only interventions.Overall, resistance exercise in addition to diet-induced weight loss had no effect on weight loss (mean difference between groups: -0.32kg, 95% confidence interval [CI] -1.00 to 0.35; p=0.35) but did preserve fat free mass (between-group standardised mean difference (SMD): 0.40, 95%, [CI] 0.18 to 0.61; p=0.0003) and increase loss of fat mass (SMD: -0.36, 95% [CI] -0.49 to -0.23; p&lt; 0.00001). Muscular strength was also improved (SMD: 2.36, 95% [CI] 1.38 to 3.34; p=0.00001) by the inclusion of resistance exercise. No effects of resistance exercise were seen in any of the other cardiometabolic markers studied, although data were limited.In people who are obese or overweight, the addition of resistance exercise to dietary restriction may enhance its beneficial effects. Current evidence, therefore, supports the inclusion of resistance exercise during weight loss to attenuate the loss of lean mass, increase fat mass loss and improve muscle strength.

Abstract 2189: Tirzepatide mitigates obesity-associated metabolic dysregulation and tumor progression in a mouse model of triple-negative breast cancer

Abstract Obesity is an established risk factor for breast cancer. Dietary and surgical weight loss interventions reduce breast cancer risk but have significant limitations to their widespread use as anticancer strategies. Incretin-based pharmaceuticals safely and effectively promote weight loss, but whether these drugs exert similar protective effects against cancer is unknown. Here we test whether weight loss induced by the glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide limits tumor growth in an orthotopic mouse model of triple-negative breast cancer. Ten-week-old female C57BL/6NCrl mice were randomized to either a 10 kcal% low-fat diet (control; n=14) or 60 kcal% high-fat diet to promote diet-induced obesity (DIO; n=43). After 18 weeks on diet, DIO mice were randomized by body weight to either i) remain on the high-fat diet (DIO; n=15); ii) lose weight with tirzepatide (TZP; n=13); or iii) lose weight with 30% daily calorie restriction relative to control mice (CR; n=15). All mice were subcutaneously injected with either TZP or vehicle every other day for 13 weeks with the following escalating dosing schedule: 3 nmol/kg TZP in week 1; 10 nmol/kg TZP in weeks 2-3; 20 nmol/kg TZP in weeks 4-7; 30 nmol/kg TZP in weeks 8-11; and 40 nmol/kg TZP in weeks 12-13. Fasting blood glucose and body composition was assessed after 9 weeks of weight loss, and 35,000 E0771 cells were orthotopically transplanted into the 4th mammary fat pad. Tumors growth was monitored for 4 weeks. TZP-treated mice lost on average &amp;gt;20% weight loss by week 4 and remained at or below 20% weight loss for the remainder of the study. Directly prior to E0771 tumor cell injections, TZP-treated mice had lost 23.6±8.9% body weight, versus 39.7±3.6% in CR mice. Relative to DIO mice, blood glucose control was restored in both weight loss groups (DIO: 149.5±18.5 mg/dl; TZP: 124.5±15.5 mg/dl; CR: 107.6±18.8 mg/dl) and &amp;gt;87.5% of the lost weight was attributed to fat mass, rather than lean mass, for TZP-treated and CR mice. Notably, tirzepatide suppressed tumor growth relative to DIO, but the CR group had a greater anticancer effect than TZP. Reduced tumor mass in both weight loss groups was accompanied by a significant reduction in circulating IGF-1, insulin, and leptin relative to DIO mice. These findings are timely and important because i) obesity is a highly prevalent metabolic disease that increases risk and progression of breast cancer and &amp;gt;13 other cancers; ii) incretin therapies, which show promise as highly effective weight loss drugs, are increasingly being prescribed; and iii) the tumor suppressive effects of tirzepatide described herein newly suggest incretin agonism as another propitious option for breaking the obesity-cancer link. Citation Format: Elaine M. Glenny, Alyssa N. Ho, Violet A. Kiesel, Fangxin Chen, Claire E. Gates, Evan M. Paules, Ruihan Xu, C. Alex Holt, Michael F. Coleman, Stephen D. Hursting. Tirzepatide mitigates obesity-associated metabolic dysregulation and tumor progression in a mouse model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2189.

Abstract P348: Weight Loss of Machine Learning Identified Metabolic Subtypes in Response to Dietary Interventions

Introduction: Metabolic syndrome is a constellation of metabolic risk factors. However, various combinations of metabolic disorders may exhibit distinct responses to weight loss interventions. Objective: To identify metabolic subtypes using the machine learning method and assess their associations with weight loss response to dietary interventions. Methods: The study includes 645 participants from the POUNDS Lost trial. Five criteria for metabolic syndrome were used as the grouping factors. Hierarchical clustering was performed with an 8:2 train/test ratio. Results: Three metabolic subtypes were identified and validated among the POUNDS Lost participants. Cluster 1 was characterized by high proportions of central obesity and high blood pressure but low triglycerides; Cluster 2 showed central obesity with relatively low blood pressure; Cluster 3 had the lowest level of central obesity and blood pressure but the highest triglycerides level. Changes in body weight varied significantly across clusters (p=0.003 at 6 months and p&amp;lt; 0.001 at 2 years). At 6 months, adjusted least-square mean (SE) weights were: -6.5 (0.8) kg in cluster 1, -5.4 (0.6) kg in cluster 2, and -4.2 (0.7) kg in cluster 3. Participants regained weight after 6 months, but the difference across the clusters persisted: -5.5 (1.0) kg in Cluster 1, -3.1 (0.8) kg in Cluster 2, and -1.7 (0.8) kg in Cluster 3. Conclusion: We identified 3 metabolic subtypes that predict different responses to dietary weight loss interventions, which may contribute to subtype-specific precision medicine for obesity prevention and management.

Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial

BackgroundDistinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. ObjectivesWe investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. MethodsThis study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 mo after the weight-loss diet intervention. The ASCVD risk estimates were calculated using the validated equations. ResultsAt baseline, higher concentrations of specific BA subtypes were related to higher concentrations of atherogenic very low-density lipoprotein lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions in triglycerides and total cholesterol [every 1 standard deviation (SD) decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to β (standard error) –3.3 (1.3), –3.4 (1.3), or –3.8 (1.3) mg/dL, respectively; PFDR < 0.05 for all]. Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 mo; there was β –4.0 (1.1) mg/dL per 1-SD decrease of glycoursodeoxycholate (PFDR =0.003) for changes in low-density lipoprotein cholesterol. We found significant interactions (P-interaction < 0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet, but not after consuming a low-fat diet. ConclusionsDecreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk.This trial was registered at clinicaltrials.gov as NCT00072995

Circulating MicroRNA-19 and cardiovascular risk reduction in response to weight-loss diets

MicroRNA-19 (miR-19) plays a critical role in cardiac development and cardiovascular disease (CVD). We examined whether change in circulating miR-19 was associated with change in CVD risk during weight loss. This study included 509 participants with overweight or obesity from the 24-month weight-loss diet intervention study (the POUNDS Lost trial) and with available data on circulating miR-19a-3p and miR-19b-3p at baseline and 6 months. The primary outcome for this analysis was the change in atherosclerotic CVD (ASCVD) risk at 6 and 24 months, which estimates the 10-year probability of hard ASCVD events. Secondary outcomes were the changes in ASCVD risk score components. Circulating miR-19a-3p and miR-19b-3p levels significantly decreased during the initial 6-month dietary intervention period (P=0.008, 0.0004, respectively). We found that a greater decrease in miR-19a-3p or miR-19b-3p was related to a greater reduction in ASCVD risk (β[SE]=0.33 [0.13], P=0.01 for miR-19a-3p; β[SE]=0.3 [0.12], P=0.017 for miR-19b-3p) over 6 months, independent of concurrent weight loss. Moreover, we found significant interactions between change in miR-19 and sleep disturbance on change in ASCVD risk over 24 months of intervention (P interaction=0.01 and 0.008 for miR-19a-3p and miR-19b-3p, respectively). Participants with a greater decrease in miR-19 without sleep disturbance had a greater reduction of ASCVD risk than those with slight/moderate/great amounts of sleep disturbance. In addition, change in physical activity significantly modified the associations between change in miR-19 and change in ASCVD risk over 24 months (P interaction=0.006 and 0.004 for miR-19a-3p and miR-19b-3p, respectively). A greater decrease in miR-19 was significantly associated with a greater reduction in ASCVD risk among participants with an increase in physical activity, while non-significant inverse associations were observed among those without an increase in physical activity. In conclusion, decreased circulating miR-19 levels during dietary weight-loss interventions were related to a significant reduction in ASCVD risk, and these associations were more evident in people with no sleep disturbance or increase in physical activity. ClinicalTrials.gov NCT00072995.

The effects of a dietary intervention for weight loss and gene-diet interactions on body composition in adults

The effects of a dietary intervention for weight loss and gene-diet interactions on body composition in adults

Transcriptional and epigenetic changes after dietary and surgical weight loss interventions in an animal model of obesity.

Identifying determinants that can predict response to weight loss interventions is imperative for optimizing therapeutic benefit. We aimed to identify changes in DNA methylation and mRNA expression of a subset of target genes following dietary and surgical interventions in high-fat-diet (HFD)-induced obese rats. Forty-two adult Wistar Han male rats were divided into two groups: control rats (n = 7) and obese rats (n = 28), fed a HFD for 10 weeks (t10). Obese rats were randomly subdivided into five intervention groups (seven animals per group): (i) HFD; (ii) very-low-calorie diet (VLCD); (iii) sham surgery, and (iv) sleeve gastrectomy (SG). At week sixteen (t16), animals were sacrificed and tissue samples were collected to analyze changes in DNA methylation and mRNA expression of the selected genes. By type of intervention, the surgical procedures led to the greatest weight loss. Changes in methylation and/or expression of candidate genes occurred proportionally to the effectiveness of the weight loss interventions. Leptin expression, increased sixfold in the visceral fat of the obese rats, was partially normalized after all interventions. The expression of fatty acid synthase (FASN) and monocyte chemoattractant protein 1 (MCP-1) genes, which was reduced 0.5- and 0.15-fold, respectively, in the liver tissue of obese rats, were completely normalized after weight loss interventions, particularly after surgical interventions. The upregulation of FASN and MCP-1 gene expression was accompanied by a significant reduction in promoter methylation, up to 0.5-fold decrease in the case of the FASN (all intervention groups) and a 0.8-fold decrease in the case of the MCP-1 (SG group). Changes in tissue expression of specific genes involved in the pathophysiological mechanisms of obesity can be significantly attenuated following weight loss interventions, particularly surgery. Some of these genes are regulated by epigenetic mechanisms.

DNA Methylation at ABCG1 and Long-term Changes in Adiposity and Fat Distribution in Response to Dietary Interventions: The POUNDS Lost Trial.

To examine whether participants with different levels of diabetes-related DNA methylation at ABCG1 might respond differently to dietary weight loss interventions with long-term changes in adiposity and body fat distribution. The current study included overweight/obese participants from the POUNDS Lost trial. Blood levels of regional DNA methylation at ABCG1 were profiled by high-resolution methylC-capture sequencing at baseline among 673 participants, of whom 598 were followed up at 6 months and 543 at 2 years. Two-year changes in adiposity and computed tomography-measured body fat distribution were calculated. Regional DNA methylation at ABCG1 showed significantly different associations with long-term changes in body weight and waist circumference at 6 months and 2 years in dietary interventions varying in protein intake (interaction P < 0.05 for all). Among participants assigned to an average-protein (15%) diet, lower baseline regional DNA methylation at ABCG1 was associated with greater reductions in body weight and waist circumference at 6 months and 2 years, whereas opposite associations were found among those assigned to a high-protein (25%) diet. Similar interaction patterns were also observed for body fat distribution, including visceral adipose tissue, subcutaneous adipose tissue, deep subcutaneous adipose tissue, and total adipose tissue at 6 months and 2 years (interaction P < 0.05 for all). Baseline DNA methylation at ABCG1 interacted with dietary protein intake on long-term decreases in adiposity and body fat distribution. Participants with lower methylation at ABCG1 benefitted more in long-term reductions in body weight, waist circumference, and body fat distribution when consuming an average-protein diet.

Evaluation of the "Shifting Weight using Intermittent Fasting in night-shift workers" weight loss interventions: a mixed-methods protocol.

Shift workers are at a greater risk for obesity-related conditions. The impacts of working at night presents a challenge for designing effective dietary weight-loss interventions for this population group. The Shifting Weight using Intermittent Fasting in night-shift workers (SWIFt) study is a world-first, randomized controlled trial that compares three weight-loss interventions. While the trial will evaluate the effectiveness of weight-loss outcomes, this mixed-methods evaluation aims to explore for who weight-loss outcomes are achieved and what factors (intervention features, individual, social, organisational and wider environmental) contribute to this. A convergent, mixed-methods evaluation design was chosen where quantitative and qualitative data collection occurs concurrently, analyzed separately, and converged in a final synthesis. Quantitative measures include participant engagement assessed via: dietary consult attendance, fulfillment of dietary goals, dietary energy intake, adherence to self-monitoring, and rates for participant drop-out; analyzed for frequency and proportions. Regression models will determine associations between engagement measures, participant characteristics (sex, age, ethnicity, occupation, shift type, night-shifts per week, years in night shift), intervention group, and weight change. Qualitative measures include semi-structured interviews with participants at baseline, 24-weeks, and 18-months, and fortnightly audio-diaries during the 24-week intervention. Interviews/diaries will be transcribed verbatim and analyzed using five-step thematic framework analysis in NVivo. Results from the quantitative and qualitative data will be integrated via table and narrative form to interrogate the validity of conclusions. The SWIFt study is a world-first trial that compares the effectiveness of three weight-loss interventions for night shift workers. This mixed-methods evaluation aims to further explore the effectiveness of the interventions. The evaluation will determine for who the SWIFt interventions work best for, what intervention features are important, and what external factors need to be addressed to strengthen an approach. The findings will be useful for tailoring future scalability of dietary weight-loss interventions for night-shift workers.Clinical trial registration: This evaluation is based on the SWIFt trial registered with the Australian New Zealand Clinical Trials Registry [ACTRN 12619001035112].

1257-P: Changes in Circulating Pancreatic Islet-Specific MicroRNA-375 Levels and Improvements in Insulin Sensitivity and Glucose Metabolism in Response to Weight-Loss Diets with Different Compositions of Macronutrients—The POUNDS Lost Trial

Pancreatic islet-specific microRNA-375 (miR-375) regulates insulin secretion and has an essential role in β-cell compensation when escalating insulin demand. We recently reported that changes in circulating miR-375 were associated with improved diabetogenic fat depots. Here, we investigated whether changes in circulating miR-375 induced by weight-loss diet interventions with different macronutrient intakes (fat, carbohydrate (carb), and protein) were related to improved insulin sensitivity and glucose metabolism. This study included participants from the POUNDS Lost trial with available data on circulating miR-375-3p at baseline (n=520) and its changes from baseline to 6 months after weight-loss diet interventions (n=508). At baseline, higher levels of miR-375 were related to lower degrees of BMI, total adipose tissue mass, and whole-body fat content (P &amp;lt;0.05 for all). There was a significant increase in miR-375 levels from baseline to 6 months (P by paired t-test &amp;lt;0.001). We found that associations of changes in miR-375 with changes in fasting insulin, glucose, and insulin resistance (HOMA-IR) were significantly modified by carb and fat intakes (P interaction &amp;lt;0.05 for all). In response to a low-fat and high-carb diet, a greater increase in miR-375 was significantly associated with larger reductions of fasting insulin and HOMA-IR at 6 months, regardless of baseline miR-375 levels. On the other hand, in response to a high-fat and low-carb diet intervention, there were significant positive associations between miR-375 changes and changes in glucose, insulin, and HOMA-IR. These results suggest that changes in the pancreatic islet-specific miRNA expression are associated with weight-loss diet intervention outcomes on insulin sensitivity and glucose metabolism. Different macronutrient intakes may modify these associations. Disclosure Y.Heianza: None. Q.Xue: None. H.Ma: None. G.Bray: Advisory Panel; Medifast, Inc., Herbalife International of America, Inc. F.Sacks: None. L.Qi: None. Funding National Institutes of Health (DK091718, DK100383, DK115679)

48-LB: Changes in Plasma Levels of Nonnutritive Sweetener Erythritol Are Related to Two-Year Changes of Insulin Sensitivity in Response to Weight-Loss Diets—The POUNDS Lost trial

Evidence on the benefits of non-nutritive sweeteners for weight management and improving insulin sensitivity and glucose metabolism is inconsistent. Recently, high levels of circulating erythritol, a sugar alcohol used as one of the non-nutritive sweeteners, have been linked to increased risks of type 2 diabetes and its vascular complications. Whether changes in circulating erythritol levels are related to insulin sensitivity and glucose metabolism remains unknown. Here, we investigated whether changes in plasma erythritol induced by weight-loss diet interventions were related to improved insulin sensitivity and glucose metabolism. This study included overweight or obese participants without diabetes or unstable cardiovascular disease from the POUNDS Lost trial with available data on circulating erythritol at baseline (n=805) and its changes from baseline to 6 months (n=670) and 2 years (n=533) during weight-loss diet interventions. At baseline, higher plasma levels of erythritol were related to hyperinsulinemia and greater degrees of insulin resistance assessed by HOMA-IR, even after adjusting for covariates, including BMI (P &amp;lt;0.05 for all). In response to weight-loss dietary interventions, a greater decrease in plasma erythritol was significantly associated with larger reductions of fasting insulin (p= 0.0001) and HOMA-IR (p=0.039) at 6 months, regardless of the initial levels of BMI, erythritol, and the respective outcome. Similarly, we found a significant association between long-term changes in erythritol and a 2-year reduction of fasting insulin (p=0.0027). In conclusion, circulating plasma erythritol, a marker of non-nutritive sweetener consumption, was significantly associated with hyperinsulinemia and insulin sensitivity among adults with overweight or obesity. Weight-loss diet-induced decreases in plasma erythritol were related to improved insulin sensitivity. Disclosure Y. Heianza: None. Q. Xue: None. J. Rood: None. G. Bray: Advisory Panel; Medifast, Inc., Herbalife International of America, Inc. F. Sacks: None. L. Qi: None. Funding National Institutes of Health (DK091718, DK100383, DK115679, 2P20GM109036-06A1-7233)

Effects of lifestyle and associated diseases on serum CC16 suggest complex interactions among metabolism, heart and lungs

IntroductionClara cell 16-kDa protein (CC16) is an anti-inflammatory, immunomodulatory secreted pulmonary protein with reduced serum concentrations in obesity according to recent data. ObjectiveStudies focused solely on bodyweight, which does not properly reflect obesity-associated implications of the metabolic and reno-cardio-vascular system. The purpose of this study was therefore to examine CC16 in a broad physiological context considering cardio-metabolic comorbidities of primary pulmonary diseases. MethodsCC16 was quantified in serum samples in a subset of the FoCus (N = 497) and two weight loss intervention cohorts (N = 99) using ELISA. Correlation and general linear regression analyses were applied to assess CC16 effects of lifestyle, gut microbiota, disease occurrence and treatment strategies. Importance and intercorrelation of determinants were validated using random forest algorithms. ResultsCC16 A38G gene mutation, smoking and low microbial diversity significantly decreased CC16. Pre-menopausal female displayed lower CC16 compared to post-menopausal female and male participants. Biological age and uricosuric medications increased CC16 (all p < 0.01). Adjusted linear regression revealed CC16 lowering effects of high waist-to-hip ratio (est. −11.19 [−19.4; −2.97], p = 7.99 × 10−3), severe obesity (est. −2.58 [−4.33; −0.82], p = 4.14 × 10−3) and hypertension (est. −4.31 [−7.5; −1.12], p = 8.48 × 10−3). ACEi/ARB medication (p = 2.5 × 10−2) and chronic heart failure (est. 4.69 [1.37; 8.02], p = 5.91 × 10−3) presented increasing effects on CC16. Mild associations of CC16 were observed with blood pressure, HOMA-IR and NT-proBNP, but not manifest hyperlipidemia, type 2 diabetes, diet quality and dietary weight loss intervention. ConclusionA role of metabolic and cardiovascular abnormalities in the regulation of CC16 and its modifiability by behavioral and pharmacological interventions is indicated. Alterations by ACEi/ARB and uricosurics could point towards regulatory axes comprising the renin-angiotensin-aldosterone system and purine metabolism. Findings altogether strengthen the importance of interactions among metabolism, heart and lungs.

0001 Effect of Time-Restricted Eating on Actigraphy-Derived Sleep Parameters

Abstract Introduction Time-restricted eating (TRE) is an emerging dietary intervention for weight loss. Sleep can be influenced by timing of food intake. Nevertheless, the impact of TRE on sleep patterns remains under-explored. The Time-Restricted Intake of Meals (TRIM) study was a parallel-arm, controlled feeding trial in 41 adults with obesity and prediabetes or untreated diabetes, randomized to TRE (8am-6pm) or usual eating pattern (UEP; 8am-12am) for 12 weeks, where the primary outcome was weight change. We hypothesized that TRE would cause changes in sleep/wake patterns. Methods This was a post-hoc analysis of TRIM using wrist actigraphy data obtained at baseline and week-12. We applied an objective process to determine sleep parameters after sleep estimation (Cole-Kripke) from actigraphy data. We analyzed 6 days/nights of recordings for each participant at each timepoint. Outcomes were sleep duration defined by mean total sleep time per 24-hour period (TST), sleep timing measured by mid-sleep time, sleep onset/offset, and sleep continuity. We used paired t-tests or Wilcoxon signed rank tests to compare data between baseline and week-12 within intervention arms and Mann-Whitney U tests or Wilcoxon signed rank tests to compare changes between intervention arms. Results 38 participants (20 UEP; 18 TRE) with adequate actigraphy data (mean age 60 years, 92% female, and 92% Black) were analyzed. Baseline TST (mean□SD) was 394□90 minutes and 386□81 minutes for UEP and TRE, respectively. Week-12 TST was 397□92 minutes and 444□95 minutes for UEP and TRE, respectively. Compared to UEP, TRE increased TST by 55 minutes (p=0.03). TRE shifted mid-sleep time to 44 minutes earlier, from 3:24am to 2:40am (p=0.01), while UEP maintained the same mid-sleep time at 3:15am. Sleep onset shifted from a median of 12:22am to 11:52pm in TRE (p=0.03) while it remained stable in UEP (p=0.97). There were no differences in sleep offset and sleep continuity within and between intervention arms. Conclusion Sleep behaviors were different by treatment arm with increased total sleep time and earlier sleep onset in TRE participants. TRE may have ancillary consequences on sleep, which could have clinical implications for sleep regulation. Support (if any) AHA SFRN 17SFRN33590069 K23DK133690

The administration of Exendin-4 and CCK affects food intake differentially in female and male rats tested on an alternate day fasting paradigm

Alternate day fasting (ADF) which involves the repetition of a 2-day cycle of a day of free access to food followed by a day of limited or no access to food, is an effective dietary intervention for weight loss in both humans and rats. We have previously reported that when presented with a high energy (HE) and standard chow diet, rats maintained on an ADF schedule displayed decreased HE diet preference compared to controls. Both male and female ADF rats increased overall intake of chow. However, this increase was driven by both meal size and meal number for males and only number of meals for females. Administration of cholecystokinin (CCK) or the glucagon-like peptide 1 (GLP-1) receptor agonist Exendin-4 (Ex-4) reduces food intake. It appears that CCK decreases food intake primarily through satiety signals whereas GLP-1 signaling may reduce intake by satiety and reward cues. Here, female and male rats were administered (i.p.) saline, 3.0 µg/kg Ex-4 (3 h before test), 3.0 µg/kg CCK (15 min before test) or a combination of both. Next, all rats were presented 23-h access to both HE diet and chow following food-restriction (ADF) or free access to chow (CON). Compared to saline-control sessions, administration of the combination of Ex-4 and CCK, but not Ex-4 or CCK alone, resulted in a decrease in both HE and chow intake early in the session for male ADF rats but the combination primarily decreased chow diet intake early in the session for female ADF rats. Thus, it appears that under these energy homeostatic conditions, administration of Ex-4 or CCK alone does not affect intake in ADF rats, but the combination produces decreases in feeding that are more than the sum of their individual effects. These findings support a role for the combination of GLP-1 and CCK signaling in the changes in diet preference induced by an alternate day fasting paradigm differentially in female and male rats.

Cognitive-behavioral and dietary weight loss intervention in adult kidney transplant recipients with overweight and obesity: Results of a pilot RCT study (Adi-KTx).

The obesity epidemic and its health consequences have not spared the population of kidney transplant (KTx) candidates and recipients. In addition, KTx recipients are susceptible to weight gain after transplantation. Overweight and obesity after KTx are strongly associated with adverse outcomes. Therefore, we designed a randomized controlled, mono-center study to specifically test the effectiveness of a primarily cognitive-behavioral approach supplemented by nutritional counseling for weight reduction following KTx as the intervention group (IG) in comparison to a brief self-guided intervention as control group (CG). The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00017226). Fifty-six KTx patients with a BMI from 27 to 40 kg/m2 were included in this study and randomized to the IG or CG. Main outcome was the number of participants achieving a 5% weight loss during the treatment phase. Additionally, participants were assessed 6 and 12 months after the end of the 6-month treatment phase. Participants significantly lost weight without group differences. 32.0% (n = 8) of the patients in the IG and 16.7% (n = 4) of the patients in the CG achieved a weight loss of 5% or more. Weight loss was largely maintained during follow-up. Retention and acceptance rate in the IG was high, with 25 (out of 28) patients completing all 12 sessions and one patient completing 11 sessions. Short-term, cognitive-behaviorally oriented weight loss treatment seems to be feasible and acceptable for patients after KTx who suffer from overweight or obesity. This clinical trial was ongoing at the onset of the COVID-19 pandemic which might have influenced study conduct and results. Clinical Trial Registration: https://clinicaltrials.gov/ DRKS-ID: DRKS00017226.

Sustainable dietary weight loss intervention and its effects on cardiometabolic parameters and greenhouse gas emissions: study protocol of a randomised controlled trial with overweight and obese adults in Ouagadougou, Burkina Faso

IntroductionThe global obesity epidemic and its adverse health effects have reached sub-Saharan Africa. In some urban settings, like Burkina Faso’s capital Ouagadougou, up to 43% of the adult population are...