Weight Loss Response Research Articles

Efficacy of levothyroxine monotherapy in achieving clinical euthyroidism and its impact on weight loss in women with hypothyroidism and obesity

In light of research indicating that normal TSH levels do not necessarily reflect clinical euthyroidism in hypothyroid patients, and given the patient dissatisfaction with levothyroxine (LT4) monotherapy, we evaluate the response to weight loss treatment in patients with obesity and primary hypothyroidism who are euthyroid under LT4 therapy, with a focus on weight and metabolic parameters. The retrospective study included 138 subjects with obesity (BMI ≥ 30 kg/m2), 69 women with hypothyroidism on levothyroxine, and 69 age- and BMI-matched women without thyroid disease. Secondary causes of obesity, medications that may affect thyroid functions and metabolic parameters, chronic and oncological disease, pregnancy, TSH outside the reference range, follow-up periods of less than one year, and bariatric surgery were the exclusion criteria. Patients’ characteristics and metabolic responses to weight reduction treatment consisting of calorie restriction, moderate exercise, and metformin if needed were evaluated. TSH and fT4 levels were higher, and fT3 and T3/T4 ratios were lower all within the reference ranges in hypothyroid women. They were less insulin resistant. Both patient’ groups experienced a significant decrease in body weight, BMI, and atherogenic index of plasma (AIP) during the follow-up (p = 0.001). Insulin resistance was not changed. The groups’ body weight, BMI, HOMA-IR, and AIP changes were similar at the end of the study (p = 0.876, p = 0.850, p = 0.555, p = 0.293). The results suggest that achieving euthyroid status via levothyroxine monotherapy in hypothyroid women leads to weight loss responses comparable to those in women with normal thyroid. This supports the effectiveness of current hypothyroidism treatment strategies, emphasizing TSH level normalization, in achieving clinical euthyroidism concerning weight loss outcomes.

Abstract 4133460: VCAM1 contributes to pathogenesis during influenza-induced exacerbation of atherosclerosis.

Background and hypothesis: Influenza is a significant public health and economic threat around the world. Although pneumonia is the most common complication associated with influenza, there are several clinical reports demonstrating increased risk for cardiovascular disease. Influenza infection induces interferons, proinflammatory cytokines and chemokines, and recruits’ macrophages and neutrophils to control the virus. However, an excessive influx of innate immune cells and dysregulated production of inflammatory mediators results in pathological responses during influenza infection. Studies have shown that influenza infection correlates with increased incidence of myocardial infarction. Atherosclerosis is the most known cause of ischemic heart diseases and stroke. Vascular cell adhesion molecule-1 (VCAM1) has been shown to promote adhesion of monocytes and promotes atherosclerosis. In this study, we hypothesize that VCAM1 plays a role in exacerbation of atherosclerosis during influenza infection. Methods: High-Fat diet (HFD)-fed Apoe -/- mice were infected with influenza A/PR/8/34 (H1N1) and weight loss, survival rate, and gene expression of vascular endothelial adhesion molecules, inflammatory cytokines and chemokines were measured. HFD-fed Apoe -/- mice were infected with influenza, and treated with anti-VCAM1 antibody, and weight loss and cellular responses were measured. Results and conclusions: Increased weight loss and decreased survival of mice were observed in response to influenza infection in HFD-induced atherosclerosis in Apoe -/- mice. Further, the expression of VCAM1, and the levels of IL-6, CCL2, CCL3, CCL5 were significantly increased in aorta in Apoe -/- mice when compared to PBS-treated controls. Increased survival, decreased weight loss, decreased lesion area, decreased frequency of CD11b + F4/80 + Ly6C + , CD4 + RORgt + cells and increased frequency of CD4 + FoxP3 + Treg cells were observed in aorta in response to antibody mediated VCAM1 neutralization. These results suggest that VCAM1 plays a pathological role in influenza-induced exacerbation of atherosclerosis.

Influence of the Brain-Derived Neurotrophic Factor Gene Polymorphism on Weight Loss Following Intragastric Balloon Intervention: A Cross-Sectional Study.

There is noticeable heterogeneity in weight loss outcomes following intragastric balloon (IGB) treatment, with average weight loss ranging between 11% to 15% of total body weight. Genetic variations associated with obesity have been found to influence weight loss response, however such variations are limited. Therefore, the aim of this study is to investigate the impact of the obesity associated brain-derived neurotrophic factor (BDNF) gene polymorphism rs11030104 with weight loss outcomes following IGB treatment. In this cross-sectional study, BDNF rs11030104 was analysed in 106 individuals who underwent intragastric balloon treatment. Weight loss metrics were evaluated at the three-month follow-up: percentage of total weight loss (%TWL), percentage of excess weight loss (%EWL), and percentage of body mass index loss (%EBMIL). The effects of additive and dominant genetic models were evaluated. Both linear and logistic regression were applied to assess associations between rs11030104 genotypes and weight loss metrics. A total of 71 participants completed the 3-month follow-up assessment (loss to follow-up: 33%). This study found a significant association between the BDNF rs11030104 polymorphism and weight loss. A-allele carriers showed a better response to IGB treatment. Individuals carrying the AA genotype were found to have a greater %TWL than those carrying the GG genotype at 3 months post-IGB treatment (11.05% vs 5.09%, p=0.003). Our results suggest that BDNF rs11030104 influences the response to weight loss after IGB treatment and therefore could be added to the growing list of genetic variants that predict greater weight loss response.

Association of preoperative frailty with suboptimal weight loss response among patients undergoing metabolic and bariatric surgery.

Preoperative patient frailty (i.e., aging-related functional decline across multiple physiological systems) has been linked to greater perioperative complications following metabolic bariatric surgery (MBS). This study evaluated whether preoperative patient frailty predicts 1-year suboptimal weight loss response after primary sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). The Bariatric Frailty Score (BFS), an adapted version of the Canadian Study of Health and Aging-Frailty Index based on 10 variables from MBSAQIP, assessed degree of frailty based on number of deficits (i.e., 0-10). Suboptimal response to MBS was defined as < 20% and < 30% percentage total weight loss (%TWL) at 1year following SG and RYGB, respectively. Multiple linear and logistic regression models evaluated associations of preoperative BFS score with %TWL and %TWL response thresholds, respectively. Patients (n = 1574; 78.9% female, 28.3% non-white, mean age 45 ± 12year; 67% SG) had a mean BFS of 1.6 ± 1.3 (range = 0-7). Overall, higher BFS related to lower %TWL after SG and RYGB (ß = - 0.12 and ß = - 0.17, respectively, p = 0.001). Compared to patients with 0-1 deficits (BFS score ≤ 1; n = 785, 49.9%), those with multiple deficits (BFS score ≥ 2; n = 789, 50.1%) had higher odds of suboptimal weight loss response after SG (OR 1.88, 95% CI 1.40-2.52, p < 0.001) and RYGB (OR 2.18, 95% CI 1.43-3.32, p < 0.001). Having multiple preoperative frailty deficits is associated with higher odds of suboptimal weight loss response after MBS. These findings point to the need for increased frailty screening and appropriate adjunctive interventions (i.e., exercise, nutrition, and cognitive), as these interventions may improve frailty status and MBS outcomes.

Neighborhood Characteristics Related to Changes in Anthropometrics During a Lifestyle Intervention for Persons with Obesity.

Since obesity has emerged as a major public health concern, there is an urgent need to better understand factors related to weight gain and treatment success. This study included 118 persons with obesity who participated in a multidisciplinary combined lifestyle intervention with cognitive-behavioral therapy at the outpatient clinic ofthe Obesity Center CGG at Erasmus University Medical Center, Rotterdam, The Netherlands. Neighborhood characteristics were assessed using a 13-item questionnaire. Multiple regression analyses were performed to examine the association between perceived safety, social cohesion, and the availability of facilities on relative changes in body mass index and waist circumference changes, adjusted for corresponding neighborhood socioeconomic status scores. Higher total scores, indicating more unfavorable neighborhood perceptions, were associated with less relative improvements in BMI and waist circumference after 1.5years (β = 3.2, 95%CI 0.3-6.0; β = 3.4, 95%CI 0.3-6.6, respectively). Also, more neighborhood unsafety was associated with less relative improvements in BMI and waist circumference on the long term (β = 3.1, 95%CI 1.1-5.1; β = 2.8, 95%CI 0.6-5.1, respectively). The results indicate that living in a neighborhood perceived as less favorable may lower the chances of successful weight loss in response to combined lifestyle interventions in persons with obesity.

Prediction of individual weight loss using supervised learning: findings from the CALERIETM 2 study

BackgroundPredicting individual weight loss (WL) responses to lifestyle interventions is challenging but might help practitioners and clinicians select the most promising approach for each individual. ObjectiveThe primary aim of this study was to develop machine learning (ML) models to predict individual WL responses using only variables known before starting the intervention. In addition, we used ML to identify pre-intervention variables influencing the individual WL response. MethodsWe used 12-mo data from the comprehensive assessment of long-term effects of reducing intake of energy (CALERIETM) phase 2 study, which aimed to analyze the long-term effects of caloric restriction on human longevity. On the basis of the data from 130 subjects in the intervention group, we developed classification models to predict binary (“Success” and “No/low success”) or multiclass (“High success,” “Medium success,” and “Low/no success”) WL outcomes. Additionally, regression models were developed to predict individual weight change (percent). Models were evaluated on the basis of accuracy, sensitivity, specificity (classification models), and root mean squared error (RMSE; regression models). ResultsBest classification models used 20–40 predictors and achieved 89%–97% accuracy, 91%–100% sensitivity, and 56%–86% specificity for binary classification. For multiclass classification, accuracy (69%) and sensitivity (50%) tended to be lower. The best regression performance was obtained with 36 variables with an RMSE of 2.84%. Among the 21 variables predicting individual weight change most consistently, we identified 2 novel predictors, namely orgasm satisfaction and sexual behavior/experience. Other common predictors have previously been associated with WL (16) or are already used in traditional prediction models (3). ConclusionsThe prediction models could be implemented by practitioners and clinicians to support the decision of whether lifestyle interventions are sufficient or more aggressive interventions are needed for a given individual, thereby supporting better, faster, data-driven, and unbiased decisions.The CALERIETM phase 2 study was registered at clinicaltrials.gov as NCT00427193.

Abstract 41: SerpinA3N in Leptin Receptor Neurons Regulates Metabolic Homeostasis and Cardiovascular Function

Obesity and associated conditions such as type 2 diabetes are among the most concerning health issues in the U.S. Leptin receptor (LepR) signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. SerpinA3N is a serine protease inhibitor which is highly expressed in the arcuate nucleus of the hypothalamus, upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the LepR expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis confirmed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the LepR positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in LepR expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3N fl/fl ) with mice expressing Cre recombinase driven by the LepR (LepRb Cre ). We found that female, but not male, conditional knockout (CKO, LepRb Cre /SerpinA3N fl/fl ) mice have significantly lower body weight when fed HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response to leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but no change in insulin sensitivity. Insulin-induced phosphorylation of AKT was elevated only in skeletal muscleof CKO mice relative to controls. Finally, systolic arterial blood pressure of CKO mice fed HFHSD trend to be lower during dark time compared to controls (142±6.4 vs 127.9±7.1 mmHg, p=0.06), although heart rate was not changed. These results demonstrate that SerpinA3N in LepRb-expressing neurons regulate energy and glucose homeostasis in a sex-dependent manner,and may protect from HFHSD induced hypertension.

Opportunities to optimize lifestyle interventions in combination with glucagon-like peptide-1-based therapy.

Obesity is a chronic multi-system disease and major driver of type 2 diabetes and cardiometabolic disease. Nutritional interventions form the cornerstone of obesity and type 2 diabetes management. Some interventions such as Mediterranean diet can reduce incident cardiovascular disease, probably independently of weight loss. Weight loss of 5% or greater can improve many adiposity-related comorbidities. Although this can be achieved with lifestyle intervention, it is often difficult to sustain in the longer term due to adaptive endocrine changes. In recent years glucagon-like-peptide-1 receptor agonists (GLP-1RAs) have emerged as effective treatments for both type 2 diabetes and obesity. Newer GLP-1RAs can achieve average weight loss of 15% or greater and improve cardiometabolic health. There is heterogeneity in the weight loss response to GLP-1RAs, with a substantial number of patients unable to achieve 5% or greater weight. Weight loss, on average, is lower in older adults, male patients and people with type 2 diabetes. Mechanistic studies are needed to understand the aetiology of this variable response. Gastrointestinal side effects leading to medication discontinuation are a concern with GLP-1RA treatment, based on real-world data. With weight loss of 20% or higher with newer GLP-1RAs, nutritional deficiency and sarcopenia are also potential concerns. Lifestyle interventions that may potentially mitigate the side effects of GLP-1RA treatment and enhance weight loss are discussed here. The efficacy of such interventions awaits confirmation with well-designed randomized controlled trials.

A novel nomogram for predicting optimal weight loss response following diet and exercise intervention in patients with obesity

This study aimed to identify factors associated with optimal weight loss response by analyzing pre-weight loss data from a cohort of 2577 patients with obesity who visited weight management clinics between 2013 and 2022. Out of these, 1276 patients had follow-up data available. Following dietary and exercise interventions, 580 participants achieved optimal weight loss outcomes. Participants were subsequently divided into two groups based on their weight loss outcomes: those who achieved optimal weight loss response and those who did not. Statistical analysis, conducted using RStudio, identified thirteen predictor variables through LASSO and logistic regression, with age emerging as the most influential predictor. A nomogram was developed to predict optimal weight loss response, showing good predictive performance (AUC = 0.807) and clinical applicability, validated by internal validation methods. Decision curve analysis (DCA) further illustrated the nomogram's clinical utility. The developed nomogram prediction model for optimal weight loss response is user-friendly, highly accurate, and demonstrates excellent discriminative and calibration capabilities.

Efficacy of antiobesity medications among breast cancer survivors taking aromatase inhibitors.

Aromatase inhibitors (AI) block estrogen synthesis and are used as long-term adjuvant treatment for breast cancer in postmenopausal women. AI use can be associated with weight gain that can lead to increased cardiometabolic risk. The response to anti-obesity medications (AOM) in patients using AI has yet to be studied. We sought to investigate weight loss outcomes of AOM in patients taking AI for breast cancer treatment. This is a matched retrospective cohort study of breast cancer survivors on AI using AOM (AOM/AI group). We compared their weight loss outcomes with a group of female patients with obesity, without a history of breast cancer or AI use, on AOM (AOM group). The primary endpoint was total body weight loss percentage (TBWL %) at the last follow-up. We performed mixed linear regression models, including diabetes status at baseline, to assess associations between use of AOM with/without AI with total body weight loss percentage (TBWL%). We included 124 patients: 62 in the AOM/AI group (63.6 ± 10years, body mass index [BMI] 34.3 ± 7.1kg/m2) and 62 in the AOM group (62.8 ± 9.9years, BMI 34.6 ± 6.5kg/m2). The mean time of follow up was 9.3 ± 3.5months, with no differences among the two groups. The AOM/AI group had a lower TBWL% compared to the AOM group at the last follow-up -5.3 ± 5.0 vs. -8.2 ± 6.3 (p = 0.005). The results remained significant after adjusting for diabetes status (p = 0.0002). At 12months, the AOM/AI group had a lower TBWL% compared to the AOM group 6.4 ± 0.8% vs. 9.8 ± 0.9% (p = 0.04). The percentage of patients achieving ≥ 5%, ≥ 10%, and ≥ 15% of weight loss at 12months was greater in the AOM compared to the AOM/AI group. Although the weight loss response was suboptimal, patients in the AOM/AI group had improvement in fasting glucose, glycated hemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol. The use of AI in breast cancer survivors is associated with less weight loss response to AOM compared to patients without breast cancer history and who do not take AI. Studies are needed to assess the mechanisms behind the differential weight loss response to AOM in women taking AI.

Effectiveness and predictors of weight loss response to phentermine plus lifestyle modifications among youth in a paediatric weight management clinical setting.

Anti-obesity medications (AOMs) are promising lifestyle modification (LSM) adjuncts for obesity treatment, and phentermine is commonly prescribed in paediatric weight management clinics. Determining 'real-world' AOM effectiveness and characteristics predicting response is important. We sought to describe phentermine plus LSM effectiveness and identify baseline characteristics predicting response. This was a retrospective cohort study among youth seen in a US academic-based weight management clinic from 2012 to 2020. Baseline characteristics (e.g., body mass index (BMI), liver transaminases, eating-related behaviours) and outcomes (%BMI of 95th percentile (%BMIp95), BMI, %BMI change, weight) were determined through electronic health records and intake surveys. Among 91 youth prescribed phentermine plus LSM over 8 years (mean %BMIp95 150%), %BMIp95 was statistically significantly reduced at 1.5, 3, 6 and 12 months (peak reduction 10.9 percentage points at 6 months; p < 0.001). Considering multiple comparisons, the presence of baseline elevated alanine aminotransferase was associated with statistically significant smaller 1.5-month %BMIp95 reductions (p = 0.001) and higher food responsiveness with smaller 3- (p = 0.001) and 6-month (p < 0.001) reductions. Phentermine plus LSM reduced %BMIp95 among youth in a weight management clinic, and baseline characteristics may help determine those more or less likely to respond. Prospective studies are needed to further characterize effectiveness and confirm response predictors.

A predictive model for medium-term weight loss response in people with type 2 diabetes engaging in behavioural weight management interventions.

To develop and evaluate prediction models for medium-term weight loss response in behavioural weight management programmes. We conducted three longitudinal analyses using the Action for HEalth in Diabetes (LookAHEAD) trial, Weight loss Referrals for Adults in Primary care (WRAP) trial, and routine data from the National Health Service Greater Glasgow and Clyde Weight Management Service (NHS-GGCWMS). We investigated predictors of medium-term weight loss (>5% body weight) over 3 years in NHS-GGCWMS and, separately, predictors of weight loss response in LookAHEAD over 4 years. We validated predictors in both studies using WRAP over 5 years. Predictors of interest included demographic and clinical variables, early weight change in-programme (first 4 weeks) and overall in-programme weight change. In LookAHEAD and WRAP the only baseline variables consistently associated with weight loss response were female sex and older age. Of 1152 participants in NHS-GGCWMS (mean age 57.8 years, 60% female, type 2 diabetes diagnosed for a median of 5.3 years), 139 lost weight over 3 years (12%). The strongest predictor of weight loss response was early weight change (odds ratio 2.22, 95% confidence interval 1.92-2.56) per 1% weight loss. Losing 0.5% weight in the first 4 weeks predicted medium-term weight loss (sensitivity 89.9%, specificity 49.5%, negative predictive value 97.3%). Overall in-programme weight change was also associated with weight loss response over 3 years in NHS-GGCWMS and over 5 years in WRAP. Not attaining a weight loss threshold of 0.5% early in weight management programmes may identify participants who would benefit from alternative interventions.

Alleviating depressive-like behavior in DSS-induced colitis mice: Exploring naringin and poncirin from Poncirus trifoliata extracts

Patients with inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), often have concomitant mental disorders such as depression and anxiety. Therefore, a bidirectional approach involving the gut and brain axes is necessary for the prevention and treatment thereof. In this study, we explored the potential of Poncirus trifoliata extract (PT), traditionally known for its neuroprotective effects against gastrointestinal diseases, as a natural treatment agent for IBD in a dextran sulfate sodium (DSS)-induced colitis model. Oral administration of PT ameliorated weight loss and inflammatory responses in mice with DSS-induced colitis. Furthermore, PT treatment effectively restored the colon length and ameliorated enterocyte death by inhibiting DSS-induced reactive oxygen species (ROS)-mediated necroptosis. The main bioactive components of PT, poncirin and naringin, confirmed using ultra-performance liquid chromatography-quadrupole time-of-flight (UPLC-qTOF), can be utilized to regulate necroptosis. The antidepressant-like effects of PT were confirmed using open field test (OFT) and tail suspension test (TST). PT treatment also restored vascular endothelial cell integrity in the hippocampus. In the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) regions of the hippocampus, PT controlled the neuroinflammatory responses of proliferated microglia. In conclusion, PT, which contains high levels of poncirin and naringin, has potential as a bidirectional therapeutic agent that can simultaneously improve IBD-associated intestinal and mental disorders.

Early Successful Experiences of Surgical Conversion of Endoscopic Gastric Plication to Roux-en-Y Gastric Bypass.

The primary obesity surgery endoluminal (POSE) procedure is an innovative incision-less endoscopic bariatric procedure that is increasingly used. However, variable weight loss response and recurrence post-endoscopic bariatric procedures have at times necessitated laparoscopic bariatric conversion. The safety and approach of conversion to laparoscopic sleeve gastrectomy (LSG) or Roux-en-Y gastric bypass (RYGB), however, have been an active point of discussion within revisional bariatric surgery. This retrospective review of four consecutive patients is the largest description of medium-term postoperative outcomes and technical highlights of a laparoscopic conversion of POSE to RYGB. Chart review was completed to evaluate patients' post-POSE clinical course and perioperative outcomes after surgical conversion. Early data suggests varied weight loss trajectory with POSE and marked improvement in weight response after surgical conversion. Qualitative review reveals successful single-staged conversions contrary to previous smaller case series describing staged conversions involving endoscopic removal of plications followed by RYGB. Review additionally reveals key perioperative considerations for successful conversions to include intraoperative endoscopy, upper gastrointestinal fluoroscopic studies, and at times computed tomography. The latter study and laparoscopic view of the post-POSE stomach challenge the prior notion that distal POSE allows for easy revision to LSG. Our case series underscores the complex multifactorial nature of metabolic disease and the increasing importance of a conscientious approach to conversion bariatric surgery as the adoption of POSE and the bariatric patient population continues to grow.

Weight loss outcomes with semaglutide based on diabetes severity using the individualized metabolic surgery score

Semaglutide demonstrated inferior weight loss responses in patients with type 2 diabetes (T2D) compared to patients with obesity without T2D. The individualized metabolic surgery (IMS) score was validated to predict T2D remission after bariatric surgery. The parameters of the IMS are HbA1c (<7%), insulin use, T2D medications and T2D duration. We aim to assess weight loss outcomes of semaglutide based on IMS score in patients with obesity and T2D. This is a retrospective multicentered cohort study of patients with T2D and BMI≥ 27kg/m2 taking ≥1mg of semaglutide recruited from January 2020 to December 2022. We excluded patients with a history of bariatric surgery or taking other anti-obesity medications. IMS was calculated at baseline and patients weight change was recorded at baseline, 3, 6, 9 and 12 months. IMS was classified as mild (0-24.9 points), moderate (25-94.9 points), and severe (95-180 points). Analysis was performed based on IMS score quartiles and combination of Mild-Moderate vs Severe categories. We performed mixed linear regression models including age, sex, and baseline weight to assess associations between IMS categories with total body weight loss percentage (TBWL%). We included 297 patients (42% female, mean age 62±12 years) in the analysis. At 12 months, there was a stepwise decrease in weight loss outcomes when comparing patients by IMS quartiles (LS mean TBWL%± SE): 8.8±0.8% vs 6.9±0.8% vs 5.7±0.9% vs 5.0±0.8%. In the mixed linear model, patients in the mild-moderate category achieved significantly superior weight loss outcomes (LS mean TBWL± SE:-8.3±0.7%) than patients in the severe category (-5.5±0.6%; difference:-2.9, 95% CI:-5.2 to-0.5, p=0.006) at 12 months. There was no significant difference in glycemic improvement regardless of IMS severity at baseline. In our cohort, lower IMS severity was associated with more weight loss in patients with obesity and T2D. Further studies are needed to understand T2D severity and its effect on semaglutide outcomes. Beyond payment to the research staff by Mayo Clinic, this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Hypothalamic Inflammation Improves Through Bariatric Surgery, and Hypothalamic Volume Predicts Short-Term Weight Loss Response in Adults With or Without Type 2 Diabetes.

Preclinical research implicates hypothalamic inflammation (HI) in obesity and type 2 diabetes pathophysiology. However, their pathophysiological relevance and potential reversibility need to be better defined. We sought to evaluate the effect of bariatric surgery (BS) on radiological biomarkers of HI and the association between the severity of such radiological alterations and post-BS weight loss (WL) trajectories. The utility of cerebrospinal fluid large extracellular vesicles (CSF-lEVs) enriched for microglial and astrocyte markers in studying HI was also explored. We included 72 individuals with obesity (20 with and 52 without type 2 diabetes) and 24 control individuals. Participants underwent lumbar puncture and 3-T MRI at baseline and 1-year post-BS. We assessed hypothalamic mean diffusivity (MD) (higher values indicate lesser microstructural integrity) and the volume of the whole and main hypothalamic subregions. CSF-lEVs enriched for glial and astrocyte markers were determined by flow cytometry. Compared with control group, the obesity and type 2 diabetes groups showed a larger volume and higher MD in the hypothalamic tubular inferior region, the area encompassing the arcuate nucleus. These radiological alterations were positively associated with baseline anthropometric and metabolic measures and improved post-BS. A larger baseline tubular inferior hypothalamic volume was independently related to lesser WL 1 and 2 years after BS. CSF-lEVs did not differ among groups and were unrelated to WL trajectories. These findings suggest HI improvement after BS and may support a role for HI in modulating the WL response to these interventions.

The effects of dietary macronutrient composition on resting energy expenditure following active weight loss: A systematic review and meta-analysis.

A systematic review and meta-analysis was conducted to evaluate the relative effectiveness of different dietary macronutrient patterns on changes in resting energy expenditure (REE) in relation to weight loss, categorized as minimal (<5%) and moderate to high (>5%). Changes in REE were assessed using a DerSimonian and Laird random-effects meta-analysis. A diet lower in carbohydrates (CHO) or higher in fat and protein was associated with smaller reductions in REE, with these trends being more pronounced among participants who experienced moderate to high weight loss. Adjusted meta-regression analysis indicated that, within the participants who experienced moderate to high weight loss, each 1% increase in CHO intake was associated with a reduction of 2.30 kcal/day in REE (95% CI: -4.11 to -0.47, p = 0.013). In contrast, a 1% increase in protein and fat intake was correlated with an increase in REE by 3.00 (95% confidence interval [CI] [1.02, 5.07], p = 0.003) and 0.5 (95% CI [-2.43, 3.41], p = 0.740) kcal/day, respectively. No significant associations were found among participants who experienced minimal weight loss. These findings indicate that, under a caloric deficit, the impact of dietary macronutrient composition on REE may vary depending on the degree of weight loss and individual metabolic responses.

SerpinA3N in Leptin Receptor Neurons Regulates Metabolic and Glucose Homeostasis

Obesity and associated conditions such as type 2 diabetes are among the most concerning issues for health in the U.S. Leptin receptor signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. High fat diet induces inflammation within the hypothalamus, leading to leptin insensitivity which contribute to obesity. Previous studies have shown that a novel gene SerpinA3N, a serine protease inhibitor, which is highly expressed in the arcuate nucleus of the hypothalamus, where the leptin receptor is also highly expressed, is upregulated in diet-induced obesity and by leptin stimulation. However, the role of SerpinA3N in the leptin receptor expressing cells in the control of body weight and glucose homeostasis remain unknown. RNAseq analysis showed that SerpinA3N mRNA levels were significantly upregulated in the hypothalamus of mice fed high fat high sucrose diet (HFHSD) for 12 weeks. Upregulation of hypothalamic SerpinA3N in HFHSD fed mice was confirmed by Western blot. This increase in hypothalamic SerpinA3N appears to be caused by excess of nutrient as we found that exposure to fatty acid significantly increased SerpeinA3N promoter activity in mouse hypothalamic N39 cells. Using immunofluorescence staining, we confirmed that SerpinA3N is expressed the leptin receptor positive cells of the hypothalamus. Next, we investigated whether loss of SerpinA3N in leptin receptor expressing neurons affects metabolic and glucose homeostasis. For this, we crossed mice harboring floxed alleles of the SerpinA3N gene (SerpinA3Nfl/fl) with mice expressing Cre recombinase in leptin receptor cells (LepRCre). We found that female, but not male, conditional knockout (CKO, LepRCre/SerpinA3Nfl/fl) mice have significantly lower body weight when fed normal chow or HFHSD. This lower body weight was due to decreased fat mass, measured by NMR. However, no alteration in food intake was observed between female CKO mice and controls, indicating that increased energy expenditure may account for the lower body weight in female CKO mice. Interestingly, CKO mice displayed exaggerated weight loss and anorectic response following leptin treatment (1 mg/g, twice daily, IP), indicating that loss of SerpinA3N enhances leptin sensitivity. Female CKO mice fed normal chow diet also exhibited enhanced insulin sensitivity compared to control animals. On the other hand, male CKO mice displayed significantly improved glucose handling, but not change in insulin sensitivity, only when fed HFHSD. Finally, insulin-induced phosphorylation of AKT was elevated in skeletal muscle, but not in liver and white adipose tissue, of CKO mice relative to controls. These results demonstrate that SerpinA3N in leptin receptor-expressing neurons regulate body weight and glucose homeostasis in a sex-dependent manner. NIH and VA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Glycemic Control and Body Weight Reduction with Once-Weekly Semaglutide in Colombian Adults with Type 2 Diabetes: Findings from the COLIBRI Study.

Type 2 diabetes is a prevalent condition. The change in glucose control and body weight with the use of once-weekly semaglutide was evaluated in individuals with Type 2 diabetes in Colombia. This was a real-world, multi-centre, single-arm study involving adults in Colombia with Type 2 diabetes treated with once-weekly subcutaneous semaglutide for approximately 26 weeks. The primary endpoint assessed the change in glycated hemoglobin (HbA1c) from baseline to end of study. Secondary endpoints included changes in body weight from baseline to end of study. The study also explored the proportion of participants achieving predefined HbA1c targets and weight-loss responses at the end of the study. Data from 225 patients across 11 centers were collected. Most patients were women (65%), and the mean age of the population was 57 years with a median HbA1c of 7.6% and a median body weight of 86 kg. After approximately 26 weeks, semaglutide was associated with a significant reduction in HbA1c of -0.88 and a body weight reduction of -4.04kg. The proportion of patients with HbA1c < 7% increased from 32 to 66% at end of study. Patients treated with once-weekly semaglutide experienced a clinically significant reduction in HbA1c and body weight. These results are in line with previous clinical trials.

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.