bluuebunny/crossref_metadata_2025_split huggingface dataset:
1656-P: In Vivo Downregulation of Transglutaminase 2 in High Fat Diet (HFD)-Induced Obese Mice Reduces Metabolic Syndrome–Associated Factors
Authors: ELIZONDO DIANA , HOLLIS MELANIE , PATEL TUSHAR P. , ROBERSON ROBIN , CHEN JOCELYN , YANOVSKI JACK A. 
Published: June 2024

Introduction and Objective: Metabolic syndrome (MetS) in obesity increases the risk for type 2 diabetes, stroke, and heart disease. Fundamental gaps in the field remain to establish specific molecular targets to counteract MetS. Transglutaminase 2 (TGM2), a multifunctional enzyme known to crosslink proteins important for GTPase, cell adhesion, and scaffold activities has been implicated in adipose tissue growth and functioning. The objective of this study was to investigate TGM2 effects in MetS in a diet-induced obese mouse model.
Methods: C57BL/6 mice were placed on HFD for 10 weeks and silenced for TGM2 via in vivo RNAi silencing or received a scramble sequence control. Readout indices to evaluate MetS included glucose and insulin tolerance tests, body weight and food consumption monitoring, body DEXA scan, excised tissue phenotyping via histology, qPCR, RNAseq and western blot. Serum was assessed for adiponectin, leptin, free fatty acids and inflammatory parameters.
Results: Successful TGM2 silencing was found predominantly in epididymal white adipose tissue (eWAT) and liver. Diet-induced obese mice silenced for TGM2 had lower total body weight that was accompanied with improved glucose sensitivity, lower serum leptin and free fatty acid concentrations, reduced mean adipocyte size and increased adipocyte number in eWAT, along with reduced expression of molecular pathways associated with adipose tissue growth. Furthermore, there was an observed reduction in liver weight and hepatic steatosis and increased total lean mass.
Conclusion: Results suggest that reducing TGM2 expression reduced obesity and improved glucose homeostasis, making TGM2 modulation in obesity a promising therapeutic approach targeting MetS.

Disclosure
D. Elizondo: None. M. Hollis: None. T.P. Patel: None. R. Roberson: None. J. Chen: None. J.A. Yanovski: Research Support; Rhythm Pharmaceuticals, Inc., Soleno Pharmaceuticals, Inc, Versanis Bil, Hikma Pharmaceuticals, Inc., National Institutes of Health.

Funding
National Institute of Child Health and Human Development (ZIAHD00641); National Institute of Diabetes and Digestive and Kidney Diseases (1K99DK136921)
1659-P: Tirzepatide Compared with Semaglutide for the Functions and Mechanisms of Ameliorating Lipid-Metabolism Disorders in Type 2 Diabetic Mice
Authors: CHEN LIMING 
Published: June 2024

Objective: To reveal the role and different underlying mechanisms of tirzepatide (Tzp) and semaglutide (Sema) in ameliorating lipid-metabolism disorders.
Methods: High-fat diet, streptozotocin-induced mice and db/db mice were received a daily injection of vehicle or Sema (40.79nmol/kg) or Tzp (16.87nmol/kg) for 5 weeks. Then biochemical indexes and fat content were detected, and histological staining was performed. Lastly, the transcriptome sequencing was performed in all groups of eWAT and liver tissues.
Results: Tzp or Sema reduced fasting blood-glucose, body weight, food intake, triglyceride, cholesterol levels and liver, eWAT, iWAT, BAT weights and alleviated liver pathology in both type 2 diabetic mouse models. Notably, in comparison with Sema, Tzp treatment showed lower body weight, triglyceride levels, iWAT and eWAT weights and adipocyte diameters. But the effects of BAT and liver did not differ between Tzp and Sema. Tzp and Sema regulated many common pathways and specific pathways. Additionally, in the same effect of regulating mitochondrial function, Tzp preferentially regulated endoplasmic reticulum stress, while Sema preferentially regulated inflammation. In the mechanisms of alleviating liver steatosis between Tzp and Sema, NF-kappaB and calcium-mediated signaling were enriched in the Tzp-treated group and the pathways related to cell cycle process and apoptosis were heavily enriched in Sema-treated mice.
Conclusion: The mechanism of attenuating abnormal lipid accumulation of Tzp was attribute to affecting endoplasmic reticulum stress, NF-kappaB and calcium-mediated signaling in eWAT and liver tissues while Sema preferentially regulated inflammation, cell cycle process and apoptosis. Remarkably, a smaller dosage of Tzp delivered more pronounced weight loss compared with high-dose Sema. Our study provided new insights into comparing the effects in reducing lipid-metabolism disorders between Tzp and Sema.

Disclosure
L. Chen: None.
1668-P: Novel Once-Weekly Amylin Analog Petrelintide (ZP8396) Is Well Tolerated with Improved GI Tolerability after Multiple Dosing
Authors: GRIFFIN JON , HÖVELMANN ULRIKE , MELGAARD ANITA E. , MACURA STANISLAVA , HAMMER METTE , JOHANSEN THUE , OLSEN MINNA B. 
Published: June 2024

Petrelintide (ZP8396) has demonstrated potential to reduce body weight after single and multiple dosing (SD and MD) in humans. The tolerability of doses, with similar exposure levels, was compared.
SAD and MAD trials assessed safety, PK, and PD of petrelintide in healthy, lean and overweight males. 56 participants (mean BMI 25.6 kg/m2) were randomized to a SD of petrelintide or placebo (6:2) across seven dose cohorts (0.04 to 2.4 mg). 20 participants (mean BMI 25.4 kg/m2) were randomized to six once-weekly doses (MD) of petrelintide or placebo (7:3) across two dose cohorts (0.6 and 1.2 mg), without dose titration.   Body weight reduction and adverse events (AEs) from Gastrointestinal (GI) and Metabolism and Nutrition SOC are compared descriptively.
SD of 1.4 and 2.4 mg resulted in similar exposures in terms of Cmax and AUCtau as MD doses of 0.6 and 1.2 mg at steady state, respectively. All AEs were mild to moderate, with no serious or severe AEs reported, and no treatment discontinuations. No moderate GI AEs were seen after MD. The most frequently related AEs were decreased appetite, nausea and vomiting. A lower percentage of participants reported nausea or vomiting after MD compared to a SD. For 0.6 mg MD, 14% reported nausea vs 67% for 1.4 mg SD. For 1.2 mg MD, 29% reported nausea vs 83% for 2.4 mg SD. Reporting of vomiting was similarly low for 0.6 mg MD and 1.4 mg SD cohorts, 1 participant in each cohort. For 1.2 mg MD, none reported vomiting whilst 67% reported after 2.4 mg SD. The percentage of participants reporting either decreased appetite and/or early satiety were similar after SD and MD. The mean body weight reduction was 3.6% and 4.2% in SAD cohorts and 5.3% and 5.1% in MAD cohorts, after one or six weeks of dosing, respectively.
Results indicate improved GI tolerability of petrelintide when exposure is gradually increased. AEs of decreased appetite and early satiety were similar after SD and MD. Higher doses are being explored to assess the potential for the management of obesity.

Disclosure
J. Griffin: Employee; Zealand Pharma A/S. U. Hövelmann: None. A.E. Melgaard: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. S. Macura: Employee; Novo Nordisk A/S, Zealand Pharma A/S. M. Hammer: Employee; Zealand Pharma A/S. T. Johansen: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. M.B. Olsen: None.
1672-P: Weight Changes after Tirzepatide Cessation in Chinese Adults with Overweight/Obesity—A Real-World Follow-up Study of SURMOUNT-CN Trial
Authors: CHEN YING , CHEN CONGLING , ZHAO LIN , LU YIBING , FAN XIAOFANG , XU LAN , WANG YIHUA , DONG YU , LI YUANYUAN , XU JIAWEI , SI SI , ZHANG XUE , LI XIAOYING 
Published: June 2024

Introduction & Objective: The GIP/GLP-1 receptor agonist tirzepatide (TZP) achieved body weight loss near 20% in Chinese adults with overweight (24 kg/m2≤BMI&lt;28 kg/m2) with at least one weight-related comorbidity or obesity (BMI ≥28 kg/m2) in SURMOUNT-CN. Weight regain post-TZP cessation in Chinese population is unknown. Hence, we examined the changes in body weight (BW) and waist circumference (WC) after TZP cessation in the trial extension.
Methods: SURMOUNT-CN randomized (1:1:1) Chinese adults (n=210) with a BMI of ≥28 kg/m2, or ≥24 kg/m2 and weight-related comorbidities, excluding diabetes, to receive TZP 10 mg / 15 mg / placebo (PBO) for 52 weeks. Our study enrolled those who completed 52 weeks of TZP / PBO and followed them for 6 months. Participants with neither anti-obesity medication (AOM) nor bariatric procedures during follow-up (FU) were eligible analysis population (EAP). Changes of BW and WC at 3- and 6-month FU (±6 weeks) were analyzed using descriptive statistics.
Results: Among 160 enrolled, 152 (TZP 10 mg: 57; TZP 15 mg: 51; PBO: 44) constituted EAP, excluding 8 for AOM use. For EAP, from trial baseline to week 52, TZP showed marked BW and WC reduction: -15.33% (SD: 8.04%) and -12.82 cm (SD: 6.86) for 10 mg, -19.88% (SD: 8.78%) and -15.59 cm (SD: 7.26) for 15 mg, against PBO’s -3.80% (SD: 6.08%) and -3.70 cm (SD: 4.51). From week 52 to 6-month FU, BW and WC increased for TZP 10 mg (9.06% [SD: 7.41%], 2.89 cm [SD: 7.48]), and 15 mg (12.33% [SD: 9.88%], 5.53 cm [SD: 6.52]), while PBO showed slight change (1.83% [SD: 5.17%] and -0.52 cm [SD: 5.58]). Overall, from trial baseline to 6-month FU, changes in BW and WC with TZP 10 mg, 15 mg and PBO were -8.74% (SD: 6.93%) and -10.50 cm (SD: 8.07), -10.57% (SD: 10.23%) and -10.61 cm (SD: 9.29), -2.47% (SD: 7.03%) and -4.02 cm (SD: 7.21).
Conclusion: While over 50% of net weight loss was maintained after 6 months of TZP cessation, the increase in BW and WC from drug cessation supports continued weight management in clinical practice.

Disclosure
Y. Chen: None. C. Chen: None. L. Zhao: None. Y. Lu: None. X. Fan: None. L. Xu: None. Y. Wang: Employee; Eli Lilly and Company. Y. Dong: Employee; Eli Lilly and Company. Y. Li: None. J. Xu: None. S. Si: None. X. Zhang: Employee; Eli Lilly and Company. X. Li: None.
1686-P: Liver Fat as a Potential Marker for Subclinical Myocardial Remodeling and Dysfunction in Obese Adults
Authors: WAN XU , YUE JIANG , ZHAO HANG , HE SHENGYUN , QI YICHENG , YANG MINGLAN , CHE JIE , LU QING , JIANG MENG , BU JUN , MA JING 
Published: June 2024

Background: Obesity has been recognized as a risk factor for cardiovascular disease. The association between fat distribution and subclinical myocardial remodeling and dysfunction among the obese population remains unclear.
Methods: A total of 114 participants were included in this study. Liver and pancreas were assessed using MRI-proton density fat fraction (PDFF) technology, and subclinical myocardial fibrosis were evaluated using cardiac magnetic resonance derived extracellular volume fraction (ECV) and native T2 values. Systolic and diastolic dysfunction was defined using values of global longitudinal peak systolic (GLS) and early diastolic longitudinal strain rates.
Results: Patients with NAFLD, defined as liver fat content ≥6%, had a higher prevalence of metabolic disorders, myocardial fibrosis and worse absolute GLS compared to those without NAFLD. Among multiple indicators of visceral fat, liver fat content (LFC) was significantly correlated with epicardial adipose tissue, and subclinical myocardial remodeling markers. This association remained significant after further adjustment for age, sex, waist, drugs and other potential HF risk factors. Multivariable linear regression and moderator analyses revealed that BMI might positively moderate the effect between liver fat and fibrosis indicators, for increased
LFC with higher ECV in highest tertile BMI group (β= 0.130 per SD, p=0.008), while lower ECV in lowest tertile group (β=-0.110 per SD), after adjusting for potential confounders.
Conclusion: Ectopic fat accumulation in liver may be significant risk factor to predict the occurrence and future development of myocardial fibrosis in obese adults.

Disclosure
X. Wan: None. J. Yue: None. H. Zhao: None. S. He: None. Y. Qi: None. M. Yang: None. J. Che: None. Q. Lu: None. M. Jiang: None. J. Bu: None. J. Ma: None.
1695-P: The Evaluation of Clinical Outcomes Assessments and Digital Health Technologies in Obesity Clinical Trials
Authors: GOETZ IRIS A. , SUTTER CAROLYN , ABRAHAM TRACI H. , KANU CHISOM , BOYE KRISTINA , SYMONDS TARA 
Published: June 2024

Introduction & Objective: Trials in obesity have traditionally focused on weight loss and resolution of comorbidities as primary outcomes. However, secondary outcomes, such as the impact of weight reduction on the patient experience like health-related quality of life (HRQoL), have increasingly been recognized as important. Therefore, a review was conducted to determine the clinical outcome assessments (COAs) and digital health technologies (DHTs) used in clinical trials to assess patient experience.
Methods: Two clinical trial databases (US & EU) were reviewed to identify phase 2-4 obesity clinical trials (2018-2023). A literature review was also conducted using the OVID database to identify obesity clinical trial publications which included COAs/DHTs (2010-2023).
Results: Trials from the databases (n=53) and publications (n=42) were included in data extraction. This resulted in identification of 111 COAs, the majority being patient-reported outcomes (PROs; n=86), and 2 DHTs. The most frequent COAs were the Short Form 36 (SF-36v2) and Impact of Weight on Quality of Life-Lite Clinical Trials (IWQoL-Lite-CT), although 24 performance outcomes (PerfOs) were also identified, with the 6-minute walk test (6MWT) being most common. These measures were used as either confirmatory or supportive secondary endpoints, with physical function (PF) being the most frequently specified domain. Measures of eating-related thoughts and behaviours and disordered eating were also frequently included, although individual measures varied widely across trials.
Conclusion: Review of COAs/DHTs in registered clinical trials and publications found that multidimensional PRO measures assessing HRQoL were most often used in obesitytrials with limited use currently of DHTs. PROs were typically used as secondary (confirmatory and supportive) endpoints to assess PF. Further work is warranted to assess how these PRO data were viewed by regulators and payers.

Disclosure
I.A. Goetz: Employee; Eli Lilly and Company. C. Sutter: Consultant; Eli Lilly and Company. T.H. Abraham: Consultant; Eli Lilly and Company. C. Kanu: None. K. Boye: Employee; Eli Lilly and Company. T. Symonds: None.
1696-P: Early Predictors of Maternal Metabolic Health—Utility of Regional and Overall Body Composition Measures
Authors: INGRAM KATHERINE , EHO AMI , MCDONALD BREANNA , AMASON JANEEN 
Published: June 2024

Pregnancy is characterized by reduced insulin sensitivity, which can advance to gestational diabetes in at-risk individuals. Identifying early predictors of GDM would help pregnancy outcomes by improving the time to intervention in this group.
Objective: To test body composition measures as potential early predictors of gestational insulin resistance.
Methods: At 19-20 weeks gestation, 32 nulliparous women (aged 27.2± 4.5 yrs) received body composition measures including percent body fat (PBF), fat and lean mass by bioimpedance; abdominal adipose via ultrasound (intra-abdominal, IAAT; subcutaneous, SAT); and skinfolds. Homeostasis assessment model of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin at 24-26 weeks and log-transformed for normality. Missing data was imputed by linear trend. One individual was excluded due to extreme BMI (&gt;50). RESULTS: In analyses controlled for age and race, pre-pregnancy BMI and most measures of overall and regional body composition were associated with HOMA-IR (BMI: r=.523; PBF: r=.481; IAAT: r=.421; SAT: r=.611; fat mass: r=.569; lean mass: r=.434; p&lt;.05 for all). In a regression model with age, race, and lean mass, fat mass was the only significant predictor of HOMA-IR (Model: R2= .345, p=.022; Fat Mass: Std. β= .501, p=.025; Lean Mass: β= .131, p=.535). Replacing lean mass with IAAT and SAT improved the association with HOMA-IR (Model R2=.559, p=.004), with SAT as the only significant predictor (β =.479, p&lt;.01). Skinfold measures did not improve the model or achieve significance.
Conclusion: Body composition measures, especially SAT, may serve as potential early predictors of gestational insulin resistance. Adopting such early predictors may have a significant impact on maternal health by facilitating the implementation of earlier interventions for metabolic health.

Disclosure
K. Ingram: Stock/Shareholder; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Dexcom, Inc. A. Eho: None. B. McDonald: None. J. Amason: None.

Funding
National Institutes of Health (3R15HD102957-01S1)
1698-P: Partial Least Squares Discrimination Analysis of Cytokine Profiles in T Cells with Inflammation in Subjects with Obesity
Authors: SARASWAT SHUBH , SANTACRUZ CALVO SARA , KERN PHILIP A. , NIKOLAJCZYK BARBARA , ZHANG XIAOHUA D. 
Published: June 2024

Introduction & Objective: We aims to use Partial Least Squares-Discrimination Analysis (PLS-DA) to analyze cytokine profiles in T cells in the context of obesity.
Methods: PLS-DA is a robust statistical method that facilitates the identification of intricate patterns within complex cytokine data sets. We applied PLS-DA to investigate combinatorial cytokine profiles that differentiate T cells of old and young subjects with obesity. Additionally, we evaluated the effect of metformin on these profiles, focusing on its potential impact across age groups in individuals with obesity.
Results: Our PLS-DA analysis distinguished cytokine profiles produced by T cells from old and young subjects with obesity with a 74% accuracy. PLS-DA indicated a borderline effect of metformin on cytokine profiles generated by T cells from older subjects with obesity, with a model accuracy of 67%. Lastly, PLS-DA indicated no impact of metformin on cytokine profiles produced by T cells from younger subjects with obesity, with a model accuracy of 52%. The outcomes contrast with the strong impact of metformin on cytokine profiles produced by T cells from lean older and younger adults (Bharath et al, Cell Metab 2020).
Conclusion: PLS-DA analysis revealed differences in cytokine profiles among old and young subjects with obesity. This analytical method highlighted the differential impact of metformin on cells from these groups, showing a moderate effect on cells from older subjects with obesity and no significant impact on cells from younger subjects with obesity. These findings emphasize the importance of age and obesity status in cytokine profile alterations and impact of these variables on efficacy of treatments like metformin.

Disclosure
S. Saraswat: None. S. Calvo: None. P.A. Kern: None. B. Nikolajczyk: None. X.D. Zhang: None.

Funding
National Institutes of Health (UL1TR001998, 1U01DK135111 and OT2HL161847) and by the DRC at Washington University (P30 DK020579).
170-OR: Case-Control Study on Whole-Methylome Analysis of Monocytes in Acute Diabetic Charcot Foot—Identifying Differentially Methylated Genes
Authors: KUMAR NAWEEN , BHARTI BISHWA B. , KARN JYOTI P.L. , JHA SUDHIR C. 
Published: June 2024

Introduction: Diabetic Charcot Foot (DCF) is a serious diabetes complication that damages bones and joints. Monocyte epigenetic modifications, notably DNA methylation, during DCF are unresolved. This study aims to analyze the whole-methylome of monocytes in acute DCF to identify differentially methylated genes involved in cell migration, differentiation, and osteoclast formation.
Methods: In this case-control study, 30 patients with acute DCF and 30 matched healthy controls were recruited. Monocytes were isolated from peripheral blood samples, and DNA was extracted. Whole-methylome analysis was performed using bisulfite sequencing. Differentially methylated regions (DMRs) were identified and associated with genes involved in monocyte migration, differentiation, and osteoclast formation. Gene expression was further confirmed through qPCR.
Results: Significant differences in methylation patterns were observed between DCF patients and controls. A total of 150 DMRs were identified, with 90 being hypomethylated and 60 hypermethylated in DCF patients. These regions were associated with genes crucial for monocyte function, including those involved in migration (e.g., CXCR4), differentiation (e.g., MAFB), and osteoclast formation (e.g., NFATC1). Gene expression analysis confirmed the upregulation of these genes in DCF patients compared to controls.
Conclusion: This study determined that DCF monocytes had differently methylated genes involved in cell migration, differentiation, and osteoclast formation. These epigenetic alterations may contribute to DCF pathophysiology, providing treatment targets. Further study is needed to understand how these epigenetic modifications affect DCF progression and their potential as biomarkers or therapeutic targets.

Disclosure
N. Kumar: None. B.B. Bharti: None. J.P.L. Karn: None. S.C. Jha: None.
171-OR: Tissue Nanotransfection–Based Endothelial-Targeted Epigenetic Gene Editing In Vivo to Rescue Diabetic Ischemic Wounds
Authors: SINGH KANHAIYA , VERMA SUMIT S. , GNYAWALI SURYA C. , SEN CHANDAN K. 
Published: June 2024

Our previous work (PMID: 35192691) has identified that genetically silenced phospholipase Cγ2 (PLCγ2) hinders VEGF therapy of the diabetic ischemic limb. Hyperglycemia caused hypermethylation of endothelial specific gene promoter. Given that epigenetic changes are reversible, this work tests the significance of gene-targeted therapeutic DNA demethylation in improving blood flow to diabetic ischemic wounds. Bipedicle ischemic wounds were placed in streptozotocin (STZ) induced acute diabetic C57BL6 mice. In wound tissue, PLCγ2 promoter CpG methylation levels were analyzed using bisulfite sequencing. Next, to specifically demethylate PLCγ2 promoter in endothelial cells, a demethylation cocktail was designed: (i) (scFv)-TET1 catalytic domain (TET1CD) system capable of inducing targeted DNA methylation, and (ii) endothelial specific guide RNAs. This demethylation cocktail was delivered at the diabetic ischemic wound-edge employing topical tissue nano-transfection (TNT) technology. PLCγ2 protein expression outcomes were assessed using flow cytometry. Functional outcome of such demethylation was assessed using Laser Speckle Perfusion imaging and ultrasonography (Vevo 2100) at days 3, 7&10 post-surgery. Overall DNA hyper methylation was prominent in murine ischemic flaps as demonstrated by the increased ratio of 5-methylcytosine (5-mc, methylation mark) to 5-hydroxymethylcytosine (5-hmC, demethylation mark) (n = 5). Specifically, the PLCγ2 promoter was hypermethylated (n=5). TNT mediated endothelial-targeted demethylation of the PLCγ2 promoter increased the expression of this gene in endothelial cells (n=4). Such demethylation-based upregulation of PLCγ2 improved wound tissue blood flow with increased abundance of VWF+/PLCG2+ vascular elements (n=4). Taken together, topical TNT-based endothelial demethylation of the PLCγ2 gene promoter improved perfusion of cutaneous diabetic wounds resulting in improved closure.

Disclosure
K. Singh: None. S.S. Verma: None. S.C. Gnyawali: None. C.K. Sen: Consultant; SouthWest Technologies. Board Member; VisopalExo. Consultant; Vomaris Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK136814, DK128845, DK135447, DK125835); Department of Defense (W81XWH-21-1-0033, W81XWH-22-1-0146)