bluuebunny/crossref_metadata_2025_split huggingface dataset:
1627-P: A Novel Compound Identified by High-Throughput Screening Activates UCP1 and Inhibits Obesity and Related-Metabolic Disorders
Authors: ONODERA KEN , HASEGAWA YUTAKA , ISHIGAKI YASUSHI 
Published: June 2024

Introduction and Objective: Obesity and its related metabolic complications are major public health problems. Promoting thermogenesis in adipose tissue has been a promising strategy for the treatment of obesity and related metabolic complications. Our objective is to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism.
Methods: To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that activates uncoupling protein 1 (Ucp1) expression in adipocytes.
Results: Through consecutive screenings, we identified one candidate compound as a potential UCP1 activator. Further characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with little cytotoxicity. In addition, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure in a diet-induced obesity model. Mechanistically, this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds revealed two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627).
Conclusions: The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play a crucial role in UCP1-dependent thermogenesis in adipocytes.

Disclosure
K. Onodera: None. Y. Hasegawa: None. Y. Ishigaki: None.
1631-P: Cardiac-Specific mGPDH Deficiency Promotes Adipose Tissue Thermogenesis and Improves Obesity via SERPINA1E Secretion
Authors: QU HUA 
Published: June 2024

Despite its well-documented effectiveness for treating obesity and type 2 diabetes, the clinical approved medicines for weight loss are still limited due to the unclear underlying mechanisms. Current study identified a mitochondrial protein mGPDH, and found that its globally knockout (GKO) resistant to HFD-induced obesity. mGPDH GKO showed 16.7% reduction of body weight compared with WT mice. Further MRI composition analyzer showed that fat mass, but not lean mass was significantly reduced after GKO. The volume and mass of iWAT were reduced significantly in GKO mice, but not eWAT or BAT. Food consumption was similar between GKO and WT mice fed with HFD, while energy expenditure assessed by metabolic cage system was significantly increased in both light and dark phases in HFD-GKO mice. Unexpectedly, neither the adipose- nor liver-specific mGPDH KO could repeat the protective role of GKO on HFD-induced obesity, while the cardiac-specific KO did. Mechanically, by compared tissue and serum proteomics, we identified a secretory protein SERPINA1E and preliminarily proved that it might mediate the obesity against effects of cardiac mGPDH. In sum, our study highlights a novel cross-organ mechanisms underlying weight loss, and mGPDH/SERPINA1E pathway might serve as a potential therapeutic target for obesity and its related diseases.

Disclosure
H. Qu: None.
1637-P: TLC-6740, a Liver-Targeted Mitochondrial Protonophore, Increases Energy Expenditure and Lipid Utilization in Obese Mice
Authors: SRODA NATALIE , VIJAYAKUMAR ARCHANA , MURAKAMI EISUKE , WENG STEVE , SHULMAN GERALD I. , MYERS ROBERT P. , SUBRAMANIAN MANI 
Published: June 2024

Background: TLC-6740, a liver-targeted mitochondrial protonophore, causes dose-dependent weight loss and metabolic benefit in diet-induced obese mice. Here, we evaluated mechanisms of TLC-6740-induced weight loss.
Methods: Male C57 BL/6 mice housed at thermoneutrality (28°C) were fed a high-fat diet for &gt;25 wk and dosed with vehicle (Veh) or TLC-6740 (60mg/kg) PO BID for 8 days. Energy expenditure (EE) was measured by indirect calorimetry (Days -1, 1, 6-7) and energy balance was calculated by subtracting EE from energy intake (EI).
Results: On Day 1, TLC-6740 increased EE in the dark phase by 18% compared to pre-treatment and by 24% vs Veh (Fig A). EI decreased 26% with TLC-6740 and increased 43% with Veh. Consequently, TLC-6740 induced negative energy balance (Day -1 vs 1: +1.9 vs -1.9 kcal/d) whereas a positive balance was observed with Veh (-0.06 vs +3.4 kcal/d) (Fig B). Respiratory exchange ratio (RER) decreased with TLC-6740, but not Veh, indicating a shift towards increased whole-body lipid utilization (Fig C). Increased EE with TLC-6740 (16% vs Veh) persisted over 6-7 days of dosing leading to 5% weight loss at Day 7.
Conclusions: The protonophore TLC-6740 increases EE, inducing negative energy balance and weight loss. These data support evaluation of TLC-6740 for obesity and highlights the complementarity of this mechanism to agents that reduce oral intake (e.g., incretins).

Disclosure
N. Sroda: Employee; OrsoBio, Inc. A. Vijayakumar: Employee; OrsoBio, Inc. E. Murakami: Employee; OrsoBio, Inc. S. Weng: Employee; OrsoBio, Inc. G.I. Shulman: None. R.P. Myers: Employee; OrsoBio, Inc. M. Subramanian: Board Member; OrsoBio, Inc.
165-OR: Lipid Signaling in Macrophages Contributes to Inflammatory Transcriptome in Immune Cells
Authors: ALMUTAIRI ABDULAZIZ , WELNER ROBERT S. , WHITE TAYLEUR , TUSING YING , RAMANADHAM SASANKA 
Published: June 2024

Macrophages and T-cells play critical roles in β-cell death leading to T1D. We find that reduction of Ca2+-independent phospholipase A2β in macrophages alone reduces T1D. To explore the potential mechanism, we examined changes in immune-responsive genes by single-cell RNAseq analysis using a false discovery rate (FDR)&lt;1e10-8. In the BMDM from NOD.cM ΦiPLA2 β-/-, relative to NOD, we find that genes (Slc25a5, Ephx1, Zcchc14) related to inflammation, immune cell infiltration, T-cell activation, antigen presentation, MΦ proliferation, and mitochondrial metabolism were down-regulated, and those that promote M2M Φ polarization (Ccl6) and MΦ-phagocytosis (Tbc1d10c), and reduce MΦ infiltration (Creb313), CD8 T-cell activation (Ccl4), and mitochondrial production of anti-inflammatory itaconate (Acod1) were up-regulated. Intriguingly, nearly 30 DEGs were noted in islet CD4 and CD8 T-cells from NOD.cM ΦiPLA2 β-/-, relative to NOD. In the CD4 cells, genes (Tnfrs23, Jak2, H2-Aa) related to inflammation, activation of T-cells, and antigen presentation were downregulated, whereas genes related to Treg generation (Gpr83) and negative regulation of Th-cell activation (Cd160) were upregulated. In the CD8 cells, genes associated with enhancing inflammation (Epas1, Gata3), CD8 T-cell activation (Nkg7, Ctla2b), CD4 T-cell activation (Gldc), and (4) negative modulation of Treg cell generation (Ctla2a) were down-regulated, while genes (Gbp2b, Gpr83) associated with Tregs were upregulated. Importantly, the top 7 of 16 shared T-cell pathways were related to inflammation. Similar transcriptome profiles were also evident in NOD.cM ΦiPLA2 β-/- islet B and NK cells, relative to NOD. These findings reveal that lipid signaling from macrophages affects the transcriptome in macrophages, triggering islet immune cell transcriptome favoring an inflammatory phenotype. They further suggest that targeting iPLA2β-derived lipid signaling in macrophages is a means to reduce T1D incidence.

Disclosure
A. Almutairi: None. R.S. Welner: None. T. White: None. Y. Tusing: None. S. Ramanadham: None.

Funding
NIH/NIAID 1R21AI169214-01JDRF 2-SRA-2022-1210-S-BJDRF 1-INO-2023-1344-A-NNIH/NIAID 1 R21 AI 146743UAB Department of CDIBUAB Comprehensive Diabetes Center
1661-P: Petrelintide (ZP8396) Selectively Reduces Intake of High-Fat Diet in DIO Rats
Authors: VESTERGAARD BILL , BAADER-PAGLER TAMARA , GRIFFIN JON 
Published: June 2024

The obesity pandemic is a major health crisis and there is a need for effective pharmacotherapies. Overconsumption of highly palatable food is associated with obesity. Petrelintide, a novel once-weekly amylin analog currently in phase 1 clinical testing, induces meaningful reductions in body weight in lean and overweight subjects. Here we investigate the effect of petrelintide on food preference in DIO (diet-induced obese) rats to determine whether petrelintide holds the potential to address overconsumption of highly palatable food in humans.DIO rats were given ad libitum access to chow diet and high fat diet during a 30-day treatment period. Animals were treated with either vehicle (every second day), liraglutide (5 nmol/kg twice daily) or petrelintide (2 nmol/kg every second day or 10 nmol/kg every fourth day). Body weight, chow intake and high fat diet intake were measured daily.
Treatment with liraglutide and petrelintide resulted in significant lower relative body weight compared to vehicle (3.3 % ± 0.7 vehicle, -0.1 % ± 1.1 liraglutide, -4.1 % ±0.6 petrelintide 2 nmol/kg, -7.8 % ± 0.7 petrelintide 10 nmol/kg; relative to initial body weights ± SEM). Treatment with petrelintide resulted in significant reduction of total cumulative intake of high fat diet compared to vehicle, in contrast to liraglutide (834 g ± 31.1 vehicle, 796 g ± 25.6 liraglutide, 646 g ± 22.3 petrelintide 2 nmol/kg, 576 g ± 17.4 petrelintide 10 nmol/kg; g ± SEM). No change in total cumulative intake of chow was observed in any groups compared to vehicle.
In conclusion, petrelintide reduces food intake and body weight in DIO rats primarily by lowering intake of high fat diet. Based on these findings petrelintide might hold the potential to address overconsumption of highly palatable food in humans. Petrelintide is currently being explored in a multiple ascending dose (MAD) study to assess the potential for the management of obesity.

Disclosure
B. Vestergaard: Employee; Zealand Pharma A/S, Novo Nordisk A/S. T. Baader-Pagler: Employee; Boehringer-Ingelheim. J. Griffin: Employee; Zealand Pharma A/S.
1667-P: Mesenteric Visceral Lipectomy (MVL) Improves Glucose Tolerance in Patients with Type 2 Diabetes (T2D)
Authors: BASKOY GOZDE , PETERSON RICHARD M. , KEMPENICH JASON W. , TRIPLITT CURTIS L. , CLARKE GEOFFREY D. , CERSOSIMO EUGENIO , ANDREW MARK S. , MEROVCI AURORA , LAVRYNENKO OLGA , HANSIS-DIARTE ANDREA A. , SOLIS-HERRERA CAROLINA , CHAVEZ ALBERTO , SALEHI MARZIEH , DEFRONZO RALPH A. 
Published: June 2024

Aim: To evaluate the safety and metabolic effects of mesenteric visceral lipectomy in individuals with T2D.
Methods & Study Design: Eight T2D subjects (age = 52±4 y; BMI = 34.1±1.0; stable diabetes meds/weight for 3 months) underwent pre-MVL assessment including OGTT, CGM, euglycemic insulin clamp with 3H-glucose, and MRI imaging. Repeat measurements were made at 6- and 12-months post-surgery. Exclusion criteria included prior insulin/TZD use. Insulin secretion [IS], Disposition Index [DI] and Matsuda index [MI] of insulin sensitivity were calculated with standard formulae.
Results: At month 6, HbA1c decreased from 9.0% to 8.1% (p=0.08) and persisted at 8.4% at month 12 (p=0.19). CGM time-in-range increased significantly at 6 and 12 months (25% to 76%) (p&lt;0.05). Suppression of hepatic glucose production increased at months 6 and 12 (p&lt;0.05). Body weight and % body fat decreased slightly at month 12 (p&lt;0.05). Insulin secretion and disposition index during OGTT increased more than 2-fold at month 6 and persisted at month 12.

Disclosure
G. Baskoy: None. R.M. Peterson: Consultant; Teleflex/Standard Bariatrics. J.W. Kempenich: Consultant; Intuitive Surgical. C.L. Triplitt: Speaker's Bureau; Novo Nordisk. Consultant; Eli Lilly and Company. Other Relationship; American Diabetes Association. G.D. Clarke: None. E. Cersosimo: None. M.S. Andrew: Employee; Medality Medical, Inc. A. Merovci: None. O. Lavrynenko: None. A.A. Hansis-Diarte: None. C. Solis-Herrera: Advisory Panel; Novo Nordisk, Bayer Inc. A. Chavez: None. M. Salehi: None. R.A. DeFronzo: Advisory Panel; AstraZeneca, Novo Nordisk, Boehringer-Ingelheim, Intarcia Therapeutics, Inc., Aardvark, Renalytix, Corcept Therapeutics, Alnylam Pharmaceuticals, Inc. Research Support; Boehringer-Ingelheim, AstraZeneca, 89bio, Inc., Amgen Inc., Medality, Corcept Therapeutics. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Renalytix.

Funding
Medality
1687-P: Similarities and Differences between Metabolically Unhealthy Lean and Metabolically Unhealthy Obese Individuals
Authors: ANAND SEERAT , PASUPNETI TEJASVI , PAK YOUNGJU , GARG RAJESH K. 
Published: June 2024

Metabolic abnormalities are present in 15-25% adults with BMI &lt;25 kg/m2. Studies have shown an increased amount of visceral fat in metabolically unhealthy lean (MUL) individuals as compared to metabolically healthy lean (MHL) individuals. The same is true for metabolically unhealthy obese (MUO) as compared to metabolically healthy obese (MHO) individuals. However, the lean and obese groups have not been compared for other similarities or differences. We used NHANES data for years 2011 - 2018 and downloaded variables related to demographics, laboratory, and dual energy x-ray absorptiometry. Being metabolically unhealthy was defined as the presence of ≥2 components of the metabolic syndrome other than obesity. After excluding those &lt;18 years, the study sample included 6,834 subjects with BMI &lt;25 kg/m2 and 8,564 with BMI ≥30 kg/m2. The comparisons between MUL Vs MHL and MUO Vs MHO are shown in the table. We found that MUL individuals had increased total percent fat mass and increased android percent fat as compared to MHL individuals. However, MUO individuals had similar total and android fat but lower gynoid fat as compared to MHO individuals. Thus, while MUL and MUO subjects both had increased android to gynoid ratio, there were differences in fat distribution. This suggests that the underlying mechanisms in MUL individuals may be different from the MUO individuals and need further investigation.

Disclosure
S. Anand: None. T. Pasupneti: None. Y. Pak: None. R.K. Garg: None.
1688-P: Type 2 Diabetes Remission after Metabolic and Bariatric Surgery—A Systematic Review and Meta-analysis Comparing Less Obese and Severely Obese Individuals
Authors: HYUN BAE JAE , HOON KIM NAM 
Published: June 2024

Introduction & Objective: Metabolic and bariatric surgery (MBS) effectively induces diabetes remission in severely obese individuals. However, its impact on those with less severe obesity remains uncertain. We investigated type 2 diabetes remission after MBS based on preoperative body mass index (BMI).
Methods: We searched MEDLINE, Embase, and the Cochrane Library databases up to May 2021, focusing on diabetes remission concerning BMI without restricting to intervention-comparison studies. We included clinical trials, cohort studies, and consecutive case series involving ≥50 individuals with type 2 diabetes who underwent MBS and reported diabetes remission. Studies were categorized by preoperative BMI (&lt;35 kg/m2 or ≥35 kg/m2). The primary outcome was diabetes remission (HbA1c &lt;6.5% without antidiabetic medication) at different post-surgery intervals, with analysis of HbA1c and BMI changes. We used meta-regression for between-group comparisons and assessed potential bias.
Results: Eighty-one studies were included (23 with BMI &lt;35 kg/m2, 58 with BMI ≥35 kg/m2). At 12 months, diabetes remission rates were 0.59 (95% CI 0.49 to 0.70) for BMI &lt;35 kg/m2, and 0.61 (0.55 to 0.67) for BMI ≥35 kg/m2. No significant between-group differences were observed at 12 months (adjusted weighted mean difference [WMD] −0.01, 95% CI −0.14 to 0.12), 24 months (adjusted WMD −0.04, 95% CI −0.29 to 0.21), 36 months (adjusted WMD 0.00, 95% CI −0.22 to 0.23), and ≥60 months (adjusted WMD −0.02, 95% CI −0.25 to 0.22). Achieved HbA1c levels were comparable, but BMI remained higher in those with BMI ≥35 kg/m2.
Conclusions: Our study demonstrates that diabetes remission after MBS is similar between individuals with BMI &lt;35 kg/m2 and BMI ≥35 kg/m2 over the long-term follow-up.

Disclosure
J. Bae: None. N. Kim: None.
1706-P: Software-Aided Self Selection of Weight Loss Diet Plan for Facilitating Diabetes Management in Primary Care
Authors: WHIGHAM LEAH , DHURANDHAR NIKHIL 
Published: June 2024

Introduction and Objectives: The addition of a new anti-diabetes drugs have further strengthened pharmacological management of diabetes. However, attention to diet continues to be a cornerstone of diabetes management, particularly because of the preponderance of obesity in individuals with diabetes. Our objective was to address the gap experienced by many diabetes care providers in providing effective dietary guidance.
Methods: We developed Small Changes, a software program that facilitates patient-selected meal planning. Bilingual videos instruct patients on selection of meal options that align with their usual eating habits and dietary preferences, including options for from-scratch recipe, convenience foods, and restaurant options. The algorithm provides a structured meal plan that includes instructions and recipes based on patient selections and tailored to the patient’s calorie needs for weight loss (~ 500 Calorie deficit from daily energy requirements based on Mifflin St. Jeor equation). Macronutrients are distributed throughout the day to optimize fat loss and reduce hunger (~20% Cal as protein, &lt;30% as fat), while providing patients with moderate flexibility in choices to enhance compliance.
Results: Mixed methods pilot testing in multiple settings indicates high patient and provider satisfaction and average weight loss that is clinically significant (&gt;5%). Providers indicated program addressed a need for dietary guidance that was not time consuming and did not require clinic personnel to have extensive nutrition knowledge. Patients expressed appreciation for variety and flexibility of the program.
Conclusion: Software-based tools that support nutrition guidance for weight loss offer a scalable approach to meet an important need in diabetes management.

Disclosure
L. Whigham: None. N. Dhurandhar: Advisory Panel; Medifast, Inc. Research Support; Insparin Inc, Borealis Foods, National Cattleman's Beef Association, Novo Nordisk.
1707-P: Real-World 12-Month Weight Loss Outcomes of Tirzepatide—The Mayo Clinic Experience
Authors: FANSA SIMA , TAMA ELIF , SAFWAN NANCY , GHUSN WISSAM , ANAZCO DIEGO , ACOSTA ANDRES , HURTADO MARIA D. 
Published: June 2024

Introduction: Tirzepatide, a dual GIP/GLP-1 receptor agonist, has been recently approved for the treatment of overweight and obesity given its proven effectiveness and safety in phase 3 clinical trials. In this study, we aim to evaluate weight loss outcomes associated with tirzepatide in the real-world setting.
Methods: This is a retrospective cohort study of adults taking tirzepatide for the treatment of overweight or obesity. Endpoints: total body weight loss percentage (TBWL%) at 3, 6, and 12 months; TBWL% difference by type 2 diabetes (T2D) status; proportion of patients achieving ≥5%, ≥10%, ≥15% and ≥20% of TBWL% at 12 months; and side effects. We used paired t-test to assess TBWL% compared to baseline and non-paired t-test to compare TBWL% by T2D status. Results are presented as mean ± standard deviation.
Results: We included 200 patients: 78% female, 91% White, age 50±12 y, BMI 39±8 kg/m2, 36.5% with T2D. Most patients were on 15 mg (26.5%) or 7.5 mg (20.0%) of tirzepatide weekly. TBWL% at 3, 6, and 12 months were -9±5% (n= 138, p&lt;0.001), -12±6% (n= 113, p&lt;0.001), and -17±9% (n= 97, p&lt;0.001), respectively. Compared to patients without T2D, those with T2D lost less weight at 12 months: -14±9% vs. -19±9%, p=0.01. The percentages of patients losing ≥5%, ≥10%, ≥15% and ≥20% of TBWL% at 12 months were 90%, 73%, 57%, and 40%. Only 11% and 6% of patients received nutritional and behavioral support, respectively. Side effects were reported by 29% of patients. The most frequent was nausea (18%). Seven patients (4%) discontinued tirzepatide due to side effects.
Conclusion: In the real-world setting, tirzepatide led to substantial weight loss at 12 months in patients with and without T2D, comparable to what has been reported in pivotal trials. Future real-world studies with a larger number of participants are needed to better assess the long-term efficacy, safety, and tolerability of tirzepatide in this setting.

Disclosure
S. Fansa: None. E. Tama: None. N. Safwan: None. W. Ghusn: None. D. Anazco: None. A. Acosta: Consultant; Amgen Inc., Regeneron Pharmaceuticals Inc., Nestlé Health Science, Structure Therapeutics, Inc., Boehringer-Ingelheim. Research Support; Vivus. Consultant; Currax. Other Relationship; Gila Therapeutics, Phenomix Sciences. Speaker's Bureau; Eli Lilly and Company. M.D. Hurtado: None.

Funding
National Institutes of Health (K12AR084222)
1713-P: Acute Beta Cell Deletion of Grp78 Causes Diabetes in Adult Male Mice
Authors: BURTON JOSHUA , CASTRO THALIA , HASSAN HIBO A. , DIAZ MOSQUEA HILLARY , ALONSO LAURA C. 
Published: June 2024

Introduction: GRP78 is a stress-inducible endoplasmic reticulum (ER) chaperone and a key regulator of the unfolded protein response (UPR). Pancreatic beta cells are particularly susceptible to ER stress in order to adapt to increased insulin demand. It is unknown whether mature beta cells require GRP78 function for basal homeostasis. In this study, we investigated the impact of reducing GRP78 abundance in beta cells of adult mice in unstressed conditions. We hypothesized that loss of GRP78 activity results in decompensation and beta cell failure.
Methods: MIP-CreERT mice were bred to mice harboring loxP sites flanking exons 5-7 of the Grp78 gene. Male and female adults, genotypes Cre+Grp78 +/+ ("+/+"), Cre+Grp78 f/+ (“f/+”), and Cre+Grp78 f/f (“f/f"), were administered five daily doses of tamoxifen by oral gavage. Metabolic parameters were assessed and mice were sacrificed 10 days after the last tamoxifen dose for pancreas histology.
Results: GRP78 protein abundance was reduced in f/f beta cells relative to f/+ and +/+ beta cells by immunofluorescence. Grp78 deletion increased random blood glucose in male and female f/f mice compared to f/+ and +/+ controls. Males were more severely affected than females; f/f males also had elevated fasting glucose, impaired glucose tolerance, and weight loss. Random plasma insulin levels were reduced in some but not all mice. Pancreas weight was unaffected by Grp78 deletion. Beta cell mass was reduced in male f/f mice, islet architecture and cellular composition were distorted, with reduced frequency of beta cells and increased relative frequency of alpha cells. Interestingly, beta cell proliferation and beta cell death death were both significantly increased by Grp78 deletion.
Conclusions: Acute deletion of Grp78 in beta cells rapidly induces beta cell loss and diabetes in adult male mice. Beta cell GRP78 is important for maintaining whole-body glucose homeostasis. Impairment in GRP78 abundance or function in beta cells may contribute to the pathogenesis of diabetes

Disclosure
J. Burton: None. T. Castro: None. H.A. Hassan: None. H. Diaz Mosquea: None. L.C. Alonso: None.

Funding
National Institutes of Health (R01DK113300)