bluuebunny/crossref_metadata_2025_split huggingface dataset:
1614-P: H2S Improves Skeletal Muscle Insulin Resistance by Inhibiting Pyroptosis via Sirt2 Pathway
Authors: QIU KANGLI , KONG WEN 
Published: June 2024

Introduction & Objective: H2S is the third gaseous signaling molecule with a variety of biological effects.H2S may be involved in diabetes by modulating inflammation. The aim of this study was to determine the effects and mechanisms of H2S on high-fat diet-induced insulin resistance in skeletal muscle.
Methods: Mice were injected intraperitoneally with NaHS (50 μmol/kg/d ), the Sirt2 inhibitor AGK2 (1 mg/kg/d), or disulfiram (50 mg/kg/d). Body weight, IPGTT, ITT, calculation of skeletal muscle/body weight ratio, skeletal muscle muscle fiber cross sectional area and adipose tissue were detected. The effects of NaHS-induced sirt2 changes and the NLRP3/caspase-1/GSDMD pathway were detected.
Results: The SIRT2 inhibitor AGK2 accelerated blood glucose and body weight elevation and decreased skeletal muscle/body weight ratio in mice, and IPGTT and ITT indicated that AGK2 inhibited the recovery of blood glucose and exacerbated skeletal muscle atrophy and adiposity in mice.However, NaHS and disulfiram were effective in reversing the above changes.
Conclusion: H2S regulates skeletal muscle satellite cell proliferation and differentiation by activating sirt2 and thereby inhibiting NLRP3/caspase-1/GSDMD pathway-mediated skeletal muscle scorpioning, resulting in increased skeletal muscle mass and thus alleviating IR resistance.

Disclosure
K. Qiu: None. W. Kong: None.
1617-P: Diabetes and Bones—Unraveling the Biomarker Symphony and Density Dance
Authors: RASMUSSEN NICKLAS H. , KVIST ANNIKA V. , VAN DEN BERGH JOOP , VESTERGAARD PETER 
Published: June 2024

Introduction & Aim: This study delved into essential bone biomarkers in T1D and T2D, investigating their connections with areal bone mineral density (aBMD) and volumetric BMD (vBMD).
Methods: In a cross-sectional study, 543 adults participated, including 111 with T1D, 106 with T2D, and 328 controls. Employing DXA and HR-pQCT scans, a range of biochemical bone biomarkers (CTX, P1NP, sclerostin, osteopontin, OCN, and IGF-1) were analyzed. Group comparisons and regression models, adjusting for relevant factors, were executed. Correlation analyses, utilizing Spearman with Bonferroni correction, explored associations between bone parameters and biomarkers for intergroup comparison.
Results: Results revealed significantly reduced CTX1, P1NP, IGF-1, OCN, and osteopontin in T1D and T2D (p&lt;0.05), with T2D having the lowest (p=0.01). Conversely, sclerostin was higher in both T1D and T2D than controls (p=0.001). T2D showed elevated neck aBMD (0.85g/cm2, p=0.011) and tibial vBMD (300.6HA/cm3, p=0.004) in contrast to T1D and controls. In T2D, neck aBMD correlated negatively with CTX1 (r=-0.332, p=0.001), P1NP (r=-0.278, p=0.005), OCN (r=-0.397, p=0.001), and positively with sclerostin (r=0.229, p=0.041). In T1D, CTX1 correlated negatively, while IGF-1 correlated positively with neck aBMD (r=-0.301, p=0.002, r=0.329, p=0.001, resp). Controls exhibited positive correlations of IGF-1 (r=0.321, p=0.001) and negative correlations of sclerostin (r=-0.151, p=0.008) with neck aBMD. Tibial vBMD was negatively correlated with P1NP in T2D (r=-0.231, p=0.024) and positively correlated with IGF-1 in T1D and controls (p&lt;0.011). Sclerostin strongly correlated with diabetes duration in both T1D and T2D (r=0.491, p=0.001, r=0.342, p=0.003, respectively). IGF-1 had a negative correlation in T1D (p=0.001).
Conclusion: Individuals with T1D and T2D present distinctive bone biomarker profiles and associations with aBMD and vBMD, emphasizing the intricate interplay between diabetes and bone health.

Disclosure
N.H. Rasmussen: Other Relationship; Boehringer-Ingelheim. Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. A.V. Kvist: None. J. van den Bergh: Advisory Panel; Amgen Inc. P. Vestergaard: None.

Funding
This work was supported by a research grant from the Danish Diabetes and Endocrine Academy, which is funded by the Novo Nordisk Foundation (NNF22SA0079901)
1634-P: Changes in Bile Acid Enterohepatic Circulation in Type 2 Diabetes Mellitus Rats following Sleeve Gastrectomy
Authors: ZHAO XIANG , LIU ZITIAN , YANG GUANGWEI , GE ZHENG , DONG SHUOHUI , ZHANG XIANG , CHENG ZHIQIANG , WANG KEXIN 
Published: June 2024

Introduction & Objective: T2DM can be effectively treated by sleeve gastrectomy (SG), albeit the mechanisms underlying is elusive. Postoperative changes in serum bile acid have been found contributing to metabolism improvement. This study aims to determine the overall changes of bile acid enterohepatic circulation following SG.
Methods: SG model was established in T2DM rats. Alterations of bile acids in the bile, intestine, portal vein and inferior vena cava were evaluated by liquid chromatography-mass spectrometry. Bile acid transporters were also evaluated.
Results: Metabolism was significantly improved after SG. Intraluminal bile acids were altered from the duodenum to the colon, with glycine/taurine conjugated bile acid ratio being increased. Peripheral blood total bile acids exhibited an elevation, accompanied by intricate alterations in the composition of bile acids within both the bile and the portal vein. Postoperative liver bile acid absorption transporter NTCP, OATP and efflux transporter BSEP, MDR3 were significantly decreased, whereas intestinal uptake transporter ASBT was increased and bile acid binding protein IBABP was decreased (P&lt;0.05 all).
Conclusion: The entire pathway of bile acid enterohepatic circulation exhibited complicated changes following SG. The impact of the changes on postoperative metabolism improvement warrants further research.

Disclosure
X. Zhao: None. Z. Liu: None. G. Yang: None. Z. Ge: None. S. Dong: None. X. Zhang: None. Z. Cheng: None. K. Wang: None.

Funding
National Natural Science Foundation of China (82070852, 82270901)
164-OR: Macrophage Ucp1 Deficiency Inhibits Cold Exposure–Induced Insulin Sensitivity in High-Fat Diet Mice
Authors: SUN LIMING 
Published: June 2024

Cold exposure (CE) could increase insulin sensitivity in high-fat-diet (HFD) mice, relying on adipose tissue Ucp1-induced heat release and macrophage M2 polarization. The function of thermogenic macrophages, a new subtype of macrophages that we have recently identified, has not been clearly investigated in insulin sensitivity caused by cold exposure. We used HFD wild-type (WT) mice and Ucp1 conditionally knockout in macrophages (Ucp1-cKO) mice which housed in 16°C for 2 mouths, and detected their physiological characteristics, metabolic cage, and proteome profiles of different adipose tissues based on mass spectrometry. We found that the body weights of Ucp1-cKO mice were significantly higher than that of WT mice, and the oxygen consumption and heat release were reduced in Ucp1-cKO mice, which demonstrated a weaker metabolic activity of Ucp1-cKO mice upon CE. The glucose and insulin tolerance tests indicated that Ucp1 deletion in macrophages abated insulin sensitivity caused by CE. In addition, thermogenic proteins, represented by Ucp1, were inhibited in subcutaneous adipose tissue of Ucp1-cKO mice, suggesting that the loss of macrophage thermogenesis could reduce the thermogenesis metabolism of the whole sWAT. The adipocytes in sWAT were malformed and hypertrophied, and the cytokines secreted by macrophages were no difference between each other. These conclusions confirm the important role of thermogenic macrophages in promoting adipose tissue thermogenesis and insulin resistance in HFD mice, and provide a potential strategy for cell therapies in diabetes treatment.

Disclosure
L. Sun: None.
1642-P: Metabolic Effects of Semaglutide and Resmetirom at Thermoneutrality in the Diet-Induced Obese Mouse
Authors: TOZZI MARCO , FEIGH MICHAEL , HANSEN HENRIK H. 
Published: June 2024

Introduction & Objective: Semaglutide (GLP-1 receptor agonist) is currently approved for the treatment of type 2 diabetes and obesity and in late-stage clinical development for MASH. Resmetirom, a selective THR-β agonist, is waiting for approval for MASH. The present study aimed to compare the effects of semaglutide and resmetirom monotherapy on metabolic endpoints at thermoneutrality in diet-induced obese (DIO) mice. Methods: Male C57BL/6J mice were fed a high-fat diet (60 kcal-% fat) for 32 weeks. Animals were acclimatized to thermoneutrality (28◦C) for 2 weeks prior to study start and randomized into treatment groups based on body weight and whole-body fat mass. DIO mice were administered vehicle, semaglutide (10 nmol/kg, SC, QD) or resmetirom (10 mg/kg, PO, QD) for 4 weeks. Chow-fed mice served as lean controls. Endpoints included body weight, food intake, whole-body fat/lean mass (echoMRI), plasma biochemistry and energy expenditure (EE) assessed using indirect calorimetry.
Results: Both compounds induced a sustained body weight loss (semaglutide, 25%; resmetirom, 13%) mainly driven by reduced food intake and fat mass. Semaglutide, but not resmetirom, also reduced lean mass. Only resmetirom enhanced EE after 1 and 4 weeks of treatment. The compounds equally improved hepatomegaly, fasting blood glucose and plasma triglycerides. Semaglutide improved hyperinsulinemia while only resmetirom normalized plasma cholesterol levels.
Conclusion: At thermoneutrality, semaglutide and resmetirom both improve metabolic outcomes in DIO mice. Notably, metabolic benefits of resmetirom treatment are associated with increased EE, highlighting the use of indirect calorimetry for profiling mechanism of action of drugs with therapeutic potential in obesity and MASH.

Disclosure
M. Tozzi: None. M. Feigh: Employee; Gubra. H.H. Hansen: Employee; Gubra.
1643-P: P2Y14 Receptor Regulates Whole-Body Glucose Homeostasis in High Fat Diet-Induced Obese and Diabetic Mice
Authors: PRAMANIK ASMITA , JACOBSON KENNETH A. 
Published: June 2024

Diverse G protein-coupled receptors (GPCRs) are expressed in different metabolic tissues and are involved in the regulation of whole-body glucose and energy homeostasis. Dysregulation of glucose homeostasis contributes to hyperglycemia in obesity and type 2 diabetes (T2D). Thus, GPCRs have emerged as important therapeutic targets for anti-obesity and anti-diabetic candidate. P2Y14 receptor (P2Y14R) is a Gi-coupled purinergic receptor stimulated by endogenous UDP-glucose and functionally expressed in adipose tissue involved in glucose and lipid homeostasis. P2Y14R plays a crucial role in adipocyte metabolism, and its selective ablation in adipocytes improves metabolic phenotypes. However, the role of P2Y14R signaling in hepatic glucose production (HGP) and insulin secretion in obese mice has remained elusive. Here, we investigated this receptor in glucose metabolism using selective P2Y14R small molecule modulators. The P2Y14R mRNA level is upregulated in mouse hepatocytes and islets isolated from high fat diet-induced obese mice compared to lean control mice. A potent synthetic P2Y14R agonist (MRS2905) was administered to lean and obese mice to selectively activate P2Y14R. Surprisingly, acute activation impaired glucose homeostasis by enhancing HGP and suppressing insulin secretion in mice consuming high fat diet as well as lean mice. In contrast, P2Y14R antagonist mono-prodrug (MRS 4779) improved HGP and protected mice from metabolic deficits. Overall, our evidence suggests that P2Y14R activation triggers defects in glucose metabolism whereas antagonist prodrugs can contribute to improve whole-body glucose homeostasis in obese mice. Hence, P2Y14R antagonists and their prodrugs might have potential for use in anti-diabetic therapy.

Disclosure
A. Pramanik: None. K.A. Jacobson: None.

Funding
National Institutes of Health (ZIADK031126)
1644-P: The Dose Makes the Poison—High-Fat Diet Based on Extra Virgin Olive Oil Leads to Increased Liver Lipogenesis and Glucose Intolerance in Mice
Authors: KELLER LENA , BOSCH ANGELA J. , LOW ANDY J.Y. , STEIGER LAURA , RACHID LEILA , DE PAULA SOUZA JOYCE C. , WUEEST STEPHAN , MEIER DANIEL T. , CAVELTI-WEDER CLAUDIA 
Published: June 2024

Background & Objectives: Extra virgin olive oil (EVOO) has garnered attention for its potential anti-inflammatory and oxidative properties. However, the effect on metabolic health remains inconclusive. We previously showed that high-fat diets (HFD) based on coconut oil or lard led to glucose intolerance and inflammatory changes in gut and adipose tissue (AT). Our study aimed to investigate the metabolic and immunological consequences of an EVOO-based HFD compared to a HFD based on coconut oil.
Methods: Male mice aged 5-8 weeks were fed a coconut or EVOO-based HFD (Coco HFD, EVOO HFD) or control diet for 1 week, after which the mice underwent glucose and insulin tolerance tests. Flow cytometry was used to characterize immune cells of the colon, AT, and liver. Total liver lipids were determined by a sulfophosphovanillin reaction. qPCR was used for relative DNA quantification. Statistical analysis was performed using ordinary one-way ANOVA with multiple comparisons.
Results: Both HFDs induced hyperinsulinemia, but the EVOO HFD led to pronounced glucose intolerance and insulin resistance. Furthermore, mice fed an EVOO HFD had significantly elevated total liver lipids and increased expression of lipogenesis genes, particularly Srebp1c. However, mice on EVOO HFD showed partial protection from inflammation in the AT and colon. Neither of the HFDs resulted in systemic inflammation after 1 week.
Conclusion: Our study highlights specific metabolic and immune responses induced by different dietary fat sources. Importantly, although EVOO HFD has fewer pro-inflammatory properties compared to Coco HFD, it results in pronounced glucose intolerance. This may be related to increased hepatic lipogenesis and subsequent elevation of hepatic lipids, possibly induced by oleic acid, which accounts for approximately 70 % of EVOO.

Disclosure
L. Keller: None. A.J. Bosch: None. A.J.Y. Low: None. L. Steiger: None. L. Rachid: None. J.C. de Paula Souza: None. S. Wueest: None. D.T. Meier: None. C. Cavelti-Weder: None.

Funding
The Swiss National Science Foundation (SNSF) (32003B_204937/2)
1645-P: Metabolic and Adipogenic Effects of Di(isononyl) Cyclohexane-1,2-dicarboxylate (DINCH) In Vivo
Authors: KRUPKA SONTJE , KLÖTING NORA , BLÜHER MATTHIAS 
Published: June 2024

As a substitute for phthalate plasticizers, DINCH holds significance. Human studies indicate that lipophilic xenobiotics, including DINCH, accumulate in adipose tissue, potentially disrupting adipocyte biology and contributing to metabolic disturbances like insulin resistance and obesity. In vitro experiments demonstrate the activation of PPARg in adipocytes by DINCH. To provide further clarification on the effects of DINCH, we conducted a feeding study. A total of 144 C57BL/6NTac mice (N=144; females N=72, males N=72) were randomly assigned into four groups, each receiving distinct dietary interventions: standard chow, high-fat diet (HFD), and HFD supplemented with 4,500 ppm and 15,000 ppm DINCH. Throughout the 16-week study, animals had unrestricted access to their designated diets. To explore potential washout effects, 80 animals shifted to a standard diet for an additional 10 weeks following the initial intervention. The study included routine evaluations of body weight, blood glucose, insulin tolerance, and body composition (fat mass/lean mass). At the study's conclusion, metabolic chamber analysis assessed energy metabolism, and tissues were scrutinized at both molecular and histological levels post-euthanization. In contrast to expectations, mice fed the HFD-DINCH diet exhibited lower body weights than the standard HFD group, with minimal changes in fat and lean mass distribution. The DINCH-fed mice demonstrated increased insulin resistance and dyslipidemia, which were reversible during the washout phase. These results suggest a need to reevaluate the presumed effects of DINCH on adipocyte differentiation and lipid accumulation. They provide new insights into the interplay between DINCH exposure and metabolic responses in mice.&lt;u&gt;&lt;/u&gt;

Disclosure
S. Krupka: None. N. Klöting: None. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi.

Funding
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838
1648-P: Opposing Roles of Sphingosine 1 Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice
Authors: ASANO MOTOCHIKA , FUWA MASAYUKI , MORI ICHIRO , MORITA HIROYUKI , KAJITA KAZUO , ISHIZUKA TATSUO 
Published: June 2024

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through five cognate G protein-coupled receptors (S1P1-S1P5). However, little is known about the role of S1P in obesity formation. We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and a S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates adipogenic differentiation. In this study, we examined whether an S1P1-specific agonist SEW-2871 and VPC23019 act on obesity and glucose intolerance in ob/ob mice. The oral administration of SEW-2871 and JTE-013 induced significant reductions in body weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased mRNA levels of tumor necrosis factor-α and CD11c, whereas increased those of CD206 and adiponectin in the epididymal (not inguinal) fats isolated from ob/ob mice but not in control mice with no changes in the levels of peroxisome proliferator activated receptor gamma and its regulated genes. By contrast, VPC23019 did not cause all such alterations in these mice, however co-administration of SEW-2871 and VPC23019 abolished the effect of SEW-2871 on ob/ob mice.
In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body and improve glucose tolerance in obese mice. Therefore, endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.

Disclosure
M. Asano: None. M. Fuwa: None. I. Mori: None. H. Morita: None. K. Kajita: None. T. Ishizuka: None.
1649-P: S-309309, a Novel MGAT2 Inhibitor, Enhances Intestinal Fatty Acid Beta Oxidation and Provides Metabolic Benefits in DIO Mice
Authors: YOSHIKI RYO , TAKEMOTO KOSUKE , MORINAGA TAKUMI , TANIOKA HIDEKI , SONOYAMA TAKUHIRO , KATO HIDEAKI 
Published: June 2024

Introduction & Objective: Pharmacological inhibition of Monoacylglycerol acyltransferase 2 (MGAT2) suppresses the food intake and the gain of body weight in high fat diet (HFD)-induced obesity (DIO) mice. However, the effects on metabolic abnormalities associated with obesity and detailed mechanisms of action remain unknown. In this study, we investigated the metabolic effects of S-309309, a novel selective MGAT2 inhibitor, in DIO mice and the involvement of energy consumption in the anti-obesity effects of S-309309.
Method: Mice were fed a HFD for 4 weeks to establish a DIO model. S-309309 (3 mg/kg, b.i.d.) was orally administered to DIO mice for 13 weeks. Daily body weight and weekly food intake were recorded until Week 4, and parameters of glucose and lipid metabolism were measured on Week 12. Additionally, under pair-feeding conditions, S-309309 (3 mg/kg, b.i.d.) was orally administered to DIO mice for 6 weeks with recording daily body weight. Energy expenditure was measured during the first 7 days of S-309309 treatment, and gene expression analysis was performed 4 days after the treatment.
Results: S-309309 suppressed food intake and body weight gain in DIO mice over the course of the study. DIO mice treated with S-309309 also showed decreases in insulin resistance index, hepatic triglycerides content, plasma alanine aminotransferase and aspartate aminotransferase level, and gene expression related to fibrosis. Furthermore, S-309309 suppressed body weight gain under pair-feeding conditions with enhanced energy expenditure and upregulation of intestinal gene expression related to long-chain fatty acid beta oxidation.
Conclusion: S-309309 enhanced beta oxidation in the intestine and increased energy expenditure in DIO mice. Also, S-309309 improved insulin sensitivity and fatty liver. Taken together, these results suggest that S-309309 may be a promising anti-obesity drug that improves metabolism with multiple mechanisms of action.

Disclosure
R. Yoshiki: None. K. Takemoto: None. T. Morinaga: None. H. Tanioka: Employee; Shionogi & Co., Ltd. T. Sonoyama: Employee; Shionogi & Co., Ltd. Stock/Shareholder; Shionogi & Co., Ltd. H. Kato: None.
1655-P: Multiomics Analysis of Sarcopenic Obesity
Authors: OKAMURA TAKURO , HASEGAWA YUKA , SENMARU TAKAFUMI , HAMAGUCHI MASAHIDE , FUKUI MICHIAKI 
Published: June 2024

Background: Sarcopenic obesity is a critical characteristic of type 2 diabetes. This study aimed to investigate its pathological basis using integrated omics and db/db/mice, a model representing this condition.
Methods: The study involved housing 8-week-old db/m and db/db/mice for 8 weeks. Various analyses were conducted, including gene expression in skeletal muscle and small intestine using next-generation sequencing, cytokine arrays of serum, assessment of metabolites in skeletal muscle, stool, and serum, and analysis of the gut microbiota. Histone modifications in small intestinal epithelial cells were profiled using CUT&Tag.
Results: db/db/mice exhibited significantly lower grip strength and higher visceral fat weight (p &lt; 0.0001). Serum cytokine arrays demonstrated higher relative concentrations of VEGF-A (p &lt; 0.0001) and lower concentrations of several other cytokines in db/db/mice. Moreover, mRNA sequencing revealed downregulation of Myh expression in skeletal muscle and upregulation of lipid and glucose transporters and downregulation of amino acid transporter in the small intestine of db/db/mice. The concentrations of saturated fatty acids in skeletal muscle were significantly higher, and the levels of essential amino acids were lower in db/db/mice. Gut microbiota analysis showed lower levels of Bacteroidetes and higher levels of Firmicutes in db/db/mice (p = 0.003). The integrated signal of histone modifications of lipid and glucose transporters was higher, while the integrated signal of histone modifications of amino acid transporter was lower in the db/db/mice.
Conclusion: The multi-omics approach provided insights into the epigenomic alterations in the small intestine, suggesting their involvement in the pathogenesis of sarcopenic obesity induced by overeating and inactivity.

Disclosure
T. Okamura: Research Support; The Japan Diabetes Society, Suzuken Memorial Foundation, Nakatomi Foundation, Public Promoting Association Asano Foundation for Studies on Medicine, Uehara Memorial Foundation, Yakult Bio-Science Foundation, Japan Diabetes Foundation, Grants-in-Aid for Scientific Research. Y. Hasegawa: None. T. Senmaru: None. M. Hamaguchi: None. M. Fukui: None.