bluuebunny/crossref_metadata_2025_split huggingface dataset:
1678-P: B6-Alms1-del Mice, a Metabolic Syndrome Animal Model, Shows Semaglutide Benefits on Obesity, Hyperglycemia, and NAFL
Authors: CHEN ZHONG , GAO MAOMAO , ZHAO XINYUE , LI ZHIYING , ZHAO JING , JU CUNXIANG , GAO XIANG 
Published: June 2023

Metabolic syndrome is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and type 2 diabetes. These conditions include obesity, hyperglycemia, hypertension, hyperlipidemia. Leptin and leptin receptor mutant mice, ob/ob and db/db, are two classic metabolic syndrome animal model. However, the transient hyperglycemia of ob/ob and severe hyperglycemia induced premature death of db/db limit the application of these two models. To fill the gap, GemPharmatech developed a metabolic disorder model based on the mutation of Alms1 gene in mice (B6-Alms1-del mice). B6-Alms1-del mice gradually developed obesity from 8 weeks old with chow diet, accompanied by hyperglycemia, glucose and insulin intolerance, dyslipidemia and impaired liver function. Moreover, B6-Alms1-del mice developed severe non alcoholic fatty liver spontaneously as early as 21 weeks old and no premature death was observed around 5~8 months of ages. As B6-Alms1-del mice copied major features of metabolic syndrome, we further tested whether B6-Alms1-del mice could response to the positive drug semaglutide, an agonist of GLP-1R. 16 weeks old B6-Alms1-del mice were treated with vehicle and semaglutide for 5 weeks, respectively. Our results indicate that semaglutide lead to benefit on metabolic syndrome, including body weight control, improvement in hyperglycemia, hyperlipidemia, liver injury and hepatic steatosis. In conclusion, we have established a metabolic syndrome animal model that develop clinically relevant metabolic phenotypes and overcome the limitation of ob/ob and db/db. Furthermore, B6-Alms1-del mice responds to the approval anti-obesity drug semaglutide, which provide a useful model to assess the efficacy of novel metabolic syndrome therapies.

Disclosure
Z.Chen: None. M.Gao: None. X.Zhao: None. Z.Li: None. J.Zhao: None. C.Ju: None. X.Gao: None.
1682-P: Identification of Peridroplet Mitochondria in White Adipocyte
Authors: FUWA MASAYUKI , ASANO MOTOCHIKA , MORI ICHIRO , MORITA HIROYUKI , KAJITA KAZUO , ISHIZUKA TATSUO 
Published: June 2023

Mitochondria play various roles for biological maintenance in adipocytes. As for lipid metabolism, mitochondria have the opposite function of burning fatty acid by β-oxidation and supplying triglyceride (TAG) to lipid droplet. Recent study revealed that brown adipocytes (BA) contain cytoplasmic mitochondria (CM), which have high β-oxidation ability, and peridroplet mitochondria (PDM), which adhere lipid droplet, have high ability to generate ATP to synthesize and supply TAG to lipid droplet. On the other hand, Mitofusin 2 (Mfn2) and Mitoguardin 2 (MIGA2), and diacylglycerol acyltransferase 2 (DGAT2) are speculated to involved in interaction between mitochondria, endoplasmic reticulum and lipid droplet to promote TAG synthesis and expansion of lipid droplet. However, little is known about such mitochondrial fractions in white adipocytes (WA). In this study, we investigated whether WA isolated from mice adipose tissue may have mitochondria fractions corresponding to CM/PDM in BA. Cytoplasmic mitochondria and peridroplet mitochondria in WA (CMw/PDMw) were separated by centrifugation. Mitochondrial DNA, mitochondrial protein, incorporation of MitoTracker Red, and citrate synthase activity were detected in PDMw, as well as CMw. Electron microscopy showed larger size of mitochondria were observed in PDMw, than in CMw. Immunoblot analysis showed that Perilipin (Plin) 1 and Plin3 were detected in PDMw, but not in CMw. In addition, MIGA2 was detected in both CMw and PDMw, whereas Mfn2 and DGAT2 in PDMw. Immunoprecipitation study revealed that co-precipitation of Plin1/3 and MIGA2/Mfn2/DGAT2 was observed in the PDMw fraction. Our data indicated that mitochondria adhering lipid droplet was detected, which bind to Plin1/3. Moreover, the immunoprecipitation study suggested that mitochondria in the PDMw fraction may support TAG synthesis and expansion of lipid droplet. These results suggested that CMw and PDMw might play different roles in lipid metabolism in WA.

Disclosure
M.Fuwa: None. M.Asano: None. I.Mori: None. H.Morita: None. K.Kajita: None. T.Ishizuka: None.
1684-P: Transgene Integration-Induced Genomic Rearrangement in a Noncoding Region of Chromosome 1 Leads to Spontaneous Obesity and Type 2 Diabetes in Mice
Authors: WHITE DONNELL , WU JIAN , KANG SUNGWOOK , LAUTERBOECK LOTHAR , MOBASHERAN PARNIA , PALIARIN FRANCIELY , NGUYEN TINA , ELGAZZAZ MONA , MAIYA RAJANI , ALAHARI SURESH , LAZARTIGUES ERIC D. , YANG QINGLIN 
Published: June 2023

Obesity is a critical risk factor for type 2 diabetes (T2D) and has become a global health issue. We found that a mouse line (C57/B6J) of Floxed-stop over expression of IF1 (ATPase Inhibitory Factor 1) (hereon called FEI) develops spontaneous obesity without induction of transgenic expression. Targeted-Locus-Amplification (TLA) analyses revealed a rearrangement in upstream sequences of the transgene integration site, and a duplication downstream in a non-coding region of chromosome 1. Male and female FEI mice show early dyslipidemia before weight gain at two months, reaching 50-60 grams at 6-8 months. Body composition revealed FEI mice have markedly increased fat mass and modestly increased lean mass, consistent with morphometric findings of substantially increased peripheral fat pads. FEI mice were hyperphagic. When subjected to pair-feeding, they reverted to comparable WT body weight levels, then gained weight again when fed ad libidum. Adult FEI mice maintain comparable physical activity levels to their WT counterparts, but indirect metabolic levels among FEI mice declined. These mice exhibited glucose and insulin tolerance at six weeks of age, as well as hyperglycemia, hyper-insulinemia, and hyper-leptinemia. Histology H&E staining revealed markedly enlarged adipocytes with crown-like structures on visceral white adipose tissue sections, and increased fat deposition in liver sections. RNAseq analyses from subcutaneous white adipose tissues of 5-month-old FEI mice demonstrate upregulation of adipogenic and inflammatory genes. Isolated FEI preadipocytes exhibited increased proliferation but impaired lipid deposition. RT-PCR revealed upregulation of inflammatory genes (IFI202b, TNF-α, and IL6). Together, we show FEI mice are a novel obese mouse model. Preclinical studies using this model may help yield insights into novel pathogenic mechanisms and effective treatments for obesity.

Disclosure
D.White: None. S.Alahari: None. E.D.Lazartigues: None. Q.Yang: None. J.Wu: None. S.Kang: None. L.Lauterboeck: None. P.Mobasheran: None. F.Paliarin: None. T.Nguyen: None. M.Elgazzaz: None. R.Maiya: None.

Funding
American Diabetes Association (1-17-IBS-184 to Q.Y.)
1685-P: Comparison of Obesity and Aging Signatures in Murine Adipose Tissue at Single-Cell Resolution
Authors: LEE ERIES , KANG DU-SEOCK , MYOUNG SUH JAE 
Published: June 2023

Obesity and aging are major risk factors for various diseases and thus represent heavy socioeconomic burden to global healthcare. The two processes share similar, if not convergent, phenotypes, and increasing evidence suggests that one accelerates the other. Both obesity and aging are associated with insulin resistance, chronic low-grade inflammation and dysfunction of systemic energy homeostasis. However, there are many differences as well and the molecular mechanisms behind such similarities and differences remain unclear. Dysfunction of adipose tissue plays a significant role in both processes. Many studies have characterized adipose tissue of lean and obese mice at single-cell level, but obese and aged adipose tissue have not been directly compared side-by-side. Here, we compare single-cell transcriptomics of visceral (VAT) and subcutaneous (SAT) white adipose tissue in lean, diet-induced obesity, and aged conditions. In obese VAT, the relative frequency of macrophages increased, while that of lymphocytes decreased as expected. However, such myeloid shift was not observed in aged VAT. Metabolically, TREM2+ “lipid-associated macrophages”, which is known to increase in obese VAT, did not increase in aged VAT. Clustering of mesenchymal progenitor cells revealed depot-specific differences in previously reported cell subtypes. More cells were in a further differentiated, committed stage in VAT than in SAT. CD142+ CLEC11A+ “Aregs,” which were previously found to inhibit adipogenesis, increased in aged VAT and obese SAT. Interestingly, the frequency of endothelial cells in obese or aged state drastically decreased in SAT but not in VAT. Our comparative single-cell transcriptome atlas provides a detailed resource to analyze functional genomics behind obesity and aging.

Disclosure
E.Lee: None. D.Kang: None. J.Suh: None.
1688-P: Glucokinase Activator Triggers PERK-UPR Pathway in Diet-Induced Obese Mice via Inducing Hepatic Lipid Accumulation
Authors: CAI NAN , CHEN XUANRONG , LIU JIA , WEN ZHEYAO , WEN SIYING , ZENG WEN , LIN SHUO , CHEN YANMING , SHI GUOJUN , ZENG LONGYI 
Published: June 2023

Background: To investigate the effect of glucokinase activation on glucose and lipid metabolism in diet-induced obese mice.
Methods: Mice fed with High-fat-diet (HFD) or control diet for 16 weeks were subjected to glucokinase activator (GKA) or vehicle treatment by gavage for 4 weeks. Glucose tolerance tests were performed to evaluate the glucose-lowering effect of GKA. Hepatic lipid accumulation was assessed by H&E, Oil-red’O staining, and transmission electronic microscopy. The underlying mechanism and subsequent effects of glucokinase activation-induced lipid accumulation was analyzed in liver. Protein levels of related genes were analyzed in mouse livers or AML12 cells.
Results: Glucokinase activation improved glucose tolerance and insulin sensitivity in obese mice. Moreover, increased liver weight and TG Content were found in GKA-treated obese mice. Significant hepatic lipid accumulation was observed by multiple assays. RNA sequencing analysis indicated the increased expression of lipogenesis genes and activated PERK-UPR pathway in the liver. Inhibition of the lipogenesis-related gene Acc reduced the lipid levels caused by GKA treatment and alleviated PERK-UPR pathway in AML12 cell line.
Conclusions: Glucokinase activation improved glucose tolerance while induced hepatic lipid accumulation through increased lipogenesis, which subsequently triggered PERK-UPR signaling pathway.

Disclosure
N.Cai: None. L.Zeng: None. X.Chen: None. J.Liu: None. Z.Wen: None. S.Wen: None. W.Zeng: None. S.Lin: None. Y.Chen: None. G.Shi: None.

Funding
National Natural Science Foundation of China (81770826, 82070811); National Key R&D Program of China (2017YFA0105803); Key Area R&D Program of Guangdong Province (2019B020227003); Sci-Tech Research Development Program of Guangzhou City (202201020497); Natural Science Foundation of Guangdong Province (2018B030311012)
1690-P: Adipose Tissue Dectin-1 Upregulation in Hyperglycemic Obesity Involves TNF-α/NF-kB Mediated Signaling
Authors: AL MADHOUN ASHRAF , HADDAD DANIA , KOCHUMON SHIHAB P. , ALRASHED FATEMA , THOMAS REEBY S. , MIRANDA LAVINA P. , SINDHU SARDAR T.A.K. , AHMAD RASHEED , ALMULLA FAHD 
Published: June 2023

Dectin-1 is a pathogen recognition receptor as well as an innate immune response modulator; its function in metabolic disorders is yet unclear. Previously, we identified dectin-1 as a biomarker of metabolic inflammation in obesity. In this study, we sought to identify potential signaling pathways that could modify the expression of the dectin-1 gene and assess the expression of dectin-1 in the adipose tissue (AT) of obese patients based on their diabetic status. The study cohort included 95 obese individuals split into two groups: prediabetics with moderate glycemia (Hb1Ac 6.5%, n = 49) and diabetics with hyperglycemia (Hb1Ac 6.5%, n = 46). Dectin-1 expression was assessed using immunohistochemistry. Gene expression and inflammatory markers were determined via qRT-PCR. We found a significant positive correlation between dectin-1 expression and HbA1C levels in AT isolated from obese individuals with HbA1C levels of 6.5% or higher. Dectin-1 gene expression was significantly correlated with several inflammatory markers; however, glycemic-dependent associations were also observed. Dectin-1 and TNF-α were found to be significantly correlated in AT from individuals with Hb1Ac 6.5%, indicating a possible mechanism of gene regulation between these two factors. As a result, we investigated the observed dectin-1/TNF-α crosstalk using in vitro cell culture and animal studies. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of dectin-1 gene and protein expression in their AT, which were restored by injecting exogenous TNF-α. ChIP studies showed that TNF-α induced dectin-1 gene transcription by mediating NF-kB binding to newly identified regulatory elements located in the dectin-1 proximal regulatory region. The interplay between dectin-1 and TNF-α signaling pathways is intriguing and has the potential to be a therapeutic target in obesity and diabetes. Furthermore, dectin-1 could be a potential marker for the onset of hyperglycemia and diabetes.

Disclosure
A.Al madhoun: None. D.Haddad: None. S.P.Kochumon: None. F.Alrashed: None. R.S.Thomas: None. L.P.Miranda: None. S.T.K.Sindhu: None. R.Ahmad: None. F.Almulla: None.
1691-P: Weight Status, Longitudinal Weight Change, and Weight Loss Treatment Utilization among Primary Care Patients with Obesity
Authors: GRIAUZDE DINA H. , RICHARDSON CAROLINE R. , LEE JOYCE M. , HENDERSON JAMES , EHLERS ANNE P. 
Published: June 2023

Background: Effective weight management treatments (WMTs) include nutrition counseling, very low-calorie (VLC) meal replacement, anti-obesity medications (AOMs), and bariatric surgery. Little is known about how these WMTs influence weight change among individual primary care patients and populations.
Methods: This was a retrospective cohort study using medical record data from one academic health system. Participants were adults with primary care between October 2015 and March 2020. We used serial cross-sections to examine obesity prevalence and WMT use. We used a multistate model to investigate weight trajectories for patients with obesity and no WMT use prior to baseline. This is a time-to-event model with events representing transitions between 5 successive categories of weight change relative to baseline (i.e., ≥10% weight loss, 5-10% weight loss, baseline weight +/-5%, 5-10% weight gain, or ≥10% weight gain). The primary exposures were WMTs; controls were baseline age, BMI, and prior year primary care. Patients with WMT use were propensity matched 1:1 to controls. The primary outcome was the model-based probability of ≥5% weight loss at 1 year.
Results: Among primary patients, the prevalence of obesity increased from 39.2% in 2017 to 40.7% in 2019 (n=138,632); WMT use increased from 2.8% to 8.9% (difference: 6.1%, 95% CI: 5.8-6.4%). In the multistate model (n=10,296), the one-year probability of ≥5% weight loss among patients without WMT exposure was 15.5% [95% CI: 14.8-16.1%]. In contrast, ≥5% weight loss was more likely for patients with year-long exposures to any WMT (nutrition counseling: 23.4%, 95% CI: 21.5-25.3%; VLC meal replacement: 56.4%, 95% CI: 48.7-62.8%; AOMs: 27.8%, 95% CI: 25.1-30.5%; bariatric surgery: 94.4%, 95% CI: 91.1-96.4%).
Conclusions: Use of all WMTs increased the probability of achieving ≥5% weight loss at the individual-patient level but underutilization limits their ability to reduce weight at the population-level.

Disclosure
D.H.Griauzde: None. C.R.Richardson: Other Relationship; Annals of Family Medicine, JMIR Diabetes, Research Support; Dexcom, Inc., Blue Cross Blue Shield of Michigan, Neilson Foundation. J.M.Lee: Advisory Panel; GoodRx, Consultant; Tandem Diabetes Care, Inc. J.Henderson: None. A.P.Ehlers: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK123416)
1695-P: On the Temporal Relationship between Telomere Length and Adiposity Levels
Authors: HSUEH WEN-CHI , LIN JUE , HANSON ROBERT L. 
Published: June 2023

Short telomere length (TL) has been found to be associated with obesity related traits. However, most studies were cross-sectional in nature and conducted in adult subjects only. We aimed at examining the temporal relationship between telomere length and adiposity levels, measured by BMI, in both adults and youth. Our samples were selected from a population-based prospective cohort study in Southwest Amerindians who are at high risk for metabolic disorders. We obtained TL measures at 2 time points &gt;10 years apart for 805 individuals who had concomitant BMI measures, and designated these as baseline and follow-up (f/u) exams; 1/3 were male and 1/3 were aged &lt;18 years at baseline The means (range) of TL (measured in SD units), age at baseline, BMI at baseline, and the f/u period were 4.8±1.0 (2.2-8.5) SD units, 24.6±10.3 (5-63) years, 31.7±7.9 (15-63) kg/m2, and 13.6±1.7 years (11-18.4 years), respectively. No significant sex difference was observed, and 48% of subjects had longer TL at f/u. TL at baseline in youth was 14% longer than that of adults on average (p&lt;E-4). There was no association between BMI at baseline and change in TL at f/u (β=-0.0036±0.0048 SD unit/kg*m-2, p=0.45 in the entire sample, similar results observed in adults or youth only), adjusted for effects of age, sex, ancestry, assay batches and the length of f/u. Longer TL at baseline had a modest association with lower change in BMI at f/u in youth (β=-2.89±1.47 kg*m-2/SD unit, p=0.050) but not in adults (β=0.96±0.96, p=0.32). In conclusion, our findings suggest that TL may be a risk factor for obesity, especially in younger people, but not the other way around. A larger study is underway to provide more robust estimates.

Disclosure
W.Hsueh: None. J.Lin: None. R.L.Hanson: None.

Funding
National Institutes of Health
1696-P: Changes in Clinical and Metabolic Parameters Related to NAFLD in Obese Subjects Who Underwent Laparoscopic Sleeve Gastrectomy
Authors: HO LEE DAE , BYUNG PARK IE 
Published: June 2023

More research is needed on the effect of laparoscopic sleeve gastrectomy (LSG) on NAFLD and related parameters. A total of 51 morbidly obese subjects with NAFLD who would undergo LSG were included, with liver biopsy performed during LSG in 46 patients. Various clinical parameters and blood biomarkers related to NAFLD were measured before and 6 months after LSG, which included fat content in the liver (LFC) and pancreas (PFC) by MRI-PDFF, liver stiffness measurement by MR elastography (MRE-LSM), and others. After LSG, there was a significant decrease in body weight and LFC: 102.0 ± 15.3 vs. 76.3 ± 14.3 kg and 19.4 ± 9.1% vs. 5.7 ± 2.9%, respectively, p &lt;0.001 each. And, body fat on DXA, PFC, and visceral fat area measured by MRI, and, fasting plasma levels of total GIP and glucagon decreased significantly after bariatric surgery, with no change in total GLP-1 and peptide YY levels. Notably, there was a marked increase in plasma levels of FGF21 (547.1 ± 890.5 pg/ml vs. 1085 pg/ml ± 1883.75, p&lt;0.05) and oxyntomodulin (436.0 ± 351.4 pg/ml vs. 1533.6 ± 624.4 pg/ml, p&lt;0.001). These changes were accompanied by a significant reduction of NASH blood biomarkers such AKR1B10, cytokeratin 18, and complement C3. And, MRE-LSM, a marker of liver fibrosis, decreased significantly after LSG (3.1 ± 0.8 kPa vs. 2.7 ± 0.1 kPa, p &lt;0.01), but enhanced liver fibrosis score did not. Only 15.2% of patients with biopsy-proven NAFLD showed more than 25% decrease in MRE-LSM, and baseline fibrosis degree was only the predictor of this decrease in MRE-LSM after LSG. Our results show that in patients with morbid obesity, marked reduction of body weight and LFC and a significant increase in plasma FGF21 and oxyntomodulin levels were observed 6 months after LSG, with the reduction of several markers of NASH. However, a meaningful MRE-LSM improvement was observed only in a small proportion of patients, which warrants long-term follow-up of patients with NASH/fibrosis who underwent LSG.

Disclosure
D.Lee: None. I.Park: None.

Funding
National Research Foundation of Korea (2021R1A5A2030333, 2019R1I1A2A02062305)
1699-P: Association between Insulin Resistance and Myosteatosis Measured by Abdominal Computed Tomography
Authors: JIN KIM MYUNG , KYUNG CHO YUN , NA JUNG HAN , HEE JUNG CHANG , CHUL WON JONG , PARK JOONG-YEOL , KIM HONG-KYU , JE LEE WOO 
Published: June 2023

Background: Ectopic fat deposition in skeletal muscle, termed myosteatosis, is a key factor in developing insulin resistance. We aimed to evaluate the association between insulin resistance and myosteatosis in a large Asian population.
Methods: A total of 18,251 participants who had abdominal computed tomography from 2012 to 2013 were included. The total abdominal muscle area (TAMA) at the L3 vertebral level was segmented into normal-attenuation muscle area (NAMA), low-attenuation muscle area (LAMA), and intramuscular adipose tissue (IMAT). The ratios of NAMA/BMI, LAMA/BMI, and NAMA/TAMA were used as myosteatosis indices.
Results: NAMA/BMI and NAMA/TAMA index showed downward trends with higher HOMA-IR levels, while LAMA/BMI showed upward trends. As HOMA-IR levels increased, the odds ratios (ORs) of the highest quartile of NAMA/BMI and NAMA/TAMA index decreased and that of LAMA/BMI increased. Compared with the lowest HOMA-IR group, the adjusted ORs (95% confidence intervals [CI]) in the highest HOMA-IR group for the lowest NAMA/TAMA quartile were 0.414 (0.364-0.471) in males and 0.464 (0.384-0.562) in females. HOMA-IR showed a negative correlation with NAMA/TAMA index (r = -0.211 for men and r = -0.214 for women, p &lt;0.001 for both).
Conclusion: A higher HOMA-IR level was significantly associated with a high risk of myosteatosis.

Disclosure
M.Kim: None. Y.Cho: None. H.Jung: None. C.Jung: None. J.Won: None. J.Park: None. H.Kim: None. W.Lee: None.