bluuebunny/crossref_metadata_2025_split huggingface dataset:
1396-P: Critical Cellular Functions That Mediate the Early Stages of Adipogenesis Are Directly Influenced by 14-3-3zeta and Its Interactome
Authors: RIAL SABRI A. , ALKHOURY AMAL , LAVOIE GENEVIEVE , ROUX PHILIPPE , DURCAN THOMAS M. , MARTINEZ-SANCHEZ AIDA , LIM GARETH E. 
Published: May 2022

Aim: We previously discovered that 14-3-3-zeta (14-3-3ζ) was essential for adipocyte differentiation. Although 14-3-3ζ scaffold is not a transcription factor (TF) , it undergoes nuclear translocation during adipogenesis. Considering its diverse interactome, we hypothesized that 14-3-3ζ anchors, nucleates and regulates essential transcriptional complexes required for adipogenesis.
Methods: 3T3-L1 pre-adipocytes were modified by CRISPR-Cas9 to express a TAP (Flag-HA) -tagged 14-3-3ζ protein. At 48 first hours of adipogenesis, nuclear TAP-14-3-3-ζ complexes were purified to identify and annotate the 14-3-3ζ interactome by MS and Gene Ontology. Highly enriched proteins functions were assessed for their roles in adipogenesis using pharmacological inhibitors or siRNA. In parallel, chromatin accessibility was assessed by ATAC-Seq from control or 14-3-3ζ-depleted 3T3-L1 cells during early adipogenesis.
Results: We found that the 14-3-3ζ nuclear interactome during the early stages of adipogenesis was significantly enriched with 133 proteins, including CEBP-β, an early adipogenic TF. According to GO analysis, proteins within the 14-3-3ζ interactome were primarily associated (FDR ≤ 0.01) with histone H2B ubiquitination, DNA unwinding for replication, DNA hypermethylation and ribosome assembly. Pharmacological inhibition or depletion by siRNA of these proteins significantly dampened adipocyte differentiation. Principal component analysis of ATAC-seq results revealed that samples from 14-3-3ζ-depleted cells differed from controls in term of whole chromatin accessibility, and DESeq2 identified nearly 3400 (p&lt;0.05) differentially accessible regions of open chromatin following 14-3-3ζ depletion.
Conclusion: These results reveal that via critical protein interactions, 14-3-3ζ has essential roles in chromatin accessibility, DNA replication, and mRNA translation, which are crucial events for the early adipogenesis.

Disclosure
S.A.Rial: None. A.Alkhoury: None. G.Lavoie: None. P.Roux: None. T.M.Durcan: None. A.Martinez-sanchez: None. G.E.Lim: None.

Funding
Natural Sciences and Engineering Research Council of Canada (NSERC) ; Canada Research Chairs (CRC) ; Fonds de recherche du Québec-Nature and Technologies (FRQNT)
14-OR: Harmine and Exenatide Combination Increases Human ß-Cell Survival
Authors: ROSSELOT CAROLINA , LI YANSUI , GUEVARA DANIELA , BELIARD KARA A. , KANG RANDY , WANG PENG , THAKKAR KEYA , LU GEMING , DEVITA ROBERT J. , STEWART ANDREW F. , GARCIA-OCANA ADOLFO 
Published: May 2022

GLP1R agonists such as Exendin-4 (E) together with DYRK1A inhibitors such as Harmine (H) significantly increase human β-cell replication in vitro and in vivo. Importantly, 3-month treatment with H+E combination markedly increases human beta cell mass (∼7-fold) in islets transplanted in immunosuppressed mice, beyond the increase induced by proliferation. Therefore, we addressed whether H+E also enhances β-cell survival and that contributes to the increased human β-cell mass expansion in vivo. Treatment with H+E significantly decreased β-cell apoptosis in dispersed primary human islet cells treated in vitro with either thapsigargin (ER stress) , cytokines (inflammation) and H2O2 (ROS) , while the drugs alone or vehicle (V) did not induce such effect. Importantly, H+E treatment for 7 days significantly reduced β-cell apoptosis in human islet grafts transplanted in immunosuppressed mice assessed by insulin and TUNEL staining. Human β-cell mass analysis of these grafts by iDISCO+ revealed a significant ∼50% increase in H+E-treated mice compared with mice treated with drugs alone or V. Human α-cell mass was unchanged. To address the signaling pathways modulated by H+E after 7-day treatment, we performed RNA-seq analysis of these human islet grafts. We identified 29 differentially expressed human genes (&gt; 2-fold, p&lt;0.05) in H+E-treated human islet grafts. GSEA analysis revealed cell adhesion, survival, vascularization and secretion as the main pathways induced by H+E. Among the upregulated genes, VGF (VGF Nerve Growth Factor Inducible) is known to regulate insulin secretion and β-cell survival. We found that H+E treatment of human islets in vitro increases 2-to-3-fold VGF mRNA and secretion. We are now determining VGF involvement in H+E-induced human β-cell survival.
In conclusion, we have uncovered a novel prosurvival function of H+E in human β-cells with the potential implication of VGF in these effects. These studies can lead to the discovery of future β-cell protection and regeneration therapies for diabetes.

Disclosure
C.Rosselot: None. A.F.Stewart: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. Y.Li: None. D.Guevara: None. K.A.Beliard: None. R.Kang: None. P.Wang: None. K.Thakkar: None. G.Lu: None. R.J.Devita: None.

Funding
DYRK Inhibitors for Human Beta Cell Expansion RDK105015
1404-P: High Cardiorespiratory Fitness Exerts Metabolic Protection in Obese Rats Regardless of Caloric Restriction or Short-Term Exercise
Authors: THONUSIN CHANISA , PANTIYA PATCHARAPONG , CHATTIPAKORN SIRIPORN C. , CHATTIPAKORN NIPON 
Published: May 2022

Caloric restriction (CR) and exercise (EX) attenuate metabolic impairment in obesity. High cardiorespiratory fitness (CRF) also protects against metabolic syndrome. However, the interplay between CRF, obesity, CR, and EX on metabolic health remains unclear. Male rats were fed with either a normal diet (ND; n=6) or a high-fat diet (HFD; n=30) for 12 weeks. Baseline CRF was measured. Then, ND-fed rats received a ND for 16 more weeks. HFD-fed rats were divided into 5 groups (n=6/group) to receive either a HFD for 16 weeks (OB) , 40% CR for 6 weeks followed by an ad lib ND for weeks (CR-S) , 40% CR for 16 weeks (CR-L) , a HFD + an EX for 6 weeks followed by a ND without EX for weeks (EX-S) , or a HFD + an EX for 16 weeks (EX-L) . Then, anthropometry and blood metabolic parameters were evaluated. We found that CR and EX decreased insulin resistance and dyslipidemia in obesity. High baseline CRF was correlated with favorable anthropometry and metabolic profiles at follow-up in the ND, OB, CR-S, CR-L, and EX-S rats. However, these correlations were not shown in the EX-L rats (Figure) . Our findings suggested that high CRF also protects against metabolic impairment in obesity, regardless of CR or short-term EX. Hence, an enhancement of CRF may provide the better effective therapy for obesity. Otherwise, low-CRF people may get the greatest benefit on a protection against metabolic syndrome by long-term EX.

Disclosure
P. Pantiya: None. S.C. Chattipakorn: None. N. Chattipakorn: None.
1425-P: Effect of Ghrelin on Glucose Tolerance after Sleeve Gastrectomy
Authors: HEDBÄCK NORA , DICHMAN MARIE-LOUISE , DIRKSEN CARSTEN , BOJSEN-MOLLER KIRSTINE N. , JØRGENSEN NILS B. , HINDSØ MORTEN G. , KRISTIANSEN VIGGO B. , HOLST JENS J. , SVANE MARIA S. , MADSBAD STEN 
Published: May 2022

Introduction: Ghrelin is an appetite-stimulating peptide hormone secreted from the gastric mucosa in the fasting state that decreases in response to food intake. After sleeve gastrectomy (SG) , plasma levels of ghrelin decrease dramatically, whether this may influence glucose tolerance is unknown. We therefore investigated the effects of physiological ghrelin infusions on glucose tolerance in individuals with obesity before and after SG.
Methods: Nine morbidly obese individuals with normal glucose tolerance, scheduled for SG, were enrolled. Four-hour standard mixed-meal tests with concomitant patient-blinded infusions of either acyl-ghrelin (1 pmol/kg/min) or placebo (saline) were performed in randomized order before and 3 months after surgery. All values are mean ± SEM.
Results: Before SG, fasting plasma glucose was unaffected by ghrelin infusion, whereas both peak (7.93 ± 0.3 mmol/L versus 6.98 ± 0.2, p&lt;0.001) and total area under the curve (tAUC) of plasma glucose concentrations (1874 ± 61 mmol/L*min versus 1702 ± 42, p=0.03) increased significantly during ghrelin infusion versus placebo. After SG, fasting plasma glucose was again unaffected by ghrelin infusion, whereas peak of plasma glucose increased (8.65 ± 0.5 mmol/L versus 7.92 ± 0.3 mmol/L, p=0.04) and tAUC of plasma glucose tended to increase (1817 ± 73 mmol/L*min versus 1636 ± 44 mmol/l*min, p=0.054) during ghrelin infusions versus placebo. The increase in tAUC during ghrelin infusion versus placebo was 10% before surgery and 11% after SG (p=0.98) .
Conclusion: Ghrelin infusions increased postprandial plasma glucose concentrations in obese individuals both before and following SG, suggesting a role of ghrelin in the regulation of postprandial glucose metabolism. This response appears to be maintained following SG and the low levels of ghrelin after SG may thus contribute to the improved glucose control after the operation.

Disclosure
N.Hedbäck: None. S.Madsbad: None. M.Dichman: None. C.Dirksen: None. K.N.Bojsen-moller: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S. M.G.Hindsø: Research Support; Novo Nordisk Foundation. V.B.Kristiansen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M.S.Svane: None.

Funding
European Research Council (Grant 695069-BYPASSWITHOUTSURGERY) Novo Nordisk Foundation
143-LB: Hepatic Insulin Resistance Index (HIR-I) in Youth—Does Race/Ethnicity Matter?
Authors: CHO WONHEE , BACHA FIDA , TFAYLI HALA M. , LEE SOJUNG , MICHALISZYN SARA , KIM JOON YOUNG , ARSLANIAN SILVA A. 
Published: May 2022

Surrogate indices for insulin resistance of various insulin-responsive tissues are critical in epidemiological studies of youth at risk for developing type 2 diabetes (T2D) . Having established surrogate indices for peripheral insulin sensitivity (JCEM 2011; 96:2136) , we aimed to develop HIR-I in youth spanning from normal-weight (NW) to obese and from normal glucose tolerance to impaired glucose tolerance to T2D, and assessed potential race-related differences. A total of 287 youth (146 black, 141 white) had [6,6-2H2]glucose tracer-measured HIR (hepatic glucose production x fasting insulin [FI]) , lipids and DXA body composition. To develop HIR-I, multiple stepwise linear regression was performed with variables showing r &gt;0.2 with tracer-measured HIR (Diabetologia, 2011;54:540) in each race (Table) . In black youth, HIR-I was generated from (fasting glucose [FG], FI, fat mass and VLDL) while in whites from (FG, FI and BMI) (Figure) . HIR-I correlated with tracer-measured HIR in blacks (r=0.915) and whites (r=0.923, both p&lt;0.001) (Figure) . In both black and white youth, HIR-I was lowest in NW and highest in T2D (Figure) .
In conclusion, different physical and laboratory biomarkers contribute to race-specific formulas of HIR-I with strong correlations with tracer-measured HIR in both. Race-specific HIR-I and its change across the gamut of glycemia may shed light in epidemiological studies of the development of youth T2D.

Disclosure
W. Cho: None. F. Bacha: Other Relationship; AstraZeneca, Takeda Pharmaceutical Company Limited, Research Support; National Institute of Diabetes and Digestive and Kidney Diseases, U. S. Department of Agriculture. H. M. Tfayli: Advisory Panel; Novo Nordisk, Research Support; Novartis Pharmaceuticals Corporation, Sanofi. S. Lee: None. S. Michaliszyn: None. J. Kim: n/a. S. A. Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Other Relationship; AstraZeneca, Research Support; Eli Lilly and Company, Novo Nordisk.

Funding
American Diabetes Association (7-08-JF-27) , National Institute of Child Health and Human Development grants (K24-HD01357, R01-HD27503) , National Center for Advancing Translational Sciences Clinical and Translational Science Award (UL1TR000005) , National Center for Research Resources grant (UL1RR024153) , National Institute of Diabetes and Digestive and Kidney Diseases (R21DK083654-01A1)
1431-P: Development of a New Index Based on Preoperative Serum Lipocalin 2 to Predict Post-LSG Weight Reduction
Authors: LI NANNAN , XU BEI , ZENG JIANGPING , LEI SHIHUI , GU LEI , FENG LIJIN , ZHU BING , HUANG YUEYE , WANG LU , SU LILI , QU SHEN , CHENG XIAOYUN , BU LE 
Published: May 2022

Background: Bariatric surgery is the most effective therapy for obesity, but targeted weight reduction is not always achieved. Serum lipocalin-2 (LCN2) is closely associated with obesity, but its impact on weight loss after surgery is unknown. We aimed to access the reliability of LCN2 levels and other parameters as effective predictors of excellent weight loss (≥75% excess weight loss [EWL]) 1 year after bariatric surgery.
Methods: This retrospective study evaluated 450 patients (aged 18-65 years) with obesity at 3 months and 1 year after laparoscopic sleeve gastrectomy (LSG) surgery. Seventy-four patients who underwent LSG surgery and met the inclusion and exclusion criteria were included in this study. Serum LCN2, thyroid function, and metabolic and anthropometric parameters were assessed. Weight reduction was expressed as %EWL and percent total weight loss (%TWL) at 3 months and 1 year post surgery. Multivariable logistic regression analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate predictors of ≥75%EWL.
Results: In our cohort, %EWL and %TWL were both strongly associated with preoperative serum LCN2 levels. The binary logistic regression analysis showed that preoperative LCN2, waist circumference, and glycated hemoglobin were independent predictors of excellent weight loss.
Conclusions: Based on these results, we determined a new P index with better predictive value for excellent weight reduction (≥75%EWL) 1 year after LSG surgery.

Disclosure
N.Li: None. L.Su: None. S.Qu: n/a. X.Cheng: n/a. L.Bu: None. B.Xu: None. J.Zeng: None. S.Lei: None. L.Gu: None. L.Feng: None. B.Zhu: None. Y.Huang: n/a. L.Wang: None.

Funding
The Tranditional Medicine Project of Shanghai Municipal Health Commission (grant number 2020JP013) ; Shanghai Natural Science Foundation (grant number 21ZR1449400) ; Shanghai Pujiang Talent Plan (grant number 18PJD038)
1432-P: ALT Elevation Suggestive of NAFLD in Overweight and Obese Youth on Second-Generation Antipsychotics
Authors: CRIMMINS NANCY A. , MOUZAKI MARIALENA , DELBELLO MELISSA P. , CORRELL CHRISTOPH , WELGE JEFFREY 
Published: May 2022

Second-generation antipsychotics (SGAs) increase risk for insulin resistance and metabolic syndrome. Less is known about the risk of nonalcoholic fatty liver disease (NAFLD) in youth treated with SGAs. MOBILITY is a large, multi-center, pragmatic study designed to assess the effect of metformin added to lifestyle instruction compared to lifestyle instruction alone on weight gain and metabolic parameters in youth with overweight and obesity (ages 8-19) and bipolar-spectrum disorders receiving SGAs. We examined baseline ALT as a marker for NAFLD in 840 youth in the study (78% with obesity; 46% female; 68% white; 17% black; 11% Hispanic) . Overall, 44% of subjects had mild ALT elevation (ALT&gt;22 females; ALT&gt;25 males) , and 10% had significantly elevated ALT≥ 45 (2× ULN) . Male sex (p&lt;0.001) , obesity (p=0.007) , and white race (p=0.009) were significantly associated with ALT elevation. Hispanic ethnicity and age were not significantly associated with ALT elevation. There was no difference in duration of exposure to SGAs (&lt; 1 year vs. &gt; 1 year of exposure) . There was a trend towards an association between prediabetes and significant ALT elevation (2× ULN; p=0.06) ; however, glucose was not associated with ALT elevation overall. Although we had no imaging or biopsy data in these patients, our study demonstrates that a clinically relevant percentage of youth with overweight and obesity treated with SGAs have elevated ALT suggestive of NAFLD; in fact, the prevalence of elevated ALT is higher than expected with obesity alone. Given that NAFLD is the most common liver disease now in youth and can progress to cirrhosis and liver failure, our findings suggest that pediatric psychiatrists who treat these patients must screen for NAFLD with ALT and refer patients for further evaluation and management as needed.

Disclosure
N.A.Crimmins: None. M.Mouzaki: None. M.P.Delbello: Board Member; Sage Pharmaceuticals, Consultant; Alkermes, Sunovion Pharmaceuticals Inc., Research Support; Alkermes, Johnson & Johnson, Lundbeck, Shire plc., Speaker's Bureau; Sunovion Pharmaceuticals Inc. C.Correll: Consultant; Alkermes, Janssen Pharmaceuticals, Inc., Lundbeck, Medscape, Mylan N.V., Neurocrine Biosciences, Inc., Otsuka America Pharmaceutical, Inc., Sunovion Pharmaceuticals Inc., Takeda Pharmaceutical Company Limited, Teva Pharmaceutical Industries Ltd. J.Welge: None.

Funding
Mobility: Improving Patient-Centered Outcomes Among Overweight and Obese Youth with Bipolar Spectrum Disorders Treated with Second-Generation Antipsychotics. [PICORI (Delbello) ].
1438-P: Association between Screen Time, Including That for Smartphones, and Overweight/Obesity among Children in Japan
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , MORIKAWA SAKIKO Y. , TAKEDA YASUNAGA , ISHIGURO HAJIME , YAMADA MAYUKO H. , HORIKAWA CHIKA , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , OGAWA YOHEI , SONE HIROHITO 
Published: May 2022

The association between screen time (ST) , including that for smartphones, and overweight/obesity (OW/OB) in children was examined separately for boys and girls, considering the influence of lifestyle factors including diet, physical activity, and sleep time. A cross-sectional study was conducted in 2242 Japanese children (1278 girls) aged 10-14 years. OW/OB was defined by the International Obesity Task Force. Logistic regression analysis showed that only for girls, total ST (≥4h) , smartphone ST (≥3h) and non-smartphone ST (≥2h) were all independently and significantly associated with overweight/obesity compared to &lt;2h total ST, non-use of smartphones, and &lt;1h non-smartphone ST. In girls with total ST ≥5h or &lt;4h or smartphone ST &lt;2h, the association between ST and OW/OB was not affected by physical activity or sleep time. On the other hand, when total ST was 4-5h or smartphone ST was ≥2h, the significant association with OW/OB disappeared when physical activity was ≥60 min/day and sleep time was ≥8.5h. In addition, none of these associations were significant in boys.
In Japanese girls, smartphone ST, non-smartphone ST, and total ST were all significantly associated with OW/OB. To avoid OW/OB, it is suggested to keep smartphone ST, non-smartphone ST, and total ST to &lt;3h, &lt;2h, and &lt;4h, respectively, and to engage in sufficient physical activity and sleep time.

Disclosure
K. Fujihara: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. C. Horikawa: None. Y. Ogawa: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited.
1443-P: Real-Time In Vivo Analysis of Beta-Cell Autophagy in Autoimmune Diabetes
Authors: MELNYK OLHA , MURALIDHARAN CHARANYA , IRIZARRY MICHELLE M. MARTINEZ , CROWDER JUSTIN , LINNEMANN AMELIA K. 
Published: May 2022

Type 1 Diabetes (T1D) is an autoimmune disease caused by a combination of genetic and environmental factors. The onset of disease is associated with autoimmune attack against pancreatic beta-cells leading to a reduction of their number. While a role for the beta-cell in these events is widely hypothesized, a complete understanding of disease pathogenesis is still lacking. Our group recently found that beta-cell autophagy is defective in the context of human T1D as well as in the non-obese diabetic (NOD) mouse model of autoimmune diabetes. Importantly, our data suggested that defective autophagy is present prior to the onset of diabetes but stopped short of definitively demonstrating pre-existing defects. Therefore, here we evaluated autophagic flux in the pancreatic beta-cells of live mice using a fluorescent biosensor coupled to intravital microscopy. A custom beta-cell-selective autophagy biosensor (AAV8-INS-mCherry-EGFP-LC3B) was intraperitoneally (IP) injected into 7-week-old mice of three strains: wild type C57Bl/6J, NOD and NOD scid gamma (NSG) mice. Three weeks after biosensor injections, mice were placed under inhaled isoflurane anesthesia, then externalized pancreata were imaged using a LEICA SP8 DIVE two-photon microscope mounted with a 40x/1.1NA water objective. To evaluate autophagic flux, we assessed fluorescent signal over time in response to IP infusion of either saline or chloroquine, an autophagy inhibitor. Autophagic flux was assessed by quantifying the rate of change of the ph-sensitive GFP and the ph-insensitive RFP, as well as signal colocalization. In wild type mice, we observed clear evidence of autophagic flux over time that was altered in the presence of chloroquine. However, in contrast, in pre-diabetic NOD mice, islet autophagic flux did not respond effectively to chloroquine treatment. Collectively, these data support the conclusion that autophagy defects precede hyperglycemia and suggest a potential role for these defects in beta cell demise during T1D pathogenesis.

Disclosure
O.Melnyk: None. C.Muralidharan: None. M.M.Martinez irizarry: None. J.Crowder: None. A.K.Linnemann: Consultant; Janssen Research & Development, LLC.

Funding
National Institutes of Health (R01DK124380) . Startup funds to AKL from the Herman B Wells Center for Pediatric Research at Indiana University School of Medicine
1463-P: Steroidogenic Factor 1 in ß cells Moonlights as a Brake on Glucose Intolerance in Obesity
Authors: GUO YAN , LIU LIEHUA , LI YANBING 
Published: May 2022

Pancreatic β cells compensate with intense insulin secretion in obese individuals, failure of which marks a vital step in progression to type 2 diabetes (T2DM) . Steroidogenic factor-1 (SF-1) is a nuclear receptor which also locates in non-steroidogenic tissues and participates in metabolic regulation. Through immunofluorescence conducted on the pancreas of obese mice, we detected SF1 in the β cells which was surprisingly absent in that of diabetic mice. Genetic deletion of SF1 in β cells predisposed mice to glucose intolerance upon high fat diet (HFD) by perturbing glucose-stimulated insulin secretion (GSIS) , while its ectopic expression by adeno-associated virus (AAV) improved GSIS. Furthermore, we illustrated that mitochondrial improvement may be the underlying mechanism via experiments such as oxygen consumption rate (OCR) , calcium detection and bioinformatics.
In conclusion, SF1 played an important role in β-cell adaptation to lipotoxicity in the obese individuals, which supported SF1 as a potential target for T2DM treatment.

Disclosure
Y.Guo: None. L.Liu: None. Y.Li: None.

Funding
This work was supported by National Key Research and Development Program of China (no. 2018YFC1314100) awarded to L.-Y.B.; National Natural Science Foundation of China (no. 81870557) awarded to L.-Y.B.; Key Field Research and Development Program of Guangdong Province, China (no. 2019B020230001) awarded to L.-Y.B.; Natural Science Foundation of Guangdong Province (no. 2016A030313239 and 2014A030313018) awarded to W.-X.S.; Guangdong Basic and Applied Basic Research Foundation (no. 2020A1515010049) awarded to L.H.; and Graduate Innovative Development Program (no. 19ykyjs08) awarded to G.Y