bluuebunny/crossref_metadata_2025_split huggingface dataset:
1937-P: ALK-7: A Validated Target for the Treatment of Obesity
Authors: BU YUN , ZHAO MIN , FREDERICKS MAUREEN , CANNELL MARISHKA , DAGON YOSSI , EMDIN CONNOR A. , OKUNISHI KATSUHIDE , WANG HAO , SAKO DIANNE , CASTONGUAY ROSELYNE , SURAGANI RAJASEKHAR N.V. , KATHIRESAN SEKAR , GRINBERG ASYA , KNOPF JOHN , PEARSALL ROBERT S. , KUMAR RAVINDRA , IZUMI TETSURO 
Published: June 2020

Genetic variation in the ACVR1C gene has been reported to be associated with decreased waist-to-hip ratio and risk of type 2 diabetes in humans. However, the effect of this naturally occurring variation on ALK7 function is unclear. Here we show that the human ACVR1C variant I195T, which displays the greatest effect on waist-to-hip ratio adjusted for body mass index, fails to signal in response to ALK7 ligands in a cell-based assay. This is consistent with observations in mice that impaired ALK7 signaling increases lipolysis and decreases adiposity. As further validation of ALK7 as an obesity target, we present data showing in the naturally occurring polygenic obese TSOD mouse a specific high affinity neutralizing monoclonal anti-ALK7 antibody (ALK7 mAb) dramatically decreases leptin levels, adipose macrophages and adiposity. The specificity of the ALK7 mAb is demonstrated by its lack of effect in genetically deficient ALK7 mice. These data along with the knowledge that normal Balb/c mice harbor a homozygous ALK7 nonsense mutation suggests that targeting ALK7 in humans should decrease obesity, susceptibility to diabetes and have minimal on-target negative consequences.

Disclosure
Y. Bu: None. M. Zhao: None. M. Fredericks: None. M. Cannell: None. Y. Dagon: None. C.A. Emdin: None. K. Okunishi: None. H. Wang: None. D. Sako: None. R. Castonguay: Employee; Self; Acceleron Pharma. R.N.V. Suragani: None. S. Kathiresan: Advisory Panel; Self; Regeneron Genetics Center. Consultant; Self; Color Genomics, Corvia Medical, Inc., Medgenome, Pfizer Inc. Stock/Shareholder; Self; Catabasis Pharmaceuticals, Maze Therapeutics, San THerapeutics, Verve Therapeutics. A. Grinberg: None. J. Knopf: Stock/Shareholder; Self; Acceleron Phama. R.S. Pearsall: Employee; Self; Acceleron Pharma, Inc. Stock/Shareholder; Self; Acceleron Pharma, Inc. R. Kumar: Employee; Self; Acceleron Pharma. T. Izumi: Research Support; Self; Acceleron Pharma.
194-LB: T1D Exchange Registry: Current Data Insights and Future Impact
Authors: LAFERRIERE KELSIE , LIU JINGWEN , HUGHES ALLYSON , WOLF WENDY 
Published: June 2020

In a previous T1D Exchange led initiative, the T1D Exchange Clinic Registry encompassed 25,000 participants from 81 clinic sites across the U.S. who drove type 1 diabetes (T1D) research and produced real-world data on T1D. Upon the Clinic Registry’s closing, T1D Exchange launched the online T1D Exchange Registry in June of 2019 to lower barriers to research, increase participation, and strive to develop a more diverse population. The Registry is currently recruiting adults with T1D and parents/guardians of children who have T1D, living in the U.S. The Registry is a streamlined platform where participants enroll by completing screening questions, signing consent, and answering an initial questionnaire. Participants then complete an annual questionnaire to track health, disease management, and changes in outcomes over time. As of March 2020, there are over 5,300 participants enrolled in the Registry, with over 56% having completed their initial questionnaire. Currently, 10.9% of participants are between the ages of 1-17 years, 70.2% are between 18-55 years, and 18.9% are 56 years or above. This cohort represents a wide range of years since diagnosis, with 23.4% diagnosed within the past 5 years and 24.8% diagnosed more than 30 years ago. The majority identify as Caucasian (94.1%) and female (70.2%), with geographic representation from every U.S. state and territory. Among the pediatric cohort (&lt;18 years), 24% reported A1C below 7.0%, whereas 36.1% of adults between 18-55 years reported A1C below 7.0%; 77.8% of adults 56 years or above reported A1C lower than 7.5%. The Registry cohort appears to be more technology-skilled than other T1D cohorts reported in the U.S., with 77.0% of participants currently using a CGM, and 67.2% using an insulin pump. Future projects for the Registry include analyzing longitudinal data, linking device data, sharing clinical trial opportunities, and providing additional research opportunities to participants.

Disclosure
K. LaFerriere: None. J. Liu: None. A. Hughes: None. W. Wolf: None.

Funding
The Leona M. and Harry B. Helmsley Charitable Trust (G-2018PG-T1D074)
194-OR: Impaired Awareness of Hypoglycemia and Maternal/Neonatal Outcomes in the CONCEPTT Trial
Authors: BAHRAMI JASMINE , TOMLINSON GEORGE , MURPHY HELEN R. , FEIG DENICE 
Published: June 2020

Background: Patients with diabetes and impaired awareness of hypoglycemia (IAH) are at increased risk of severe hypoglycemia (SH). IAH is increased during pregnancy. To date, maternal and neonatal outcomes of pregnant women with hypoglycemia unawareness or SH has not been well described.
Aim: To examine maternal and neonatal outcomes in women with IAH compared to women with normal awareness of hypoglycemia (NAH).
Methods: We included 214 pregnant women with type 1 diabetes who participated in the CONCEPTT trial. Participants completed Hypoglycemia Fear Surveys (HFS-II) at baseline and study completion. Post-hoc analysis of data was conducted using logical regression analysis to estimate the odds of occurrence of events by IAH versus NAH. The role of continuous glucose monitoring (CGM) use on outcomes was also examined.
Results: Overall, 30% of participants reported IAH (n=64). Women with IAH had more episodes of SH during pregnancy (mean 0.44 vs. 0.08, p&lt;0.001). Women with IAH scored significantly higher on the HFS-II worry scale (25.9 vs. 20.1, p 0.0036), indicating more fear of hypoglycemia at baseline. They also spent more time below range (&lt;63 mg/dl) at 12 weeks gestation. Higher overall HFS-II scores were associated with a higher risk of maternal SH episodes (RR 1.78, 95% CI 1.39-2.27) and a lower incidence of neonatal hypoglycemia (OR 0.597, 95% CI 0.385-0.893). There were no other differences in obstetric/neonatal outcomes between women with IAH and NAH. Higher HFS-II scores were associated with more diabetes-related complications, such as nephropathy (OR 1.907, 95% CI 1.06-3.4), independent of duration of diabetes. Finally, CGM did not affect incidence of SH (RR 0.54, 95% CI 0.12 - 2.16).
Conclusion: In pregnant women with type 1 diabetes, IAH is associated with more maternal SH episodes and more fear of hypoglycemia. Fear of hypoglycemia was associated with reduced neonatal hypoglycemia as well as more maternal diabetes-related complications.

Disclosure
J. Bahrami: None. G. Tomlinson: None. H.R. Murphy: Advisory Panel; Self; Medtronic. D. Feig: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Medtronic.

Funding
JDRF; Canadian Clinical Trial Network
1941-P: Aging Disturbs the Inflammatory Balance in Adipose Tissue
Authors: LIAN ZEQIN , PERRARD XIAOYUAN , BALLANTYNE CHRISTIE M. , WU HUAIZHU 
Published: June 2020

Background: Aging (middle age) is usually associated with obesity and progressive low-grade inflammation in adipose tissue. However, how immune components in adipose tissue respond to aging is still not fully uncovered. Here, we sought to examine immune cells and inflammation in adipose tissue in aging mice.
Methods: Bodyweight and insulin sensitivity were measured in 12-month-old (aging) and 3-month-old (young) C57BL/6J mice on a low-fat normal diet. UCP1 expression was examined in white adipose tissue after stimulation. The immune-cell composition and phenotypes in adipose tissue were analyzed by flow cytometry. The suppressive functions of adipose tissue-resident T regulatory cells (aTregs) for conventional T cell proliferation were evaluated by CFSE-labeling proliferation assay in vitro.
Results: Compared to young mice, aging mice exhibited adipose tissue expansion and insulin resistance. UCP1 was reduced in adipose tissue, indicating impaired adipose tissue browning, in aging mice compared to young mice. The frequency of resident T cells and macrophages was increased in adipose tissue of aging mice compared to those of young mice. Moreover, the Th1 subset of T cells and the M1 subset of macrophages dominated in their parent population in adipose tissue of aging mice. In contrast to diet-induced obesity that reduced aTregs, the frequency of aTregs was increased in old mice compared to young mice. However, the anti-inflammatory cytokines IL10 and inflammation-inhibitory marker CTLA4 were reduced on aTregs in aging mice than young mice. The proliferative assay showed that the suppressive capacity of Treg cell on conventional T cell proliferation was impaired in aging mice.
Conclusion: Aging in mice is associated with increased aTregs, which have reduced anti-inflammatory functions and may, therefore, contribute to increased Th1 and M1 inflammation in adipose tissue, leading to metabolic disorders in aging mice.

Disclosure
Z. Lian: None. X. Perrard: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corvidia, Denka-Seiken Co., Ltd., Esperion Therapeutics, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amgen, Esperion Therapeutics, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA. H. Wu: None.

Funding
American Diabetes Association (1-17-IBS-082 to H.W.); National Institutes of Health (R01HL098839); American Heart Association (16GRNT30410012)
1944-P: CREBZF Acetylation at Lys126 Couples Glucose to White Adipose Tissue Browning
Authors: CUI AOYUAN , SU WEITONG , XUE YAQIAN , LIU ZHENGSHUAI , MA FENGGUANG , LIU YUXIAO , HU ZHIMIN , HAN YAMEI , CAI GENXIANG , GAO JING , CHIN EUGENE , XU AIMIN , LI YU 
Published: June 2020

Glucose uptake is highly induced during cold exposure or feeding in adipocytes, which is utilized as an important energy source for most cells. However, little is known about whether glucose regulates downstream targets that govern thermogenesis and metabolic homeostasis in adipose tissue. Here, we characterize CREB/ATF bZIP transcription factor CREBZF as a novel glucose sensor and regulates thermogenesis via acetylation in adipocytes. Proteomic analysis using LC-MS/MS identifies Lys126 as an evolutionally conserved residue that is acetylated in a glucose-dependent manner. Ectopic expression of CREBZF mutant, in which Lys126 is substituted by alanine, abolishes glucose-stimulated acetylation and protein stabilization of CREBZF. The effects of glucose on protein stabilization of CREBZF are regulated by reversible acetylation that is mediated by transacetylase CBP/p300 and deacetylase HDAC3. Interestingly, endogenous levels of CREBZF are induced by pharmacological inhibition of HDAC3 RGFP966 in SVF-differentiated primary adipocytes. Adipose specific CREBZF knockout (FKO) mice were cold insensitivity and showed enhanced browning and energy metabolism. In the inguinal white adipose tissue (iWAT) of mice in response to cold exposure or β3-adrenergic receptor agonist, the activity of CREBZF is increased, leading to decreased thermogenic gene expression, energy expenditure, and cold tolerance. These findings 1) characterize glucose as a chemical signal to regulate acetylation and stabilization of CREBZF in adipocytes; 2) reveal that Lys126 may play a key role in mediating glucose’s effects on the stimulation of CREBZF activity and inhibition of white adipose tissue browning; 3) uncover an unknown mechanism of glucose sensing in the adipocyte that contributes to homeostasis of energy metabolism.

Disclosure
A. Cui: None. W. Su: None. Y. Xue: None. Z. Liu: None. F. Ma: None. Y. Liu: None. Z. Hu: None. Y. Han: None. G. Cai: None. J. Gao: None. E. Chin: None. A. Xu: None. Y. Li: None.

Funding
National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Chinese Academy of Sciences (XDA12030210); Shanghai Science and Technology Commission (19140903300)
1947-P: RE1-Silencing Transcription Factor (REST) Regulates Mitochondrial Activity in White Adipocytes
Authors: FUWA MASAYUKI , KAJITA KAZUO , TAGUCHI KOICHIRO , IKEDA TAKAHIDE , ISHIZUKA TATSUO , MORITA HIROYUKI 
Published: June 2020

RE1-silencing transcription factor (REST) is a transcriptional factor which negatively regulates the expression of numerous neuronal genes. In this study, model mice lacking REST in adipocytes were generated to investigate the role of REST in adipocytes. This was achieved by mating Rest2lox/2lox mice with Adipoq-Cre mice, and the resultant Adipoq-Cre/Rest2lox/2lox mice were compared with Adipoq-Cre mice. Adipoq-Cre/Rest2lox/2lox mice exceeding 10 weeks of age showed increased body weight, fat mass, and adipocyte size; however no difference was observed in food intake. Glucose tolerance deteriorated under a high fat diet, but not under normal diets in Adipoq-Cre/Rest2lox/2lox mice. Oxygen consumption decreased in Adipoq-Cre/Rest2lox/2lox mice. The characteristics of gene expression in epididymal fat, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT), isolated from Adipoq-Cre/Rest2lox/2lox mice, were compared by microarray with those from Adipoq-Cre mice. Although expression of numerous neuronal genes increased in Adipoq-Cre/Rest2lox/2lox mice, there were no differences in adipocyte-specific genes. Gene analyses utilizing a cluster one program detected a significant decrease in the mitochondrial translation gene group in WAT, but not BAT. There was no difference in the amount of mitochondrial DNA, whereas the expression of cytochrome C protein was reduced in WAT but not BAT, which was isolated from Adipoq-Cre/Rest2lox/2lox mice. These results indicate that obesity in Adipoq-Cre/Rest2lox/2lox mice is due to a mitochondrial dysfunction in WAT. It is also suggested that REST might regulate the mitochondrial function in WAT.

Disclosure
M. Fuwa: None. K. Kajita: None. K. Taguchi: None. T. Ikeda: None. T. Ishizuka: None. H. Morita: None.
1950-P: Fat Mass Affects Metabolic Response to Erythropoietin in Mice
Authors: ROGERS HEATHER , NOGUCHI CONSTANCE T. 
Published: June 2020

Erythropoietin (EPO) is required for erythrocyte production. However, EPO receptor (EpoR) expression extends beyond erythroid tissue. To assess EPO activity on glucose homeostasis and fat mass accumulation, wild type (WT, C57BL/6) mice, ΔEpoRE mice with EpoR restricted to hematopoietic tissue and ΔEpoRWAT mice with targeted EpoR deletion in fat tissue were fed a high fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at age 3, 4, and 6 months. EPO increased hematocrit in all mice and improved glucose tolerance when fat mass was less than 35% which included all female mice. In male WT mice EPO improved glucose tolerance and reduced fat mass which at 6 months was 40% on HFD and below 35% with HFD/EPO treatment. In female mice, estrogen interferes with EPO fat mass regulation. EPO treatment did not affect fat mass in ΔEpoRE mice, indicating that EPO regulation of fat mass is a non-hematopoietic response. EPO improved glucose tolerance in female and only age 3 month male ΔEpoRE mice when fat mass was less than 35%. In male ΔEpoRWAT mice, EPO minimally reduced fat mass indicating that EPO fat mass regulation in males is largely a direct fat tissue response. EPO treatment improved glucose tolerance in male ΔEpoRWAT mice when fat mass was below 35% but not at 6 months when fat mass exceeded 40%. These data demonstrate that EPO improved glucose tolerance when fat mass was below 35%, that the sex-dimorphic EPO regulation of fat mass is primarily mediated by EpoR in fat, and that EPO activity in glucose metabolism and fat mass is differentially regulated and does not follow EPO stimulated erythropoiesis.

Disclosure
H. Rogers: None. C.T. Noguchi: None.

Funding
National Institutes of Health
1953-P: Influence of High-Fat Diet on Adipokine, Leptin, Betatrophin, and PTX3 in Obese Sprague-Dawley Rats Undergoing Metabolic Surgery
Authors: NABRDALIK KATARZYNA , SAWCZYN TOMASZ , STYGAR DOMINIKA M. , GUMPRECHT JANUSZ 
Published: June 2020

Introduction: High-fat diet (HFD) leads to obesity which causes low grade inflammation and changes in adipokines and hepatokines. Metabolic surgery, like ileal transposition (IT) leads to beneficial metabolic effect and lowers inflammatory state. However these positive effects diminish with time and data related to dietary factors modifying these effects are scare.
Aim: To assess influence of HFD on plasma adiponectin, leptin, betatrophin and pentraxin 3 (PTX3) in obese rats undergoing metabolic surgery.
Methods: There were 24 rats fed for 8 weeks with HFD to induce obesity. After 8 weeks half of them underwent IT and half of them SHAM surgery. For 8 weeks after surgery half of the rats in the IT and in the SHAM group were fed with HFD and half of them with control diet (CD). After 8 weeks following surgery adipokines namely adiponectin and leptin as well as hepatokine namely betatrophin and inflammatory protein PTX3 were assessed.
Outcomes: When comparing HFD to CD groups following two surgery procedures rats who underwent IT comparing to SHAM surgery had significantly higher concentration of betatrophin (1751.2 vs 594.5 pg/ml; P=0.0041) when continued to be fed with HFD as well as when the diet was changed to CD (2391.2 vs 922.9 pg/ml; P=0.0047) and significantly higher concentration of adiponectin (72.6 vs 28.7 ng/ml; P=0.007) only among those rats who continued to be fad with HFD. There was higher concentration of betatrophin observed among rats who were postoperatively fed with HFD comparing to rats who were fed with CD in the IT surgery group but the difference was not significant (2301.2 vs 1751.2 pg/ml; P= 0.0552). There was no difference in PTX3 and leptin observed among IT compared to SHAM operated animals in relation to diet.
Conclusion: The study indicates that diet may modify the effects of metabolic surgery on adiponectin and betatrophin which are hormones influencing metabolic state and this may serve as a motivation to investigate this phenomenon in humans.

Disclosure
K. Nabrdalik: None. T. Sawczyn: None. D.M. Stygar: None. J. Gumprecht: Consultant; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier. Speaker’s Bureau; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier.
1959-P: Sel1l-Hrd1 ER-Associated Degradation (ERAD) Controls Mitochondrial Dynamics, ER-Mitochondrial Dynamics, and ER-Mitochondria Contacts in Brown Adipocytes
Authors: TORRES MAURICIO , ZHOU ZHANGSEN , QI LING , WANG SIWEN 
Published: June 2020

Heat generation, mediated by mitochondrial respiration in Brown Adipose Tissue (BAT), is important for defense against cold and maintenance of whole-body homeostasis. Recent works have demonstrated the presence of metabolically active BAT in adult humans, raising the prospect that augmenting brown fat abundance and/or function may provide an effective avenue for the treatment of obesity and its associated metabolic disorders. In this work, we show that the Sel1L-Hrd1 ERAD complex is essential for cold-induced thermogenesis in part by managing mitochondrial dynamics and ER-mitochondria contact in brown adipocytes. While largely indistinguishable from their wildtype littermates, adipocyte-specific Sel1L-deficient mice are cold sensitive associated with mitochondrial dysfunction. Using a combination of transmission electron microscopy (TEM), high-resolution three-dimensional (3D) imaging techniques such as Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) and Serial Block-face Scanning Electron Microscopy (SBEM), revealed that mitochondria in Sel1L-deficient brown adipocytes are dramatically enlarged and polymorphic in response to acute cold challenge. Strikingly, mitochondria in Sel1L-deficient brown adipocytes exhibit increased interaction with ER tubules leading to the formation of unique intramitochondrial tubule(s). Lastly, Sel1L affects mitochondrial biology as a part of the Hrd1 ERAD complex, as adipocyte-specific Hrd1-deficient mouse, phenocopy Sel1L-deficient mice in terms of mitochondrial phenotype. Hence, our data provide novel molecular insights and platform for future studies into ER-mitochondrial interaction and position Sel1L-Hrd1 ERAD at the center of organelle crosstalk.

Disclosure
M. Torres: None. Z. Zhou: None. L. Qi: None. S. Wang: None.

Funding
National Institutes of Health (1R35GM130292)
196-OR: A Meal Detection Algorithm for the Artificial Pancreas: A Randomized Controlled Clinical Trial in Adolescents with Type 1 Diabetes
Authors: PALISAITIS EMILIE , FATHI ANAS EL , HAIDAR AHMAD , VON OETTINGEN JULIA E. , LEGAULT LAURENT 
Published: June 2020

Background: People with type 1 diabetes occasionally forget to announce meals to their insulin pump, which degrades glycemic control. We have developed a meal detection algorithm for the artificial pancreas (AP) that detects unannounced meals and delivers boluses.
Methods: We conducted a randomized crossover trial in adolescents aged 12-18 years with type 1 diabetes. We compared (i) CSII, (ii) AP, and (iii) AP with a meal detection algorithm (AP+MDA) in controlling post-prandial glucose levels after a meal without a bolus. Participants underwent three 9-hour interventions which included breakfast with a CHO-matched bolus and lunch without a bolus. The primary outcome was the iAUC of the glucose excursions from the start of lunch to 4 hours post-lunch.
Results: 11 participants (mean age 14.9±1.3, HbA1c 8.3±0.6%) were included. Compared to CSII, AP+MDA decreased iAUC from the start of lunch to 4 hours post-lunch from 24±9.5 h.mmol/L to 15±8 h.mmol/L (p=0.03). The AP+MDA reduced time &gt; 10 mmol/L after the missed bolus by -21.6% (IQR: [-39.4- -3.8]) compared to CSII (p=0.02). The mean meal detection time was 41.8±16 minutes after meal consumption.
Conclusions: The AP+MDA successfully decreased iAUC after an unannounced meal in adolescents with type 1 diabetes. Longer and larger studies are needed to evaluate the efficacy of this meal detection algorithm in real-world settings.

Disclosure
E. Palisaitis: None. A. El Fathi: None. A. Haidar: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., Eli Lilly and Company. J.E. von Oettingen: None. L. Legault: Advisory Panel; Self; Dexcom, Inc., Lilly Diabetes. Research Support; Self; AstraZeneca K.K., Merck & Co., Inc., Sanofi-Aventis. Other Relationship; Self; Lilly Diabetes.