bluuebunny/crossref_metadata_2025_split huggingface dataset:
2012-P: The Mouse Thermoneutral Zone Is Actually a Thermoneutral Point
Authors: SKOP VOJTECH , GUO JUEN , LIU NAILI , XIAO CUIYING , HALL KEVIN D. , GAVRILOVA OKSANA , REITMAN MARC 
Published: June 2019

The mouse is widely used to study diabetes and obesity. Understanding thermal biology is essential for translating observations from mice to humans. For example, mice expend large amounts of energy to maintain body temperature, while humans do not. The thermoneutral zone (TNZ) for humans is defined as the ambient temperature (Ta) range where metabolic rate is at a minimum. Here we explore the mouse TNZ, focusing on its neglected upper boundary. Total light-phase energy expenditure (TEE) was quantitated by indirect calorimetry at various Ta, while also continuously measuring core body temperature (Tb). Broken line regression with nonlinear mixed model was used for data analysis. In wild type C57BL/6J mice, TEE decreased linearly with increasing Ta until a plateau was reached. The Ta at the break point (TNZ lower bound, called the Tlc) was 28.91 ±0.15 °C. Importantly, no increase in TEE was observed at Ta up to ∼4 °C above the Tlc. Tb was constant at cool Ta and began to rise at Ta = 28.95 ±0.12 °C. Thus, the Ta at which Tb starts to increase coincides with the Tlc and was not accompanied by an increased TEE. The generality of this unexpected observation was explored in multiple mouse models, including germline deletion of three temperature-sensing channels (TrpV1, TrpM8, TrpA1), neonatal ablation of Trpv1+ neurons, diet-induced obesity, and leptin deficiency. Over 12 cohorts (in total 66 mice), there was no difference between the Tlc and start of Tb increase (0.06 ±0.22 °C). Our novel results suggest a general property of mouse thermal physiology. Unlike humans, mouse Tb starts to increase right at the Tlc. There is no range of Tas over which both TEE and Tb are constant. The results suggest that the mouse TNZ is not the “zone” of textbooks, but rather is a fraction of a degree, a point.

Disclosure
V. Skop: None. J. Guo: None. N. Liu: None. C. Xiao: None. K.D. Hall: None. O. Gavrilova: None. M. Reitman: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK075063)
2029-P: A Simple Proximal Intestinal Bypass Surgery Directly Improves Insulin Sensitivity and Insulin Secretion in Mice
Authors: JANG HYE-MIN , HA NA-HEE , SONG MUN-GYU , LEE HYE-JIN , JIN BO-YEONG , KIM DONG-HOON , KIM NAM HOON 
Published: June 2019

Objectives: To verify foregut hypothesis, we conducted simple bariatric surgery to evaluate the effects of those operations on body weight, glucose tolerance and insulin sensitivity in mice.
Methods: We applied operation techniques which involved gastrojejunostomy (GJ), GJ with duodenojejunal exclusion (GJDE), and sham operation (control). Jejunostomy site was located in the mid-jejunum with 1.0 cm pore size. Three different fed conditions were applied; 1) C57BL/6 mice fed with 60% high-fat diet (HFD) before and after surgery (n=8). ICR mice had been fed with chow diet, followed by 2) 45% HFD (n=9), and 3) 60% HFD (n=12) after surgery.
Results: In HFD fed C57BL/6 mice, body weight following operations was significantly reduced during first 2 weeks in GJDE and GJ mice compared to control mice, thereafter the difference was gradually attenuated. OGTT and ITT at 5 and 7 weeks after surgery showed that glucose levels were significantly lower, and insulin sensitivity was significantly improved in GJ and GJDE mice compared to control. In addition, in response to high glucose administration, insulin level was significantly increased in GJ and GJDE mice. In lean ICR mice, body weight in GJ and GJDE operated mice (45% HFD after surgery) were significantly lowered than that of control mice since 3 weeks after surgery. There were no difference in glucose tolerance between groups until 7 weeks, however, AUC glucose were significantly lower in GJDE mice than GJ and control mice after 10 weeks. ITT also showed GJDE mice were more insulin sensitive than GJ and control mice. GJ and GJDE operated mice with 60% HFD after surgery also showed similar results indicating delayed improvement in insulin sensitivity with proximal intestinal bypass.
Conclusion: This simple operation of proximal intestinal bypass demonstrated its effects on improvement in glucose tolerance and insulin sensitivity in mice. Mice preconditioned with HFD before surgery was also benefited by improvement in insulin secretion.

Disclosure
H. Jang: None. N. Ha: None. M. Song: None. H. Lee: None. B. Jin: None. D. Kim: None. N. Kim: None.
2030-P: BS-016, a Novel Oleanolic Acid Derivative, Exerts Antidiabetic and Anti-Obesity Effects in Preclinical Studies
Authors: DU YONG 
Published: June 2019

There is an urgent need for innovative treatment targeting multiple pathways of type 2 diabetes such as weight loss, insulin sensitization and beta cell proliferation. Natural products have been shown to have the potential to treat diabetes. Here we develop a novel compound from oleanolic acid with improved bioavailability and efficacy. BS-016 reduces blood glucose and induces a sustained weight loss in DIO mice, producing 15% weight loss in combination study. In db/db diabetic mice, BS-016 lowers plasma glucose and improves glucose homeostasis. In vitro studies show BS-016 promotes insulin sensitivity by activating PPAR gamma and increases energy expenditure. Taken together, these results indicate BS-016 is a promising agent for treating diabetes and obesity.

Disclosure
Y. Du: None.
2034-P: The Role of 14-3-3zeta in the “Beiging” of White Adipose Tissue
Authors: DIALLO KADIDIA , LIM GARETH E. 
Published: June 2019

Adipocyte hypertrophy and hyperplasia is a hallmark of obesity, and treatments that induce the oxidation of lipid stores may represent a potential therapy. When stimulated by cold or beta-adrenergic agonists, adipocytes in inguinal white adipose tissue (iWAT) can convert to beige cells, which resemble brown adipocytes. This process can reduce body weight in rodents and improve glucose homeostasis through increased Ucp1-dependent lipid oxidation. 14-3-3?, a molecular scaffold we found to be essential for adipogenesis, regulates the enzymatic activities of tryptophan and tyrosine hydroxylases, both of which influence beiging. Thus, the aim of the current study is to investigate whether 14-3-3? influences the beiging process. Compared to control mice, acute (3 hr) and chronic (72 hr) cold (4 C) exposure in male transgenic mice over-expressing 14-3-3? led to improved cold tolerance due to significantly increased Ucp1 mRNA and protein in iWAT. Following chronic exposure, they were also able to maintain their body weight by increasing their food intake. Consistent with these data, analysis of adipocyte area revealed a decrease in the size of inguinal adipocytes in transgenic mice, suggesting increased lipid oxidation. In contrast, gonadal adipocytes were larger in transgenic mice, which may explain their ability to maintain their body weight. Systemic 14-3-3? knockout mice had significantly lower levels of Ucp1 mRNA in iWAT and BAT but did not display differences in tolerance to acute cold. Depletion of 14-3-3? by siRNA in brown adipocytes did not impair isoproterenol-mediated induction of Ucp1 mRNA, suggesting that 14-3-3? is not required for Ucp1 expression in this cell type. In future studies, we will examine if 14-3-3? influences the responsiveness of iWAT to chronic β-adrenergic stimuli and assess the impact of 14-3-3? overexpression in brown adipocyte function. Collectively, our results point to a novel role of 14-3-3? in the beiging of inguinal adipocytes and increase our understanding of how beiging is regulated.

Disclosure
K. Diallo: None. G.E. Lim: None.

Funding
Canadian Institutes of Health Research; Fonds de la recherche en santé du Québec; Centre de recherche du CHUM; Montreal Diabetes Research Center
2037-P: Characterization of Novel Unimolecular Amylin-Adrenomedullin Dual Agonists
Authors: DALBOEGE LOUISE S. , MAGOTTI PAOLA , BUCH-MÅNSON NINA , BECH ESBEN M. , FINK LISBETH N. , PEDERSEN SØREN LJUNGBERG , FOSGERAU KELD 
Published: June 2019

Amylin and Adrenomedullin both belong to the calcitonin peptide family. While amylin plays an important role in maintaining glucose and energy homeostasis, adrenomedullin is primarily known for its beneficial vasoactive effects.
We hypothesize that combining the glucoregulatory and anti-obesity properties of amylin with the cardioprotective effects of adrenomedullin could be an effective treatment strategy to address type 2 diabetes, obesity and cardiovascular diseases in one molecule. Here we report the design and receptor potencies of unimolecular peptide agonists with dual activity at the amylin and adrenomedullin receptors.
Using solid-phase peptide synthesis, an array of hybrid peptides was rationally designed by substituting amino acids essential for amylin activity into the native adrenomedullin sequence. The pharmacokinetic profile was optimized by lipidation with a C20 diacid. Functional activities of the analogues were measured using a cAMP accumulation assay in cells overexpressing the human amylin receptor subtype 3 (hAMY3-R) or human adrenomedullin receptor subtype 1 (hAM1-R).
All analogues were full agonists on both receptors. hAMY3R potencies were comparable to human native amylin, whereas hAM1-R potencies ranged from equipotent to 100-fold less potent compared to human native adrenomedullin.
In summary, we have synthesized novel hybrid amylin-adrenomedullin peptide agonists with dual activity at the hAMY3R and hAM1-R. Ongoing studies address in vivo efficacy and potency of amylin-adrenomedullin dual agonists in rodent models of obesity and diabetes.

Disclosure
L.S. Dalboege: None. P. Magotti: None. N. Buch-Månson: None. E.M. Bech: None. L.N. Fink: Employee; Self; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. S.L. Pedersen: None. K. Fosgerau: Stock/Shareholder; Self; Gubra.
2038-P: Rice Endosperm Protein Intake in Childhood Suppresses the Development of High-Fat Diet-Induced Metabolic Disorders and Kidney Disease during Adulthood in Mice
Authors: HIGUCHI YUKI , HOSOJIMA MICHIHIRO , KABASAWA HIDEYUKI , KUWAHARA SHOJI , KASEDA RYOHEI , ARAO HITOSHI , TANAKA TAKAHIRO , NARITA ICHIEI , SAITO AKIHIKO 
Published: June 2019

Introduction: Obesity is associated with lifestyle diseases such as type 2 diabetes and organ complications including kidney disease. Childhood diet has a great influence on the development of obesity and its related disorders. Rice endosperm protein (REP) has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. Therefore, we aimed to clarify the effects of REP intake during childhood on the development of high-fat-diet (HFD)-induced obesity and its related disorders during adulthood in mice.
Methods: Four-week-old male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP for 6 weeks (childhood), and subsequently, an HFD containing casein or REP for 12 weeks (adulthood). Mice were then tested for oral glucose tolerance and subjected to the analyses of growth status, biochemical parameters, kidney histology, and fecal gut microbiota by 16S rRNA gene sequencing. Antibacterial activity of REP-derived peptides against gut microbiota was evaluated in vitro.
Results: Mice fed REP in childhood showed less increase in body weight, total fat mass, blood pressure, serum total cholesterol, triglyceride, and lipopolysaccharide (LPS)-binding protein, and better glucose tolerance than those fed casein in childhood followed by HFD with casein or REP. Furthermore, HFD-induced glomerular hypertrophy, mesangial expansion, and vacuolar formation in proximal tubules were suppressed in mice fed REP than those fed casein in childhood. The intake of REP in childhood ameliorated dysbiosis caused by HFD. Additionally, REP-derived peptides showed antibacterial activity against E. coli, a major producer of LPS.
Conclusion: These results indicate that the intake of REP during childhood can inhibit the progression of HFD-induced metabolic disorders and kidney disease in adulthood, probably through the effects of REP on gut microbiota.

Disclosure
Y. Higuchi: None. M. Hosojima: Research Support; Self; Astellas Pharma Inc., Biotech Japan Corporation, Daiichi Sankyo Co.,Ltd., Eli Lilly Japan K.K., Forica Foods Co.,Ltd., Kameda Seika Co.,Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novo Nordisc Pharma Ltd., Sato Foods Industries Co.,Ltd., Taisho Toyama Pharmaceutical.Co.,Ltd., Takeda Pharmaceutical Co.,Ltd. H. Kabasawa: Research Support; Self; Astellas Pharma Inc., Biotec Japan Corporation, Daiichi Sankyo Company, Limited, Forica Foods CO.,LTD., KAMEDA SEIKA CO., LTD., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K, Novo Nordisc Pharma Ltd, Sato Foods Industries CO.,LTD., Taisho Toyama Pharmaceutical.CO.,LTD., Takeda Pharmaceutical Company Limited. S. Kuwahara: None. R. Kaseda: None. H. Arao: None. T. Tanaka: None. I. Narita: None. A. Saito: None.
204-LB: Lifestyle Risk Behaviors among Stroke Survivors With and Without Diabetes
Authors: BAILEY RYAN R. , PHAD ALLISON , MCGRATH RYAN , FORD ANDRIA , TABAK RACHEL G. , SERRANO NATALICIO H. , HAIRE-JOSHU DEBRA 
Published: June 2019

Objective: History of stroke or diabetes increases risk for cardiometabolic conditions, which can be exacerbated by the presence of modifiable lifestyle risk behaviors. The purpose of this study was to evaluate lifestyle risk behaviors among stroke survivors with and without diabetes to inform future research and healthcare intervention. Specifically, we compared the prevalence of three lifestyle risk behaviors (i.e., consuming ≤1 fruit and ≤1 vegetable daily, physical inactivity, and overweight/obesity) and total number of lifestyle risk behaviors among stroke survivors, stratified by diabetes status.
Methods: Cross-sectional data from the 2013 and 2015 Behavioral Risk Factor Surveillance System (BRFSS) were examined. Weighted and age-adjusted prevalence estimates and adjusted odds ratios (AOR, adjusted for sociodemographic characteristics) with 95% confidence intervals (CIs) were calculated to compare prevalence and odds of individual and total number of lifestyle risk behaviors between stroke survivors with and without diabetes.
Results: Prevalence and AORs were higher in stroke survivors with diabetes compared to stroke survivors without diabetes for consuming ≤1 fruit and ≤1 vegetable daily (58.8% vs. 53.7%; AOR: 1.14, CI: 1.02-1.28), physical inactivity (65.7% vs. 54.6%; AOR: 1.41, CI: 1.26-1.58), overweight/obesity (87.2% vs. 63.1%; AOR: 2.42, CI: 2.12-2.79), 2 lifestyle risk behaviors (41.1% vs. 36.7%; AOR: 1.16, CI: 1.03-1.30), and 3 lifestyle risk behaviors (35.7% vs. 21.8%; AOR: 1.54, CI: 1.36-1.74).
Conclusion: Individual and clustered lifestyle risk behaviors were present in greater proportions among stroke survivors with diabetes compared to those without diabetes. Because the co-occurrence of chronic conditions (i.e., multimorbidity) and multiple lifestyle risk behaviors increases risk for poor health and premature death, effective healthcare interventions and community programs are needed to promote health behavior change in stroke survivors.

Disclosure
R.R. Bailey: None. A. Phad: None. R. McGrath: None. A. Ford: None. R.G. Tabak: Other Relationship; Self; Envolve PeopleCare/Centene Corporation. N.H. Serrano: None. D. Haire-Joshu: Research Support; Self; Centene Corporation.

Funding
National Institutes of Health (P30DK092950, 5T32HL130357)
2041-P: Genetic Intervention in Kynurenine Pathway Alters Glucose Metabolism in Mice
Authors: YAMAMOTO TAKASHI , GOTODA TAKANARI 
Published: June 2019

Most of tryptophan is metabolized to kynurenine (KYN) to synthesize NAD+, while a subsidiary pathway changes KYN to kynurenic acid (KYNA) by kynurenine aminoltransferases (KATs). We previously reported genetic association of a mutation in the gene encoding KAT-1, an isoform of KATs, with hypertension, adiposity and glucose intolerance in rats. Although it is widely known that KYNA negatively regulates central nervous system by antagonizing neuro-receptors, its physiological role in glucose metabolism remains unclear.
To explore such role, first, we have established KAT-1 knockout mice that showed decreased levels of KAT activity in liver and brain (p&lt;0.01) and KYNA levels decreased significantly in brain and blood (p&lt;0.05) and tending to decrease in liver. The KAT-1 knockout mice also showed significantly deteriorated glucose tolerance (p&lt;0.05 at 60min after glucose i.p.) and insulin sensitivity (p&lt;0.05 at 45, 60, 75 and 90min after insulin i.p.) as compared with wild littermates. Next, to establish mice with endogenously increased levels of KYNA, the hepatic gene encoding kynurenine mono-oxygenase (KMO), a rate-limiting enzyme for conversion of KYN to NAD+, was knocked down by shRNA adenovirus. The hepatic KMO knockdown in normal mice markedly increased endogenous KYNA levels in liver, blood and several other tissues, whereas the levels of 3-hydroxykynurenine, a downstream product of KMO, were decreased in liver (p&lt;0.001). Finally, the hepatic KMO knockdown in diet-induced obese mice significantly ameliorated glucose intolerance and improved insulin sensitivity and pyruvate tolerance independently of food intake or body weight. Among the enzymes related to glucose metabolism, both the gene expression (p&lt;0.01) and the enzymatic activity (p&lt;0.05) of glucokinase were increased in the liver of the KMO knockdown group as compared with controls.
These results indicated that alterations in KYNA pathway influence glucose metabolism in vivo.

Disclosure
T. Yamamoto: None. T. Gotoda: None.
2049-P: Real-World Assessment of Orlistat and Liraglutide in Patients with Obesity: The XENSOR Study
Authors: GORGOJO-MARTINEZ JUAN J. , BELEN BASAGOITI-CARREÑO , SANZ-VELASCO ALBERTO , SERRANO-MORENO CLARA , FRANCISCA ALMODÓVAR-RUIZ 
Published: June 2019

Data on comparative effectiveness among weight-loss medications (WLMs) in real-world studies (RWS) are limited. The aim of the XENSOR study was to assess in a real-world setting the effectiveness of two WLMs, orlistat and liraglutide, in patients with obesity and insufficient weight loss (WL) after a lifestyle modification program.
A retrospective RWS was conducted comparing clinical outcomes of orlistat 120 mg tid and liraglutide (up to 3 mg daily) in adult patients with BMI ≥ 30 kg/m² (or ≥ 27 kg/m² with at least a weight-related comorbidity) who had failed to lose at least 5% of their baseline weight (BW) after 6 months (mo) of lifestyle modification. The co-primary end points, assessed at 3-6 mo (visit 2) and at the end of the follow-up (visit 3), were weight change from baseline, proportion of patients who lost at least 5% of their BW and adjusted differences in WL between both drugs.
Five hundred patients, 400 in the group of orlistat (women 75%, mean age 47.0 y, mean BW 107.8 kg), and 100 in the group of liraglutide (women 73%, mean age 51.9 y, mean BW 105.1 kg), were included. Treatment with both drugs significantly reduced weight, FPG, systolic BP, LDL-C and ALT over a median follow-up period of 7 mo. WL with liraglutide at visit 3 (-7.7 kg) was significantly greater than that observed with orlistat (-3.3 kg), adjusted mean difference -4.7 kg (95% CI -6.4 to -2.9 kg). More individuals lost at least 5% of their BW with liraglutide (64.7%) than with orlistat (27.4%) at visit 3, p&lt;0.0001. In the subset of patients with prediabetes at baseline, persistence of prediabetes or progression to T2DM was significantly lower with liraglutide (34.6%) than with orlistat (82.8%), p&lt;0.0001. At 12 mo of follow-up, 61% of patients remained on liraglutide, compared to 46.8% on orlistat (p 0.011).
In summary, in this RWS, liraglutide showed a greater effectiveness in WL compared to orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.

Disclosure
J.J. Gorgojo-Martinez: Advisory Panel; Self; Abbott, AstraZeneca, Lilly Diabetes, Mundipharma, Novo Nordisk Inc., Pfizer Inc. Research Support; Self; Novo Nordisk Inc. Other Relationship; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc. B. Basagoiti-Carreño: None. A. Sanz-Velasco: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc. C. Serrano-Moreno: Other Relationship; Self; Novo Nordisk A/S. F. Almodóvar-Ruiz: Other Relationship; Self; Novo Nordisk Inc.
205-OR: Sensitivity and Specificity of the PHQ-9 and PHQ-2 to Identify Depressive Symptoms in Teens with Type 1 Diabetes (T1D)
Authors: MARKER ARWEN M. , MCDONOUGH RYAN , EGAN ANNA , CLEMENTS MARK A. , PATTON SUSANA R. 
Published: June 2019

ADA guidelines recommend regularly screening teens for depression. We examined sensitivity and specificity of the long and short-form of the Patient Health Questionnaire (PHQ) to identify depressive disorders in teens with T1D against a gold-standard diagnostic interview.
Teens (N=100; Mean age = 15.0 ± 1.7; 60% Male; 87% white; Mean HbA1c = 8.88 ± 1.8%) completed the PHQ-9 electronically. We used the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS DSM-5) depression module to determine whether the teen met criteria for any depressive disorder (DD; e.g., major depression, dysthymia, adjustment disorder-depressed mood, bipolar). We compared teens’ pre-existing PHQ cut-off scores (PHQ-9 ≥ 10; PHQ-2 ≥ 3) to KSADS results.
Per KSADS, 15% of teens met criteria for current DD, 11% endorsed past DD, and 25% endorsed past/present suicidal ideation (SI). Only 6% and 8% of teens exceeded PHQ-9 and PHQ-2 cut-off scores, respectively, and 10% endorsed current SI on PHQ item 9. Sensitivity and specificity outcomes are in Table 1.
The PHQ-9 and PHQ-2 showed low sensitivity and high false negative rates. Lower cut-offs or alternative screening measures may be indicated to reliably identify DD in teens with T1D. High rates of reported SI, even by teens who did not meet full criteria for DD, highlight the importance of screening for suicidality and/or treating subthreshold depressive symptoms.

Disclosure
A.M. Marker: None. R. McDonough: None. A. Egan: None. M.A. Clements: Advisory Panel; Self; Glooko, Inc. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Medtronic. S.R. Patton: None.