bluuebunny/crossref_metadata_2025_split huggingface dataset:
1952-P: Vertical Sleeve Gastrectomy Induces Distinctive Gene Expression Changes in Glucose-Utilizing Peripheral Organs
Authors: AHN CHANG HO , MOON SUN JOON , CHO YOUNG MIN 
Published: June 2020

Vertical sleeve gastrectomy (VSG) improves hyperglycemia and can achieve high rate of diabetes remission. To elucidate the molecular mechanism of VSG, we performed transcriptomic analysis of liver, fat, and muscle tissues in VSG mice compared to both sham and pair-fed sham controls. C57BL/6 mice fed high fat diet were randomly assigned to sham or VSG surgery. Sham-operated mice were fed ad libitum (Sham group) or pair-fed (Sham-PF group) matching their food intake to VSG-operated mice. Body weight, food intake, glucose and insulin tolerance were measured. Comparative transcriptomic analysis of liver, epididymal fat, and soleus muscle using RNA sequencing was performed. VSG decreased body weight and maintained the reduced body weight during the whole study period (up to 8 weeks after surgery). However, food intake was only reduced during the first 2 weeks after surgery in VSG than sham group. Glucose tolerance was improved by VSG after oral glucose load, but this improvement was attenuated after intraperitoneal glucose load. In addition, VSG increased insulin sensitivity than both Sham and Sham-PF group. Clustering and principal component analysis of the gene expression profiles of liver and adipose tissue revealed that Sham-PF was closer to Sham than VSG. The number of DEG was larger in comparison between VSG vs. Sham-PF than that between Sham-PF vs. Sham. The gene expression profile of muscle was not distinctive among the three groups. In pathway analysis, immune response was the common pathway enriched in all three tissues of VSG compared to Sham-PF. These results suggest that VSG induces organ specific changes of gene expression profile in both weight-loss dependent and independent ways. Interestingly, weight-loss independent changes were more robust than weight-loss dependent changes, which suggests that the improvement of hyperglycemia may be induced not only by weight-loss dependent mechanisms, but also by weight-loss independent mechanisms of VSG.

Disclosure
C. Ahn: None. S. Moon: None. Y. Cho: None.

Funding
Korean Ministry of Health and Welfare (HI14C1277)
1957-P: Intermittent Ketogenic Diet Ameliorates Diet-Induced Obesity and Fatty Liver with Improved FGF21 Signaling
Authors: GUO WANRONG , WANG WEI , LI WUGUO , LIANG HUA , XU FEN 
Published: June 2020

Recently, ketogenic diet has been found to be effective on improving obesity. Fibroblast growth factor 21 (FGF-21) is an endocrine factor mainly synthesized in the liver and shown to impact the metabolism of multiple tissues. Here, we investigated the effect of intermittent ketogenic diet on obesity and the sensitivity of FGF-21. Eight-week-old C57BL/6 mice were subjected to a chow diet (CD group), a high fat diet (HFD group), an intermittent chow diet (iCD group) or an intermittent ketogenic diet (iKD group) for 16 weeks. The intermittent diet intervention began with an HFD and was alternated with a chow diet or a ketogenic diet biweekly. Although the average energy intake of iKD group was highest in the four groups, the body weight, fasting blood glucose, the body fat mass and the weight of liver, epididymal adipose tissues (eWAT), subcutaneous adipose tissue (sWAT) and brown adipose tissue (BAT) of iKD group were ameliorated remarkably when compared to HFD group. The insulin sensitivity of iKD group was greatly improved as well. Both the histological results and the quantification of liver triglyceride showed that hepatic steatosis was significantly alleviated in iKD group. Western blotting showed that lipid metabolism in liver was greatly improved by iKD. What’s more, the cold exposure test showed that the iKD group had the best cold tolerance in the four groups. The mRNA expression of FGF-21 was greatly upregulated and hepatic inflammation was ameliorated in livers of iKD group. HE staining showed that the adipocytes in eWAT and sWAT were smaller in iKD group. The whitening of BAT was also improved in iKD group. Both mRNA and protein levels of UCP1 and PGC1α were remarkably upregulated by iKD in eWAT, sWAT and BAT. The mRNA levels of FGFR1 and KLB, which are related to FGF-21 sensitivity, were observed to be improved in eWAT and sWAT. Our data demonstrated that iKD ameliorates diet-induced obesity and fatty liver, and improved insulin sensitivity and cold tolerance with improved FGF-21 signaling.

Disclosure
W. Guo: None. W. Wang: None. W. Li: None.
1961-P: Improved Glucose Control and Robust Weight Loss with a Long-Acting OXM-001
Authors: KAYED ASHREF , KATRI ANNA , ANDREASSEN KIM V. , KARSDAL MORTEN A. , HENRIKSEN KIM 
Published: June 2020

Oxyntomodulin has proven to be very promising with regards to weight loss and improved glucose control, however it has a very short half-life. There is a need of more potent and longer-lived molecules and therefore, we have identified a novel Oxyntomodulin analog known as OXM-001, with a better pharmacological efficacy. In vitro potency of OXM-001 was determined in both GLP-1/Glucagon receptor cell lines using β-Arrestin readout. Zucker Diabetic Sprague Dawley male rats (ZDSD) were treated with vehicle and OXM-001 (100 nmol/kg) every third day (n=6/group). The OXM-001 effects on body weight, food intake, FBG, fasting insulin and HbA1C were examined for three-weeks. HFD female C57BL/6J mice were administrated vehicle, OXM-001 (10 and 30 nmol/kg) and pair-fed to OXM-001 (50 nmol/kg) every third day and MEDI0382 (10 and 30 nmol/kg) everyday (n=8/group). Body weight, food intake and oral glucose tolerance test (OGTT) were assessed during the one-month study. OXM-001 showed to be more potent than stabilized Oxyntomodulin, both over a short 3h stimulation and a long 24h potency test. In ZDSD rats, OXM-001 significantly reduced FBG and HbA1C compared to vehicle group. Furthermore, OXM-001 improved fasting insulin due to the weight loss effect. In C57BL/6J mice, OXM-001 (30 and 50 nmol/kg) significantly reduced weight in a dose-depended manner (12.4% and 23.5% compared to vehicle) and was associated with a decreased energy intake. Both OXM-001 doses showed superiority in weight loss compared to MEDI0382. Interestingly, the pair-fed to OXM-001 lost 16.2 % of its body weight compared to vehicle, showing a superiority of the OXM-001 (50 nmol/kg) to the pair-fed group. Both OXM-001 doses improved glucose control compared to MEDI0382 during the OGTT.
In conclusion, OXM-001 significantly lowered the body weight and improved glucose tolerance in prediabetic rats and fat mice, more potent than MEDI0382, and may therefore represent a possible treatment opportunity for obesity-related co-morbidities.

Disclosure
A. Kayed: None. A. Katri: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Stock/Shareholder; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience.
1965-P: The Extracellular Matrix Modulates Adipocyte Thermogenic Capacity
Authors: GONZALEZ PORRAS MARIA A. , STOJKOVA KATERINA , VAICIK MARCELLA K. , GODDI ANNA A. , COHEN RONALD N. , BREY ERIC 
Published: June 2020

Obesity is characterized by an increase in adipose mass and is the leading risk factor for type 2 diabetes. Increasing adipose thermogenic capacity, by activation of brown or beige fat, could be a treatment for metabolic diseases. Nevertheless, many approaches fail in maintaining transformed adipose tissue in vivo, in part, due to the limited understanding of how environmental factors control cell fate and maintenance. We have shown that mice with a null mutation in the laminin α4 exhibit resistance to obesity, enhanced expression of thermogenic fat markers (UCP1) in subcutaneous white adipose tissue (sWAT), increased energy expenditure and enhanced insulin sensitivity. The knockout (KO) of Lama4 results in complex changes in overall ECM composition. We used liquid chromatography/tandem mass spectrometry (LC/MS) to evaluate ECM composition in sWAT from wild type (WT) and KO mice. In addition to the expected absence of Lama4, collagen 1A1 (Col1A1) and collagen 3A1 (Col3A1) were significantly lower in KO mice. Also, integrins α7 (ITα7) and β1 (ITβ1) were dramatically reduced. Immunohistochemical staining confirmed lower levels of Itα7 in KO compared to WT mice (P&lt;0.0001). Knocking down Itα7 with siRNA promoted UCP1 expression (P=0.003) in vitro. In addition, culture of ADSC on Lama4, Col3A1 and Col1A1 coated surfaces had lower UCP1 expression (P&lt;0.0001). Finally, mRNA levels of ITα7 and Lama4 decreased following 12 days of beige differentiation in human ADSC (P&lt;0.0001). These results demonstrate that ECM can regulate adipocyte thermogenic capacity. Specifically, Lama4, Itα7, Col1A1 and Col3A1 are involved in the modulation of metabolic function in adipocytes. A better understanding of the mechanisms underlying these interactions allows for the potential to specifically manipulate these cells to improve systemic energy metabolism and glucose homeostasis.

Disclosure
M.A. Gonzalez Porras: None. K. Stojkova: None. M.K. Vaicik: None. A.A. Goddi: None. R.N. Cohen: None. E. Brey: None.
1977-P: Whole-Exome Sequencing Followed by Functional Analysis to Identify Variants That May Influence Body Mass Index (BMI) via a Role in Adipogenesis
Authors: MULLER YUNHUA L. , DAY SAMANTHA E. , KOROGLU CIGDEM , KOBES SAYUKO , HANSON ROBERT L. , KNOWLER WILLIAM C. , KIM HYE IN , HOUT CRISTOPHER VAN , GOSALIA NEHAL , SHULDINER ALAN R. , BOGARDUS CLIFTON , BAIER LESLIE 
Published: June 2020

To identify variants that potentially impact human body fat via a role in adipogenesis, we analyzed whole-exome sequence data from a population-based sample of 6809 American Indians with longitudinal measures of BMI. A total of 623,236 exonic variants were detected and those that met the following criteria were prioritized for functional analysis: 1) non-synonymous, stop-gain or frameshift that occurred in ≥5 individuals; 2) a Combined Annotation Dependent Depletion (CADD) score ≥10 (top 10% of deleterious variants); 3) evidence for association with maximum BMI in adulthood (n=6002) or maximum BMI z-score in childhood (n=4882) (P&lt;0.001, adjusted for age, sex, birth year and the first five genetic principal components) and 4) maps to a gene highly expressed in adipose tissue with literature support for a possible role in adipogenesis. The 20 variants which met these criteria had frequency of the BMI-risk allele ranging from 0.0004-0.025 and were characterized in differentiating OP9 cells for a role in lipid accumulation. Variants in PTPRF (P891L), LAMTOR1 (E37K), CCNY (P107R) and ATG5 (I65V) affected triglyceride content, where cells expressing the BMI-risk allele had increased triglycerides as compared to the wild type allele (9.1-20.5%, P=0.05-3x10-4, n=6-10 transfections). Heterozygous carriers for these variants had a higher BMI in adulthood (39.7-54.2 vs. 36.3kg/m2, P=0.05-5x10-4) and/or higher BMI Z-score in childhood (1.2-3.0 vs. 0.3SD, P=0.01-2.1x10-5) as compared to non-carriers. Two of these 4 variants had supportive evidence in other studies; E37K in LAMTOR1 directionally replicated in its association with BMI in GoDarts (P=0.04, n=2902), while I65V in ATG5 associated with waist (P=0.02) or hip circumference (P=0.02) in T2D-GENES (n=12954).
In conclusion, whole-exome sequencing followed by in vitro analysis of lipid accumulation in OP9 cells has identified coding variants that may impact BMI via a role in adipogenesis.

Disclosure
Y.L. Muller: None. S.E. Day: None. C. Koroglu: None. S. Kobes: None. R.L. Hanson: None. W.C. Knowler: None. H. Kim: Employee; Self; Regeneron Pharmaceuticals. C. Van Hout: Employee; Self; Regeneron Genetics Center. N. Gosalia: None. A.R. Shuldiner: Employee; Self; Regeneron Genetics Center. Stock/Shareholder; Self; Regeneron Pharmaceuticals. C. Bogardus: None. L. Baier: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
1978-P: Glucose-Lipid Metabolism in Obesity with Elevated Prolactin Levels and Alteration of Prolactin Levels after Laparoscopic Sleeve Gastrectomy
Authors: QU SHEN , WANG XINGCHUN 
Published: June 2020

Prolactin (PRL) exerts favorable actions on obesity, besides lactation and reproduction. To explore those actions we investigated the metabolism in obesity with increased PRL and the change in PRL levels after laparoscopic sleeve gastrectomy (LSG). Patients with obesity were divided into two groups: obesity with normal PRL (OB, n=123) and with mildly elevated PRL (OB+PRL↑, n=108). Markers of glucose-lipid metabolism and chronic low-grade inflammation were measured. 115 obese patients (OB, n=64; OB+PRL↑, n=51) underwent LSG. PRL and metabolic markers at 6 and 12 months after LSG were measured. Results showed that blood glucose (BG) at five points of oral glucose tolerance test, blood lipid (total cholesterol (TCH), low-density lipoprotein cholesterol (LDL-C), triglyceride) and tumor necrosis factor-α were lower in OB+PRL↑ than OB group (all P&lt;0.05). PRL was negatively associated with neck circumference, waist-to-hip ratio, systolic pressure, heart rate, basal metabolic rate (BM), alkaline phosphatase (AKP), TCH and LDL in all obesity (all P&lt;0.05). PRL levels were positively associated with weight, hip circumference and BM in males while negatively associated with alanine transaminase, glutamic oxaloacetic transaminase, AKP, BG30min, BG60min, free fatty acid and TCH in females (all P&lt;0.05). PRL was descended in OB+PRL↑ (P=0.015) while increased in the OB group at 12 months after surgery(P=0.009). Increased PRL was associated with the change in TCH(P&lt;0.05).
In conclusion, we found that the increased PRL levels in obesity results in better glucose-lipid metabolism and lower chronic low-grade inflammation. LSG led to increased PRL in obesity and decreased PRL in obesity with mildly elevated PRL. Improved lipid metabolism was associated with increased PRL after surgery.

Disclosure
S. Qu: None. X. Wang: None.

Funding
National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)
1979-P: Thyroid Hormone Associated with Acanthosis Nigricans and Fat Distribution in Obese Patients Nigricans and Fat Distribution in Obese Patients
Authors: QU SHEN , WANG XINGCHUN 
Published: June 2020

Obesity exhibits subclinical hypothyroidism (SH) and acanthosis nigricans (AN) easily as an associated complication. We aimed to elucidate the triad interlink between the thyroid hormone levels, fat distribution and AN. In this cross-sectional study, 202 obese men and 239 obese women were enrolled. Anthropometric measurements, glucose-lipid metabolism, thyroid hormone levels, and fat distribution were measured. SH was defined by thyroid-stimulating hormone (TSH) less than 2.5 mU/L. Results showed that the prevalence of AN was significantly higher in the obese group with SH than without SH (47.3% vs. 36.9%, P=0.035). The number of obese women with SH was larger than men (38.1% vs. 28.2%, P=0.029). Obese women have higher TSH levels, lower free triiodothyronine (FT3) and free thyroxin (FT4) than obese men (all P&lt;0.01). In all obesity, FT3 was significantly positively associated with weight, NC, WC, WHR, SBP, DBP, FINS, UA and negatively with HDL-C (all P &lt;0.05). FT4 was significantly positively associated with weight, BMI, NC, WC, SBP, DBP, UA, HGB and FBG (all P &lt;0.05). TSH was negatively correlated with FBG and HGB (all P &lt;0.05). FT3 was positively correlated with Peripheral fat mass, total lean mass and negatively with Total Fat% and Trunk/peripheral fat mass (P=0.025;P=0.029;P&lt;0.001;P=0.034), FT4 was also positively with total lean mass and negatively with Total Fat%(P=0.008; P=0.017), and TSH was positively correlated with Total Fat%(P=0.032).
In conclusion, we found that obese patients with SH are more susceptible to AN. Relatively insufficient thyroid function with higher TSH may be a protective factor in obese women with a better metabolism. Thyroid hormone may be beneficial in improving fat distribution and building lean mass in patients with obesity.

Disclosure
S. Qu: None. X. Wang: None.

Funding
National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677)
1986-P: Plasma Retinol Binding Protein 4 and Adipsin Levels Were Not Altered after Gastric Sleeve Surgery in Adult Male Population
Authors: ALSHUBRAMI SUAD , IQBAL MUHAMMAD , ALFADDA ASSIM , ALREGAIEY KHALID 
Published: June 2020

Background: Bariatric or weight loss surgery provides the most substantial and sustainable weight loss in individuals with obesity. Caloric restriction and malabsorption are not the only mechanisms by which bariatric surgery reduces body weight and improves glycemic control. Alterations in the secretion and activity of hormones are also the contributory mechanisms in bariatric surgery. We evaluated the levels of retinol binding protein 4 (RBP4) and adipsin after gastric sleeve surgery and their relationship with insulin and lipid parameters.
Method: Thirty-three obese (BMI &gt; 38.3) healthy male subjects age ranged from 25 to 50 years were selected for this study. Plasma levels of RBP4 and adipsin were analyzed before and six months after gastric sleeve surgery by ELISA, along with plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and lipid profile.
Results: Circulating RBP4 was not significantly changed by bariatric surgery (4382.85±7.03 ng before, and 4393.28±5.769 ng after surgery, P= 0.842), neither did adipsin (2949.68±8.16 pg before, and 2917.90±7.295 pg after surgery, P=0.535). As expected, there was a reduction in BMI, insulin levels and HOMA-IR after six months of surgery. Lipid profile analysis revealed that cholesterol, high density lipoproteins (HDL), and low density lipoproteins (LDL) levels were increased after surgery (4.26±0.027 to 5.12±0.026 mmol/L and 0.90±0.007 to 1.55±0.011 mmol/L and 2.62±0.02 to 2.98±0.022 mmol/L, P&lt;0.001) respectively. However, there was no correlation between RBP4, adipsin and insulin and lipid parameters.
Conclusions: Our findings do not suggest a role for RBP4 and adipsin in the improvement of insulin sensitivity in obese male population after gastric sleeve surgery. Moreover, there was no correlation between their plasma levels and either BMI, glucose, insulin, or lipid profiles.

Disclosure
S. Alshubrami: None. M. Iqbal: None. A. Alfadda: None. K. Alregaiey: None.

Funding
King Abdulaziz City for Science and Technology (1-17-03-001-0026)
1988-P: Association between Screen Time Including Smartphone Use and Obesity and Its Associated Lifestyles in School Children in Japan
Authors: IKEDA IZUMI , FUJIHARA KAZUYA , NEDACHI RINA , MORIKAWA SAKIKO Y. , ISHIGURO HAJIME , YAMADA MAYUKO H. , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , SONE HIROHITO 
Published: June 2020

An increase in screen time (ST) is reportedly associated with insulin resistance and obesity in children. However, most studies are of TV viewing but not smartphone use. Also, little is known of the relationship between ST and diet. In this study, we clarified the relationships among ST including smartphone use, lifestyle factors including dietary content, and obesity. Cross-sectionally analyzed were 1393 children between 11-15 years of age. ST (min/day) was classified into 4 groups: &lt;120, 120-179, 180-239, ≥240. The associations of each group with dietary content and obesity were investigated. Smartphone usage time significantly increase and sleep duration significantly decreased as ST increased, which was not the case for physical activity. There was no significant difference in energy intake between the 4 groups of ST either for boys or girls, but intake of protein, vegetables green and yellow, other vegetables, and fish and shellfish decreased significantly as ST increased, as did increase in beverage intake. In addition, the association with obesity was significantly increased in the ≥240 ST group compared to the &lt;120 ST group (1.93[1.14-3.28]).
In conclusion, the increase in ST including smartphone usage was suggested to be associated with various unfavorable lifestyles including dietary habits that could be connected to obesity.

Disclosure
I. Ikeda: None. K. Fujihara: None. R. Nedachi: None. S.Y. Morikawa: None. H. Ishiguro: None. M.H. Yamada: None. Y. Matsubayashi: None. T. Yamada: None. H. Sone: Research Support; Self; Kyowa Hakko Kirin Co., Ltd., Novartis AG, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.
1998-P: Waist Circumference Change in the First Year of the Look AHEAD Trial Is Associated with Risk for Cardiovascular Morbidity and Mortality
Authors: OLSON KAYLONI L. , NEIBERG REBECCA H. , ESPELAND MARK , JOHNSON KAREN C. , KNOWLER WILLIAM C. , PI-SUNYER XAVIER , STAIANO AMANDA E. , WAGENKNECHT LYNNE E. , WING RENA R. ,   THE LOOK AHEAD GROUP
Published: June 2020

Look AHEAD found no difference between intensive lifestyle intervention (ILI) for weight loss and diabetes support and education (DSE; control) in cardiovascular (CVD) outcomes among individuals with overweight or obesity and type 2 diabetes (T2DM). This secondary analysis evaluated the association between change in weight and waist circumference (WC), a possible proxy for visceral adiposity, and risk for CVD outcomes. We classified Look AHEAD participants (n=4590) into one of four categories based on change in weight and WC from baseline to Year 1 (increase/increase, etc.) to examine the association between the categories and primary (myocardial infarction, stroke, hospitalized angina, CVD death) and secondary (primary outcomes and CABG/PTCA, hospitalized congestive heart failure, carotid endarterectomy, PVD, and total mortality) CVD outcomes from Year 1 to end of active treatment (median of 9 years). Cox proportional-hazards regression models were used to 1) compare ILI participants in the four categories to DSE and 2) evaluate the four categories within treatment groups using the group that decreased WC and weight as the reference. Compared to DSE, individuals in ILI who increased WC and weight and individuals who increased WC but decreased weight both had greater risk of secondary CVD outcomes (HR[95%CI]: 1.95 [1.33, 2.86] and 1.35 [1.02, 1.80] respectively). In analyses stratified by randomization group, DSE participants did not differ in cardiovascular events across categories. Individuals in ILI who gained WC (regardless of weight loss or gain), had increased risk of primary and secondary CVD outcomes compared to individuals in ILI who decreased weight and WC. Increased WC during weight loss treatment, regardless of weight loss or gain, is associated with greater risk for CVD outcomes in individuals with T2DM. This emphasizes the importance of measuring WC in clinical practice and testing interventions focused on decreasing WC.

Disclosure
K.L. Olson: None. R.H. Neiberg: None. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. K.C. Johnson: None. W.C. Knowler: None. A.E. Staiano: None. L.E. Wagenknecht: None. R.R. Wing: None.

Funding
National Institutes of Health