bluuebunny/crossref_metadata_2025_split huggingface dataset:
2031-P: Adipose-Specific Lack of Hexose-6-Phosphate Dehydrogenase Causes Inactivation of Adipose Glucocorticoids and Improves Metabolic Phenotype in Male Mice
Authors: WANG JIAN , WANG XINXIANG , LUTFY KABIRULLAH , FRIEDMAN THEODORE , JIANG MEISHENG , LIU YANJUN 
Published: June 2019

Excessive glucocorticoids (GCs) production in adipose tissue promotes the development of visceral obesity and the metabolic syndrome. 11β-Hydroxysteroid dehydrogenase type 1 (11 β-HSD1) is critical for controlling intracellular GC production in adipose tissue, and this process is also regulated by hexose-6-phosphate dehydrogenase (H6PDH) that provides cofactor NADPH for 11β-HSD1 amplifying local GC production. To better understand the integrated molecular and physiological role of adipose H6PDH, we created a tissue specific knockout of H6PDH gene mouse model in adipocytes (H6PDHAcKO mice) and characterized the metabolic related phenotypes. H6PDHAcKO mice had decreased levels of intra-adipose corticosterone with reduction of 11β-HSD1 activity in response to H6PDH deletion in adipose tissue. Moreover, H6PDHAcKO mice also exhibited reduced fasting blood glucose levels and increased glucose tolerance with increased insulin sensitivity. In addition, plasma FFA levels were decreased with a concomitant decrease in the expression of lipase ATGL and HSL in the abdominal adipose tissue. These results indicate that inactivation of H6PDH expression in adipose tissue is sufficient to cause intra-adipose GC inactivation leading to the favorable pattern of metabolic phenotype. These data suggest that H6PDHAcKO mice may provide a good model for study the potential contributions of fat-specific H6PDH inhibition in the metabolic phenotype and other pathological disorders in vivo.

Disclosure
J. Wang: None. X. Wang: None. K. Lutfy: None. T. Friedman: None. M. Jiang: None. Y. Liu: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (SC1DK104821)
2036-P: Gut Microbes Regulate Insulin Clearance in Mice
Authors: FOLEY KEVIN P. , ZLITNI SOUMAYA , DUGGAN BRITTANY M. , HENRIKSBO BRANDYN D. , BARRA NICOLE G. , CAVALLARI JOSEPH F. , ANHÊ FERNANDO FORATO , LAU TREVOR , CHEN YUK KWAN , SCHERTZER JONATHAN D. 
Published: June 2019

Obesity and insulin resistance are associated with hyperinsulinemia, which is caused by increased insulin secretion and/or reduced insulin clearance. Impaired insulin clearance may be caused by ectopic lipid deposition in liver and skeletal muscle, the key sites of insulin clearance and degradation. Insulin is the key hormone regulating blood glucose. The composition of the intestinal microbiota can regulate aspects of diet-induced obesity and glucose metabolism. Here we found that the microbiota also regulates insulin clearance during prolonged diet-induced obesity. Male C57Bl/6J mice fed 45% high fat diet (HFD) for a prolonged period had impaired insulin clearance relative to chow fed mice as measured by insulin/C-peptide ratio during an oral glucose tolerance test. High fat fed mice also showed impaired insulin clearance measured after injection of insulin - mice fed chow or 45% HFD had plasma insulin concentration measured at 0, 5, 30, and 60 minutes following injection of human insulin and area under the curve calculated. Treatment of 45% HFD-fed mice with an antibiotic cocktail of Neomycin/Ampicillin for 2 weeks improved insulin clearance after insulin injection. Next, we colonized previously germ-free mice with the microbiota from chow or 45% HFD-fed “donor” mice for 6 weeks. The previously germ-free “recipient” mice colonized with feces-resident microbes from chow or HFD fed donors did not differ in insulin clearance when recipient mice were fed a chow diet. However, when colonized recipient mice were switched from chow to 45% HFD for 2 weeks the recipient mice colonized with microbes from 45% HFD fed donors showed impaired insulin clearance relative to recipient mice colonized with microbes from chow fed donors. Our results demonstrate that diet-induced changes in fecal microbes are an independent factor regulating insulin clearance. Diet-induced changes in the gut microbiota and consequent impaired insulin clearance may participate in hyperinsulinemia leading to exacerbated insulin resistance and obesity.

Disclosure
K.P. Foley: None. S. Zlitni: None. B.M. Duggan: None. B.D. Henriksbo: None. N.G. Barra: None. J.F. Cavallari: None. F. Forato Anhê: None. T. Lau: None. Y. Chen: None. J.D. Schertzer: None.

Funding
Canadian Institutes of Health Research
2040-P: Sex-Dependent Effects of MC4R Genotype on HPA Axis Tone
Authors: CHAFFIN AKI T.B. , FANG YANBIN , LARSON KARLTON R. , MUL JORAM , RYAN KAREN K. 
Published: June 2019

Neuroendocrine circuits underlying stress integration and systemic fuel homeostasis are substantially intertwined. Accordingly, metabolic diseases such as obesity and diabetes have a high incidence of co-morbidity with stress-associated psychological disorders like anxiety and depression. Importantly, there is a strong female bias in both metabolic and stress-related disorders, making the understanding of sex-specific functions of these pathways critical for treatment. The hypothalamic melanocortin system is a principal regulator of energy balance and also modulates HPA responses to acute stress. Mutations in the melanocortin-4 receptor (MC4R) is the most common monogenic cause of obesity in humans and has been associated with sex-dependent effects, such as more women than men exhibiting ‘emotional’ eating, a behavior that is thought to be stress-induced. Thus, we hypothesized that MC4R deficiency may cause sexually dimorphic metabolic and stress responses. We subjected male and female rats with a MC4R loss-of-function mutation to either chronic variable stress (CVS) or no stress for 31 days. Mid-study, all rats underwent an acute restraint stress challenge. Consistent with previous reports, male and female rats with MC4R deficiency had increased food intake and body weight, which were both decreased by CVS. Contrary to expectation, MC4R genotype did not affect HPA axis or metabolic responses to chronic stress. But importantly, we observed a significant interaction between MC4R genotype and sex in HPA axis tone and acute stress reactivity, such that MC4R deficiency blunted both endpoints in males but exaggerated them in females. Females showed a dramatic 259% and 419% increase in basal corticosterone and HPA reactivity, respectively, compared to males. The heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females.

Disclosure
A.T.B. Chaffin: None. Y. Fang: None. K.R. Larson: None. J. Mul: None. K.K. Ryan: None.

Funding
National Institutes of Health (R00HL111319)
2042-P: Genetic Dissection of Leptin Signaling in AgRP Neurons
Authors: XU JIE , CHIEN CHENG-HAO , YI XINCHI , BARTOLOME CHRISTOPHER , KONG DONG 
Published: June 2019

Leptin, a hormone produced in white adipose tissue, acts in the brain to maintain body weight and blood glucose stability. Dysregulation of leptin or its receptor (LEPR) results in severe obesity and diabetes. Although intensive studies on leptin have transformed obesity and diabetes research, clinical applications of the molecule are still limited, at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. In our previous findings, we found that the hypothalamic AgRP(agouti-related peptide) neurons are the primary target for leptin to regulate both energy balance and glucose homeostasis. We show that CRISPR-mediated deletion of leptin receptor in AgRP neurons causes severe obesity and diabetes. We also uncover divergent mechanisms of acute and chronic inhibition of AgRP neurons by leptin (presynaptic potentiation of GABA (γ-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels (Katp), respectively). However, the molecular signaling involved in leptin's regulation on Katp and GABA transmission are not clear. In current study, we employed the CRISPR technology, combined with electrophysiology to further identify that the Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway plays an important role in mediating leptin's action on GABA transmission. We also tested that leptin can directly activate KATP channel and by using two-photon excitation microscopy, we proved that this activation is modulated by ATP/ADP ratio.

Disclosure
J. Xu: None. C. Chien: None. X. Yi: None. C. Bartolome: None. D. Kong: Board Member; Spouse/Partner; Jersey Biosciences Inc. Board Member; Self; PRECIDIAG INC.

Funding
American Diabetes Association (1-19-PDF-159-R to J.X.)
2058-P: Leptin and Adiponectin Concentrations Independently Predict Future Accumulation of Visceral Adiposity in Nondiabetic Japanese Americans
Authors: SONG SUN OK , KAHN STEVEN E. , LEONETTI DONNA L. , FUJIMOTO WILFRED Y. , BOYKO EDWARD J. 
Published: June 2019

Objectives: The adipokines leptin and adiponectin are associated with change in body composition and are highly correlated, raising questions about whether they exert independent effects. We investigated whether these two adipokines are independently associated with regional body fat accumulation in a prospective study of Japanese Americans.
Methods: Nondiabetic participants between the ages of 34 to 74 years were followed for 5 years to assess change in body composition. Leptin and adiponectin concentrations and single slice CT-measurements of intra-abdominal fat (IAF), abdominal (SCF) and thigh (TF) subcutaneous fat cross-sectional areas were evaluated at baseline and 5 year follow-up study visits. Multiple linear regression analysis was used to estimate the association between leptin and adiponectin and future 5-year accumulation of IAF.
Results: 96 men and 95 women without diabetes included in this analysis had the following baseline mean (SD) values: age 45.7 (3.5) years and 46.4 (3.9) years; BMI 25.5 (3.1) kg/m2 and 24.0 (3.9) kg/m2; IAF 78.7 (38.6) cm2 and 62.1 (39.0) cm2; leptin concentration 4.5 (2.3) μg/L and 10.2 (5.2) μg/L; and adiponectin concentration 7.4 (3.2) μg/mL and 10.8 (4.7) μg/mL, respectively. Baseline leptin (β = 1.7722, p=0.014) and adiponectin concentrations (β = -0.4162, p&lt;0.001) were significantly associated with ΔIAF over 5 years in multivariable models adjusting for age, sex, diabetes family history, weight change over 5 years, and baseline measurements of BMI, IAF, abdominal SCF, abdominal circumference, TF, and HOMA-IR.
Conclusions: In nondiabetic Japanese Americans, baseline concentrations of leptin and adiponectin were independent predictors of IAF accumulation at 5 years. Higher levels of leptin and adiponectin were associated with greater and lesser accumulation of IAF, respectively. These relationships were independent of age, sex, insulin sensitivity, and body composition.

Disclosure
S. Song: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. D.L. Leonetti: None. W.Y. Fujimoto: None. E.J. Boyko: None.

Funding
National Institutes of Health DK31170, HL49293); University of Washington (DK017047, DK035816, RR-000037); VA Puget Sound Health Care System (to E.J.B., S.E.K.)
206-OR: A Randomized Controlled Trial to Improve Self-Monitoring of Blood Glucose among Youth with Type 1
Authors: WAGNER JULIE , WEYMAN KATE , TICHY EILEEN M. , CENGIZ EDA , ZAJAC KRISTYN , TAMBORLANE WILLIAM V. 
Published: June 2019

Objective: This randomized, controlled trial evaluated a monetary-based reinforcement intervention for increasing self-monitoring blood glucose (SMBG) among youth with poorly controlled type 1 diabetes. SMBG frequency was the primary outcome, A1c was the secondary outcome.
Methods: After a 2-week baseline, 60 youth age 12-19 years with &lt;4 BG checks per day and A1c &gt;7.5% but ≤13% were randomized to enhanced usual care (EUC) or Reinforcers. The Reinforcers group earned monetary rewards for SMBG and associated behaviors such as uploading glucose meters, completing pattern recognition forms, and reviewing results with clinicians. Reinforcers were withdrawn at 24 weeks. A follow-up evaluation occurred at 36 weeks.
Results: Randomization produced groups that did not differ on any demographic or clinical characteristics. Participants in the Reinforcers group increased the proportion of days they completed ≥4 SMBG from 14.6% at baseline to 64.4%, 47.5%, and 37.8% at 6, 12, and 24 weeks, respectively. In contrast EUC participants declined from 22.7% at baseline to 17.5%, 10.5%, and 11.1% (ps&lt;0.01 versus EUC at all time points). Group differences were attenuated but remained significant after withdrawal of reinforcers. Effect sizes for SMBG were very large during reinforcement and large after withdrawal of reinforcers. In the Reinforcers group, mean A1c dropped from 9.5±1.2% at baseline to 9.0±1.3% at week 6 and 9.0±1.4% at week 12. For EUC, A1c was 9.2%±0.2 at baseline and ranged from 9.2±1.5% to 9.6±1.6% throughout the study (p&lt;0.05 versus EUC). Group differences in A1c were no longer significant at weeks 24 and 36. Effect sizes for A1c were small during reinforcement and also after withdrawal of reinforcement.
Conclusions: Monetary-based reinforcement of adolescents with type 1 diabetes caused durable increases in SMBG. Modification of the reinforcement structure may be needed to sustain improved metabolic control in this challenging age group.

Disclosure
J. Wagner: None. K. Weyman: None. E.M. Tichy: None. E. Cengiz: Advisory Panel; Self; Abvance, ADOCIA, MannKind Corporation, Novo Nordisk Inc. Speaker's Bureau; Self; Novo Nordisk Inc. K. Zajac: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.
2068-P: Alpha Klotho Modulation with Remission of Prediabetes in Human Subjects
Authors: STENTZ FRANKIE B. , AMMONS ANN 
Published: June 2019

Alpha klotho (αK) a protein named for its severe aging effects when under expressed has one of its primary sites of synthesis in the kidneys. Therefore, anything resulting in kidney damage may result in lower αK levels. Diabetes is one of the most common causes of kidney damage; thus, assessing αK levels in relation to glycemic control was the objective of this study.
Twelve obese subjects, age 43.1±1.3 years, with prediabetes were studied at baseline and 6 months (mo) after 10% weight loss on a diet consisting of 30% protein, 30% fat, 40% carbohydrates which resulted in 100% remission of their prediabetes to normal glucose. Glucose, insulin and αK levels were determined during a 75 gm glucose tolerance test (OGTT) at baseline and 6 mo. Soluble αK levels increased significantly from baseline to six mo. Although the microalbumin/creatinine ratio was within normal range at baseline indicating normal kidney function, the ratio improved significantly at 6 mo.
Levels of soluble αK were determined to positively covary with the glucose (r2 = 0.83) and insulin levels (r2 = 0.74) during the OGTT at both baseline and at 6 mo.
These results suggest that αK levels may be markers of very early stages of renal damage in prediabetic subjects and that glucose and insulin interact with soluble αK in a significant manner. These results imply that poor glycemic control can have earlier and more systemic effects that previously thought via altering circulating αK levels.

Disclosure
F.B. Stentz: None. A. Ammons: None.

Funding
AD Baskin
2072-P: Alterations in Fat Mass and Bone Mineral Density Are Associated with Decreased Lipocalin-2 after Laparoscopic Sleeve Gastrectomy in Obese Chinese Women
Authors: WEN XIN , MEI FANGYUN , ZHOU DONGLEI , BU LE , QU SHEN 
Published: June 2019

Objective: Lipocalin-2 (LCN2) plays an important role in the regulation of the obesity and obesity-related dysmetabolic state. This study aimed to analyze serum LCN2 level in obese Chinese women before and after laparoscopic sleeve gastrectomy (LSG) and determine the association between alteration in fat mass and bone mineral density (BMD) and LCN2 level.
Methods: Fifty-two women (38 obese and 14 with normal body mass index (BMI)) were enrolled in this study. All obese patients underwent LSG. BMDs of the arm, leg, thoracic and lumbar spine, and pelvis were measured by dual-energy X-ray absorptiometry. Body fat mass and distribution were measured by dual-energy X-ray absorptiometry, and routine anthropometric/laboratory biochemical parameters at baseline and 3 and 12 months after LSG were recorded. Serum LCN2 levels were measured using an enzyme-linked immunosorbent assay.
Results: Serum LCN2 level was significantly higher in obese women than in the controls with normal BMI (102.70±27.19 vs. 80.66±19.55, P = 0.009). LCN2 level was significantly decreased at 3 and 12 months after LSG (86.73±26.79, P&lt;0.001, and 64.79±28.39, P&lt;0.001, respectively). LSG led to marked body fat mass and slight BMD decrease. Decreased LCN2 level was significantly correlated with alterations in left and right leg BMDs and trunk fat mass at 12 months after LSG.
Conclusions: Obesity was associated with up-regulated serum LCN2 level. Decreased LCN2 level was positively correlated with changes in BMD and fat mass at 12 months after LSG in Chinese women.

Disclosure
X. Wen: None. F. Mei: None. D. Zhou: None. L. Bu: None. S. Qu: None.

Funding
Shanghai Sailing Science Fund (14YF1412400)
2075-P: Insulin Resistance Improved at Six Months following Bariatric Surgery Despite Accelerated Lipolysis and Accumulation of Lipid-Derived Acylcarnitines
Authors: TAN HONG CHANG , HSU JEAN W. , KOVALIK JEAN-PAUL , KHOO CHIN MENG , CHACKO SHAJI , GANGULY SONALI , TAI E. SHYONG , LAI OI FAH , LIM EUGENE , JAHOOR FAROOK 
Published: June 2019

Background: Accelerated lipolysis and the accumulation of incomplete products of fatty acid metabolism may contribute to insulin resistance (IR). It remains unclear whether the improvement in IR during the early period following bariatric surgery could be related to changes in lipid metabolism.
Aims and Hypothesis: In this study, we compared the rates of lipolysis, lipid-related acylcarnitines (ACs) and IR in morbidly obese individuals at baseline, 6-months after bariatric surgery and with lean controls.
Methods: 10 morbidly obese individuals scheduled for sleeve gastrectomy and 14 lean controls were recruited. IR was quantified using OGTT while body composition was measured using the 2H2O technique or DXA scans. Glycerol flux represents whole-body lipolysis and was measured using 2H5-glycerol infusion. Plasma lipid-derived ACs were measured using mass spectrometry as an indicator of complete fatty acid oxidation. Obese subjects were reassessed 6-months after bariatric surgery.
Results: Compared to lean controls, obese subjects had significantly higher fat mass (50.7 ± 1.9 vs. 16.8 ± 1.0 kg) and were significantly more IR. They had higher HOMA-IR (6.6 ± 1.0 vs. 1.43 ± 0.31), glucose and insulin AUC after OGTT. Glycerol flux (16098.1 ± 1136.2 vs. 7266.20± 497.66 umol/h), plasma glycerol (117.13 ± 10.96 vs, 46.79± 3.15 umol/L), C14 (0.225 ± 0.079 vs. 0.042± 0.012) and C16 (0.136 ± 0.016 vs. 096 ± 0.003 umol/L) ACs were significantly higher in the obese individuals. 8 subjects returned at 6-months and lost 19% of their total weight, 29% of fat mass and had a 68% decrease in HOMA-IR. Glycerol flux, plasma glycerol, C14 and C18 ACs however did not show any difference compared to baseline and remained significantly higher compared to the lean controls.
Conclusion: IR improved 6-months following sleeve gastrecotmy despite accelerated lipolysis and accumulation of byproducts of incomplete fatty acid metabolism.

Disclosure
H. Tan: None. J.W. Hsu: None. J. Kovalik: None. C. Khoo: None. S. Chacko: None. S. Ganguly: None. E. Tai: Advisory Panel; Self; Amgen Inc., BASF. O. Lai: None. E. Lim: None. F. Jahoor: None.
2077-P: Effect of Laparoscopic Sleeve Gastrectomy on Sex Hormone Level and Ovarian Volume in Female Obesity with PCOS
Authors: GAO JINGYANG , ZHANG MANNA , ZHU CUILING , WANG XINGCHUN , MEI FANGYUN , QU SHEN 
Published: June 2019

Objective: This study was designed to examine changes in body fat distribution after laparoscopic sleeve gastrectomy (LSG) and to confirm whether these changes are correlated with increased testosterone.
Methods: A retrospective study was performed in 51 obese female patients with BMI 30-45 kg/m2 who underwent LSG from Shanghai Tenth People’s Hospital, 38 of whom were PCOS patients. The anthropometric indexes, sex hormone and ovarian volume of ultrasound examinations include both sides ovarian volume, mean ovarian volume (MOV) and maximal ovarian volume (MaxOV) were observed preoperative and follow-up at 3 and 6 months after LSG. The metabolic indexes and ovarian volume were compared before and after surgery.
Results: Compared with preoperative, PCOS patients' weight, BMI, waist circumference and hip circumference were significantly lower at 3 and 6 months after operation (P&lt;0.05). Percentage of excess body weight loss(%EWL) for 3 months and 6 months after LSG was 56.32% and 75.98%. TT and cFT showed a downward trend at 3 and 6 months after surgery while SHBG showed an upward trend (P&lt;0.05). Both sides ovary volume and MOV, MaxOV all decreased at 6 months after LSG, but there was no statistically significant difference compared to baseline. Compared with patients without PCOS, the preoperative MOV, MaxOV, and left ovary volume were significantly larger (P&lt;0.05). At 6 months after surgery, the MOV, MaxOV, left ovary volume and right ovarian volume of PCOS and non-PCOS patients were all reduced. The differences in MOV, MaxOV, left ovary volume and right ovarian volume were no longer statistically significant between the two groups.
Conclusions: TT and cFT decreased and SHBG increased significantly after LSG. MOV shrinked at 6 months after LSG and was no longer different from non-PCOS patients. LSG is not only an important treatment for weight loss, but also improve PCOS and its clinical symptoms effectively in severe obese women.

Disclosure
J. Gao: None. M. Zhang: None. C. Zhu: None. X. Wang: None. F. Mei: None. S. Qu: None.

Funding
National Natural Science Foundation of China (81601269)