bluuebunny/crossref_metadata_2025_split huggingface dataset:
311-LB: Gustatory Cortex Response to Sweet Taste Is Positively Correlated with Adiposity
Authors: CONSIDINE ROBERT V. , JANETSIAN-FRITZ SARINE S. , PICKLESIMER MAKAYLA D. , WAINSCOTT SARAH E. , DZEMIDZIC MARIO , KAREKEN DAVID A. 
Published: June 2019

How sweet taste perception promotes excess caloric intake, obesity and diabetes is debated. There is little evidence for altered sweet taste in obesity, and adiposity does not predict sweet liking. However, overweight and obese subjects generally prefer high fat, sweet stimuli. The effect of adiposity on brain responses to sweet taste has not been systematically assessed, particularly in adults. In this ongoing study, 8 normal weight women (BMI 23.4±2.2 kg/m2, age 47±14 y) and 7 women with obesity (BMI 48.8±9.2 kg/m2, age 44±10 y), underwent functional magnetic resonance imaging (fMRI) on a Siemens 3T Magnetom Prisma using 32-channel head coil. fMRI assessed brain responses to 0.40M and 0.10M sucrose sprayed onto the tongue as compared to water (7 sucrose and 17 water trials in each 5:52 min long scan). Two scans were acquired at each concentration, where 0.40M and 0.10M scans alternated and the first scan sucrose concentration was counterbalanced across subjects. Across the whole sample, BOLD activation from [Sucrose (0.40M) &gt; water] was detected (p&lt;0.01, k&gt;10) in gustatory insula, sensorimotor cortex/rolandic operculum, right ventral striatum, and bilateral posterolateral orbital cortex (the latter only in [Sucrose (0.10M) &gt; water]). After including BMI as a covariate, a positive association of BMI and [Sucrose (0.40M) &gt; water] contrast was present in the left gustatory insula area (peak, p&lt;0.005), right rolandic operculum and sensorimotor cortex (ps&lt;0.008). There were no negative correlations between BMI and the [Sucrose (0.40M) &gt; water] contrast. BMI did not correlate with the [Sucrose (0.10M) &gt; water] contrast. These preliminary findings suggest that women with obesity have greater responses in gustatory cortex to sweet taste compared to lean women. This is consistent with reports that overweight and obese subjects generally prefer sweet foods. The data might also suggest that gustatory cortex reactivity is altered by excess adiposity, possibly complicating diet compliance.

Disclosure
R.V. Considine: None. S.S. Janetsian-Fritz: None. M.D. Picklesimer: None. S.E. Wainscott: None. M. Dzemidzic: None. D.A. Kareken: None.

Funding
American Diabetes Association (1-18-ICTS-036 to R.V.C.)
311-OR: CREBZF as a Novel Target of Glucose Sensing Signaling in the Control of Adaptive Thermogenesis in the Adipose Tissue
Authors: CUI AOYUAN , LIU ZHENGSHUAI , MA FENGGUANG , BAI JINYUN , XUE YAQIAN , LIU YUXIAO , HU ZHIMIN , HAN YAMEI , ZHANG FEIFEI F. , GAO JING , GAO XIN , LI YU 
Published: June 2019

Although glucose is generally considered to be required for generating heat during cold-induced nonshivering thermogenesis in the adipose tissue, whether it engages nutrient sensing pathways in the adipose tissue to negatively regulate thermogenesis and impairs metabolic homeostasis remains largely unknown. Here we report CREB/ATF bZIP transcription factor CREBZF as a key target of adipocyte glucose sensing signaling that exerts a negative effect on the adaptive thermogenesis in the adipose tissue. We found that CREBZF was significantly induced in inguinal white adipose tissue (iWAT) in response to cold exposure or β3AR agonist treatment, which was associated with an induced expression of glucose transporter genes such as GLUT1 and GLUT4. To elucidate the function of CREBZF, we generated adipose-specific CREBZF knockout (CREBZF FKO) mice. Compared with WT mice, CREBZF FKO mice exhibited enhanced browning of iWAT and thermogenic capacity in response to acute and chronic cold exposure. Moreover, CREBZF FKO mice were less cold sensitive. In the adipocyte, CREBZF was induced by glucose treatment, which was associated with increased acetylation of CREBZF. Interestingly, the protein stability of CREBZF was dynamically regulated by reversible acetylation mediated by transacetylase CREB-binding protein (CBP) and deacetylase HDAC. Deletion of CBP ameliorated glucose-induced CREBZF. Proteomic analysis was performed to identify potential acetylation sites of CREBZF. Furthermore, CREBZF associated with PGC-1α and inhibited its transcription activity. Together, we propose that in addition to its role as a fuel source to promote thermogenesis, glucose may act as a chemical signal to stimulate CREBZF activity and cause impaired browning and thermogenesis in the adipose tissue. This study uncovers an unknown mechanism of glucose sensing in the adipocyte that contributes to homeostasis of energy metabolism.

Disclosure
A. Cui: None. Z. Liu: None. F. Ma: None. J. Bai: None. Y. Xue: None. Y. Liu: None. Z. Hu: None. Y. Han: None. F.F. Zhang: None. J. Gao: None. X. Gao: None. Y. Li: None.

Funding
National Key Research and Development Program of China (2017YFC0909601); National Natural Science Foundation of China (31471129, 31671224); Chinese Academy of Sciences (KJZD-EW-G20-02); K.C. Wong Education Foundation (to Y.L.)
312-LB: Irisin, Meteorin-Like Protein, and Bone Remodeling Markers in T2D and Obesity
Authors: ABU-FARHA MOHAMED , CHERIAN PREETHI THOMAS , KHAIRI IRINA AL , JAMAL MOHAMMAD , AL-SABAH SULEIMAN , ALI HAMAD , DSOUZA CAROL , ALOTAIBI FATEMAH KULAIB , AL-ALI WALEED , AL-KHALEDI GHANIM MOHAMMAD , ABUBAKER JEHAD , AL-MULLA FAHD 
Published: June 2019

Obesity and type 2 diabetes (T2D) are linked to metabolic dysregulation and chronic inflammation. Adipose tissue and skeletal muscles are key endocrine organs. Dysregulation in adipomyokines secreted by these organs could play a role in obesity-induced complications. Obesity, T2D and bone metabolism are interrelated. Our objective was to study the expression of two adipomyokines-Irisin and Meteorin-like protein (METRNL) in obesity and T2D and understand their association with various bone markers. Overall, 228 individuals were enrolled in this study, including 124 nondiabetic and 104 T2D . Plasma level of MTRNL and irisin were assessed by ELISA. Plasma level of METRNL and irisin were significantly higher in T2D (1263.5 ± 24.9 pg/ml and 623.0± 21.8 pg/ml respectively) compared to nondiabetic individuals (1198.5 ± 24.2 pg/ml for METRNL and 508.2 ± 15.3 pg/ml for irisin) p-Value &lt; 0.05. METRNL and irisin were significantly higher in obese (1267.9 ± 24.8 pg/ml and 593.4 ± 18.1 pg/ml respectively) compared to non-obese individuals (1186.3 ± 24.2 pg/ml and 519.9 ± 19.1 respectively) p-Value &lt; 0.05. Plasma level of bone markers Osteoactivin, Syndecan, OPG and SPARC were significantly higher in obese and T2D individuals compared to non-obese and nondiabetic individuals (P-values ≤0.01). Correlation analysis on nondiabetic population showed significant positive correlation between METRNL and irisin. Irisin showed a strong positive association with Osteoactivin, Syndecan, OPG, and SPARC. A strong positive association was observed between METRNL and Osteoactivin. The interplay between these bone markers is linked to bone remodeling. The strong positive association between the adipomyokines and bone markers suggests that, a dysregulation in the functional interaction between them may play a possible role in the development of bone related complications associated with obesity and T2D. We are currently conducting further experiments to understand mechanistically the significance of their interplay.

Disclosure
M. Abu-farha: None. P.T. Cherian: None. I. Al khairi: None. M. Jamal: None. S. Al-Sabah: None. H. Ali: None. C. Dsouza: None. F.K. AlOtaibi: None. W. Al-Ali: None. G.M. Al-Khaledi: None. J. Abubaker: None. F. Al-Mulla: None.

Funding
Dasman Diabetes Institute
317-LB: Optimal Weight Loss Effect of Short-Term Low Carbohydrate Diet with Calorie Restriction on Overweight/Obese Subjects in South China—A Multicenter Randomized Controlled Trial
Authors: SUN JIA , XU NINGNING , LIN NIE , WU PEILI , YUAN KUN , AN SHENGLI , ZHANG ZHEN , RUAN YUTING , ZHANG YING , XU GUGEN , MA WENJUN , LU ZEYUAN , CHEN XIAOMING , HUANG QIYA , ZHANG XIUWEI , LI YUZHONG , LI SHU , DENG GUOBAO , LIANG YONGQIAN , LIU LISHENG , CHEN HONG 
Published: June 2019

Objective: This study aims to investigate whether there was a collaborative weight-loss effect or other metabolic benefits between low-carbohydrate (LCD) and calorie restriction (CR) on overweight/obese subjects from South China.
Methods: We enrolled 290 overweight/overweight adults with similar dietary habits from 13 hospitals in different areas of South China. Participants were randomly assigned into four diets for 12-week intervention, including normal diet, low-carbohydrate diet, calorie-restricted diet and calorie-restricted combined with low-carbohydrate diet. Covariance in quasi-factorial design was used to calculate the major effect as well as collaborative effect between low-carbohydrate and calorie restriction.
Results: A total of 259 participants completed the study for 12-week intervention. Participants in CR+LCD group lost weight by 7.99±3.57 kg, which was most significantly among 4 groups (P&lt;0.001). Similarly, the results of body composition analysis showed that the visceral fat area and body fat rate was improved after intervention, especially in the CR+LCD group (P&lt;0.001). Besides, fatty liver also alleviated substantially compared with control group (p=0.018). In addition, Significant effect of different diet intervention was shown on changes of triglycerides (P &lt;0.001), which decreased by 0.73±1.26 mmol/L in the CR+LCD group. Furthermore, the results of covariance analysis showed no collaborative effects between calorie restriction and low carbohydrates (F=0.004, P=0.950).
Conclusions: Although our study indicated that low carbohydrate combined with calorie restricted diet have more significant effect on weight loss, it’s the first time to prove that no collaborative weight-loss effect of low carbohydrate diet and calorie restriction, which may possibly due to the carbohydrate based dietary habits in South China. (Registration number, ChiCTR1800015156).

Disclosure
J. Sun: None. N. Xu: None. N. Lin: None. P. Wu: None. K. Yuan: None. S. An: None. Z. Zhang: None. Y. Ruan: None. Y. Zhang: None. G. Xu: None. W. Ma: None. Z. Lu: None. X. Chen: None. Q. Huang: None. X. Zhang: None. Y. Li: None. S. Li: None. G. Deng: None. Y. Liang: None. L. Liu: None. H. Chen: None.
318-LB: Acanthosis Nigricans and Obesity among College Students on Guam
Authors: FLISCO VICTORIA D.C. , PAULINO YVETTE C. 
Published: June 2019

Obesity has been associated to Acanthosis nigricans (AN), but there is a dearth in studies regarding this association in Pacific Islander populations. Data collected pertaining to health indicators of obesity in a cross-section of students—recruited to participate in the Pacific Islands Cohort on College Students (PICCS) during August to December 2017, was analyzed. The purpose of this analysis was to determine the relationship between obesity (obese and non-obese groups decided by using Body Mass Index (BMI)) and AN (presence/absence) of a non-random sample of 303 college students (CS) at the University of Guam. Of 299 CS, mean age was 21 ± 6 years and 45% were males and 55% were females. Anthropometric measurements were taken by undergraduate research students trained to use standardized stadiometer, weight scale, and measuring tape and ascertain AN presence/absence (neck area). Of 299 CS, height mean was 164 ± 32 cm and weight mean was 72 ± 20 kg. Of 294 CS, waist circumference mean was 88 ± 28 cm. The BMI mean of 299 CS was 27 ± 7. The relationship between presence/absence of AN in obese and non-obese groups was statistically significant, X2 (N = 282) = 16.37, (p = 0.000). Of 282 participants, 21.5% of the obese group had AN present while 5.1% of the non-obese group had AN present as well. These results may be further investigated and may assist in raising awareness regarding the association between obesity and AN presence/absence to the people of Guam; which may better assist in strategies of obesity screening.

Disclosure
V.D.C. Flisco: None. Y.C. Paulino: None.

Funding
National Institutes of Health
319-OR: Deficit of Retrograde Axonal Transportation Was Mediated via Activation of Macrophage RAGE Signaling in Experimental Diabetic Polyneuropathy
Authors: OSONOI SHO , MIZUKAMI HIROKI , TAKAHASHI KAZUHISA , KUDO KAZUHIRO , SANGO KAZUNORI , YAGIHASHI SOROKU 
Published: June 2019

Activation of AGEs-RAGE signal at macrophage (Mφ) aggravates local inflammation in diabetic polyneuropathy (DPN). Mφ skewing toward pro-inflammatory phenotype (M1) is implicated in insulin resistance (IR) in fatty tissue, suggesting activation of RAGE at Mφ may similarly trigger IR in DPN. Generally, IR leads to axonal transport deficit in peripheral nerves. The aim of this study is to clarify the role of RAGE in the inflammation of DPN and its relationship to IR and axonal transport. Male C57BL/6 mice (W) and RAGE null mice (R) were recruited and rendered diabetic with streprozotocin (STZ) (D). DPN was confirmed by delay of nerve conduction velocities (NCVs) 8 weeks later of STZ injection. Polarization of Mφ in the sciatic nerve (SN) was determined by immunofluorescence (IF) and qPCR. IR of SN was evaluated by phospho (p)-AKT expression with stimulation of 5 unit insulin. Cell size of the dorsal root ganglia (DRG) neuron was morphometrically measured. For the retrograde axonal transport, DRG was quantitatively evaluated by IF for Fluoro-Gold (FG) 7 days after subcutaneous injection of FG into the hindlimb footpad. WD showed significant delay of NCVs (p&lt;0.01, vs. W), while those were maintained in RD. Significant increase in the infiltration M1 in SN of WD (p&lt;0.05, vs. W), whereas robust infiltration of anti-inflammatory Mφ (M2) was seen in RD (p&lt;0.01, vs. R and WD). Increased nuclear translocation of NF-κB p65 and decreased pAKT expression were seen in SN of WD, but not in RD. The cell size in DRG neuron was significantly decreased in WD (p&lt;0.05, vs. W), but that was similar in R and RD. The frequency of transported FG in DRG were significantly decreased in WD (p&lt;0.05, vs. W), while maintained in RD. Taken together, our results suggest that RAGE induces inflammation in SN with skewing toward M1, which associates with IR and attenuation of the retrograde axonal transport in STZ DPN model. Those changes may contribute to the atrophic change of neuronal body in DRG of DPN.

Disclosure
S. Osonoi: None. H. Mizukami: None. K. Takahashi: None. K. Kudo: None. K. Sango: None. S. Yagihashi: None.

Funding
Japan Society for the Promotion of Science
32-OR: Coordination of Mitochondrial Uncoupling with Pyruvate Dehydrogenase Activation Safely Ameliorates Hyperglycemia through Preferential Glucose Oxidation
Authors: JIANG HAOWEN , LI JINGYA , LI JIA 
Published: June 2019

Type 2 diabetes (T2D), which is characterized by hyperglycemia and insulin resistance, has become global epidemic. Uncoupling of mitochondria by chemical uncoupler, 2,4-dinitrophenol (DNP), is an efficient way to ameliorate hyperglycemia and insulin resistance. However, DNP use ceased in 1930s due to the systemic toxicities including hyperlactacidemia, hyperthermia and even death, which were mainly resulted from uncoupling actions induced excessive fat combustion and anaerobic glycolysis. To relieve the adverse effects derived from uncoupling activity, here we identified an effect-enhancing and toxicity-reducing way linking activation of pyruvate dehydrogenase (PDH) with DNP to T2D therapy. Activation of PDH by its classical activator, dichloroacetic acid (DCA), protected mice from DNP-derived hyperlactacidemia, hyperthermia and even death. Meanwhile, DCA combined with DNP further promoted glucose disposal in streptozotocin-induced hyperglycemic mice and enhanced insulin signaling in high-fat diet mice. Mechanistically, PDH activation corrected the excessive fatty acid oxidation and anaerobic glycolysis by DNP that was strongly associated with the adverse effects, and preferentially promoted glucose oxidation to improve hyperglycemia. Based on the beneficial effects of DNP combined with DCA, a novel compound possessing both mitochondrial uncoupling and PDH activation effects, named 6j, was identified and confirmed to promote glucose oxidation preferentially in vitro and in vivo. Therefore, our study suggested that combination of mitochondrial uncoupling and PDH activation might be a novel effective pharmacological approach for safely treating T2D.

Disclosure
J. Li: None. J. Li: None.

Funding
National Natural Science Foundation of China; Chinese Academy of Sciences; Shanghai Science and Technology Commission; K.C. Wong Education Foundation
320-LB: Metabolically Unhealthy Overweight Individuals Have High Lysophosphatide Levels, Phospholipase Activity, and Oxidative Stress
Authors: HAN YOUNGMIN , KIM MINJOO , JIN YOO HYE , HO LEE JONG 
Published: June 2019

Background and Aims: Metabolically unhealthy overweight (MUO) individuals and metabolically healthy overweight (MHO) individuals differ in biomarkers of atherogenesis. Metabolomic approaches enable studies of the metabolic variables underlying these differences.
Methods: We determined the metabolomes in plasma samples from 34 MUO and 34 MHO individuals matched for sex, age, and body mass index (BMI) to identify potential metabolic markers or pathways associated with atherogenic traits.
Results: This analysis revealed that the MUO group had significantly higher levels of glycolic acid, 6 lysophosphatidylethanolamines (lysoPEs), and 12 lysophosphatidylcholines (lysoPCs). Although the two groups had similar total body fat percentages and lean body masses, MUO individuals had larger visceral fat areas (VFAs). They also had greater circulating lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and higher levels of oxidized low-density lipoprotein (ox-LDL) and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α), reflecting higher risks for oxidative and lipid-related tissue damage. The following measures were positively correlated: VFA and ox-LDL; ox-LDL and Lp-PLA2 activity; and lysoPC, lysoPE, and 8-epi-PGF2α levels. Chronic plasma lysoPC increases were associated with atherogenic traits, higher levels of mean ox-LDL, 8-epi-PGF2α, Lp-PLA2, and visceral fat accumulation in MUO compared to MHO individuals.
Conclusions: This panel of plasma metabolites distinguishes MUO from MHO individuals and will enable future research on fat dysregulation and obesity.

Disclosure
Y. Han: None. M. Kim: None. H. Yoo: None. J. Lee: None.

Funding
National Research Foundation of Korea (NRF-2017R1C1B2007195, NRF-2012M3A9C4048762)
322-LB: Balancing Act: Atf6alpha Plays Positive and Negative Roles in the Pancreatic Beta-Cell Stress Response
Authors: SHARMA ROHIT B. , DARKO CHRISTINE O. , GABLASKI BRIAN , ALONSO LAURA C. 
Published: June 2019

Diabetes is caused by loss or dysfunction of beta cells. Endoplasmic reticulum (ER) stress has been implicated in beta cell loss in both type 1 and type 2 diabetes. Hyperglycemia and increased insulin demand cause ER stress, activating the unfolded protein response (UPR). The initial beta cell response to stress increases cell number through proliferation, but prolonged stress leads to beta cell demise. Precisely characterizing the beta cell UPR could lead to a better understanding of how beta cells are lost in diabetes. In this study, mouse primary islet cells were treated with ER stressors Thapsigargin (Tg) or tunicamycin (Tm), which activate all three arms of the UPR: Atf6, Ire1 and Perk. In mouse beta cells, Tg (1uM) activated the Ire1 (tested by splicing of Xbp1) and Perk (tested by phosphorylation of eIF2-alpha) pathways within 1 hour, and induced Atf6 transcriptional targets by 4 hours. Specific roles of Atf6 in the beta cell ER stress response are not well understood, with both positive and negative roles reported in the literature. Therefore, we tested how Atf6 participates in the acute beta cell response to severe stress, including UPR pathway activation and cell death. We found that knockdown of Atf6 leads to a blunted ER stress response, with delayed activation of Atf6 target genes Grp78, Hyou1 and Pdia4, but not HerpUD1. The Ire pathway was also negatively impacted by Atf6 knockdown, with blunted activation of Xbp1 target genes Sec24D, Erdj4 and Ssr3. Perk pathway activation was not affected by knockdown of Atf6 (p-eIF2-alpha, Chop mRNA). Finally, acute knockdown of Atf6 increased beta cell death even in the absence of stress (n=4) and made beta cells more prone to stress-mediated cell death (n=2). On the other hand, overexpression of ATF6 had no impact on Tg-mediated beta cell death suggesting Atf6 was not sufficient to protect (n=2) against irreversible ER stress. In sum, our data suggest a nuanced role for Atf6 in the beta cell stress response and the cell fate choice between life and death.

Disclosure
R.B. Sharma: None. C.O. Darko: None. B. Gablaski: None. L.C. Alonso: None.

Funding
National Institutes of Health (R01DK114686); National Institute of Diabetes and Digestive and Kidney Disease (R01DK113300)
326-LB: BCL-xL/BCL2L1 Is a Critical Anti-Apoptotic Protein that Suppresses BAK to Promote Pancreatic Specification from Human Pluripotent Stem Cells
Authors: SAI WENG LOO LARRY , TEO ADRIAN , GHOSH SOUMITA , ALVIN PURNOMO SOETEDJO ANDREAS , NGUYEN LINH , KRISHNAN VIDHYA G. , HOON SHAWN 
Published: June 2019

The differentiation of human pluripotent stem cells (hPSCs) into desired cell types such as the pancreatic cells involve cellular proliferation and apoptosis during cell fate transitions. Although different rates of cell growth and death are typically observed during differentiation, its implications for pancreatic tissue formation in humans remain unclear. Here, we profiled the expression of BCL-2 family of proteins during pancreatic specification from hPSCs and observed an upregulation of BCL- XL, downregulation of BAK and corresponding downregulation of cleaved CASP3 representative of apoptosis. The inhibition or downregulation of BCL-xL reciprocally increased apoptosis and resulted in a decreased gene expression of pancreatic markers despite a compensatory increase in companion anti-apoptotic protein BCL2. RNA-Seq analyses revealed a downregulation of multiple metabolic genes upon inhibition of BCL-xL function. Bioenergetics assays then revealed a broad downregulation of both glycolysis and oxidative phosphorylation when BCL-xL function was inhibited.
In conclusion, we have identified anti-apoptotic protein BCL-xL to be necessary for suppressing the expression of pro-apoptotic protein BAK to facilitate proper pancreas formation in human cells. This is the first report that links a member of the BCL-2 family with pancreatic specification. Therefore, modulation of these two BCL-2 family of proteins can potentially increase the survival and robustness of pancreatic progenitors that ultimately defines human pancreatic beta cell mass and function.

Disclosure
L. Loo: None. A. Teo: None. S. Ghosh: None. A. Soetedjo: None. L. Nguyen: None. V.G. Krishnan: None. S. Hoon: None.

Funding
Agency for Science, Technology and Research; Institute of Molecular and Cell Biology