bluuebunny/crossref_metadata_2025_split huggingface dataset:
1935-P: Loss of µ-Crystallin Increases Adipose Tissues with Inhibitory Effects on Adipocyte Differentiation through ß-Catenin-Dependent Mechanisms in High-Fat Diet Fed Mice
Authors: OHKUBO YOHSUKE , NISHIO SHIN-ICHI , SHIMADA YASUHO , KUBOTA SATOSHI , KITAHARA JUNICHIRO , SHIBATA YUSUKE , KITAJIMA KOHEI , SEKIDO TAKASHI , SUZUKI SATORU , KOMATSU MITSUHISA 
Published: June 2020

The 3,5,3’-triiodo-L-thyronine (T3) binding protein, μ-crystalin (CRYM), regulates intracellular thyroid hormone action by controlling the concentration of T3 in the cytoplasm. As thyroid hormone plays a pivotal role on metabolic homeostasis, CRYM may have influence on cellular metabolic processes. Loss of CRYM caused obesity in high fat diet (HFD) with glucose intolerance, fatty liver and hypertrophy of epididymal adipocyte, we have previously reported (BBRC 2019;508:914-920). Although the previous study has shown that the amount of HFD which CRYM knock out (KO) mice ate was larger than the one wild type (WT) mice did, the precise metabolic mechanisms has not been determined. In this study, we assessed the metabolic effects of CRYM expression by pair-feeding. We have found that the ratio of adipose tissue to body weight in CRYM KO mice significantly increases compared to those of WT mice (WT 0.034±0.009, CRYM KO 0.044±0.008 (mean±SD), p=0.04) in the pair-feeding test. However, there were no significant difference of body weights between two groups (WT 31.8±2.0g, CRYM KO 31.3±1.5g(mean±SD)). The microarray examination using visceral adipocytes of HFD fed mice showed that the several genes related to lipid metabolisms up-regulated in CRYM KO mice. Among them, the gene expression of the WNT1 inducible signaling pathway protein 2, inhibiting adipose differentiation, was significantly up-regulated in pair-feeding HFD CRYM KO mice (Z-score 2.18). In addition, the Lrp4, fzd10 and wnt10a genes, as adipogenesis inhibitors through a β-catenin-dependent mechanism, elevated in free feeding HFD CRYM KO mice. Collectively, our data suggests that lack of CRYM causes visceral adipose tissue hypertrophy not only because of appetite, but also maybe because of inhibitory effects on adipocyte differentiation in a caloric excess environment.

Disclosure
Y. Ohkubo: None. S. Nishio: None. Y. Shimada: None. S. Kubota: None. J. Kitahara: None. Y. Shibata: None. K. Kitajima: None. T. Sekido: None. S. Suzuki: None. M. Komatsu: None.
1939-P: Sex Dimorphism in Erythropoietin Regulation of Fat Mass
Authors: LEE JEEYOUNG , ROGERS HEATHER , NOGUCHI CONSTANCE T. 
Published: June 2020

Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. In male mice and ovariectomized female mice on high fat diet (HFD), EPO treatment increased hematocrit, improved glucose tolerance and attenuated body weight gain via reduced fat mass. Estradiol supplementation abrogated the EPO effect on body weight in ovariectomized female mice, providing evidence for estrogen related gender specific EPO action in metabolic regulation. To determine estrogen response in metabolic regulation with EPO treatment, we use the estrogen receptor α knockout (ERαKO) mice and mice with targeted deletion of estrogen receptor alpha in adipose tissue (ERαadipoKO). Male and female ERαKO mice on HFD exhibit increased fat mass and glucose intolerance. EPO treatment on HFD increased hematocrit in both wild type (WT) and ERαKO mice and reduced gain in fat mass in male mice as well as female ERαKO mice but did not affect fat mass in female WT mice. The improvement in glucose tolerance and insulin tolerance with EPO treatment during HFD was significantly greater in female ERaKO mice compared with female WT. We previously demonstrated that specific deletion of EPO receptor in adipose tissue in mice decreases glucose tolerance and insulin sensitivity and increases susceptibility to diet-induced obesity. Although no decrease in body weight was observed in female WT and ERαadipoKO with EPO treatment on HFD, female ERαadipoKO also showed significantly improved glycemic control with EPO treatment compared with WT control. EPO treatment decreased white fat associated gene expression, Psat1 and Wdnm-1like in subcutaneous fat pads from both female ERαKO mice and ERαadipoKO on HFD but not WT female mice. These results confirm the role of estrogen in the sex-differential EPO effect on fat mass regulation and suggest cross talk between EPO and estrogen signaling in metabolic homeostasis and fat mass regulation via estrogen response in white adipose tissue in female mice.

Disclosure
J. Lee: None. H. Rogers: None. C.T. Noguchi: None.
1942-P: Vertical Sleeve Gastrectomy Confers Metabolic Improvements by Reducing Intestinal Bile Acids and Lipid Absorption in Mice
Authors: DING LILI , TIAN JINGYAN , HUANG WENDONG 
Published: June 2020

Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the mechanisms through which changes in BA content and signaling contribute to the metabolic effects of VSG remain poorly understood. Therefore, in this study, we aim to systematically evaluate the roles of FXR in VSG and determine the underlying mechanism by which bile acids mediate the beneficial effects of VSG. Our data demonstrated that both intestine- and liver-specific farnesoid X receptor (Fxr) knockout mice retained VSG effects and VSG did not appear to increase FXR activation in the liver or intestine, indicating that hepatic or intestinal FXR is dispensable for the metabolic improvement of VSG. We further found that VSG altered gut microbiota composition and reduced intestinal BA levels in mice, resulting in lower intestinal fat absorption and concomitant metabolic improvements similar to those observed in Fxr null mice. We then confirmed these findings in sterol 27-hydroxylase knockout (Cyp27a1-/-) mice, which exhibited low intestinal BAs and fat absorption, did not experience metabolic improvements after VSG. Our findings reveal that reductions in intestinal BAs and lipid absorption may underlie the metabolic benefits of VSG.

Disclosure
L. Ding: None. J. Tian: None. W. Huang: None.

Funding
NCIR01CA139158; Schaeffer Foundation (to W.H.); Hench Foundation (to W.H.); National Natural Science Foundation of China (81773961); Shanghai Pujiang Program (17PJ1408800 to L.D.)
1951-P: Glucose Effectiveness Fails to Compensate for Insulin Resistance after Fat Feeding in Dogs
Authors: ADER MARILYN , KOLKA CATHRYN M. , BERGMAN RICHARD N. 
Published: June 2020

Glucose homeostasis involves actions of both insulin and glucose per se (“glucose effectiveness, SG”). While consumption of a high fat diet typically induces insulin resistance, it is unclear whether SG is altered by fat feeding. We quantified SG from the intravenous glucose tolerance test (IVGTT; n=36) or hyperglycemic clamp at basal insulin (HGC; n=5) in dogs, tested before and after 6 weeks fat feeding (+ 6 g/kg per day). SG from IVGTTs were quantified by minimal model (SG-MINMOD). In HGCs, glucose was sequentially raised to 125, 180, and 250 mg/dl during somatostatin (SRIF) and basal insulin replacement; SG-HGC was calculated as the slope of steady state glucose infusion rate and plasma glucose. Insulin sensitivity (SI) was calculated from IVGTTs and from euglycemic clamps. Fat feeding induced weight gain (28.8±0.4 to 31.2±2.5 kg; p&lt;0.0001) and insulin resistance at both liver (p&lt;0.0001) and periphery (p&lt;0.0001). SG-MINMOD was reduced after fat feeding (0.036±0.002 vs. 0.041±0.002 min-1; p&lt;0.001). The direct measure of SG from HGCs at basal insulin (SG-HGC) suggest similar diet-induced reduction (21%), although sample size was diminished due to SRIF breakthrough and resulting hyperinsulinemia in 2 animals. After fat feeding, there was no increase in glucose effectiveness that may be expected as compensation for diet-induced insulin resistance. Rather, glucose effectiveness decreased. These data indicate that obesity results in diminished actions of both insulin and glucose per se on glucose homeostasis.

Disclosure
M. Ader: None. C.M. Kolka: Research Support; Self; AstraZeneca. R.N. Bergman: None.

Funding
National Institutes of Health (DK29867, DK27619)
1958-P: Neonatal Il-4 Induces a Persistent Decrease in Adipocyte Maturation
Authors: YING TAMMY , SEALE PATRICK , SIMMONS REBECCA A. 
Published: June 2020

Adipose tissue is a central node for the dynamic regulation of systemic metabolism and energy expenditure. Little is known about adipogenesis in the newborn which is the critical window of adipose tissue development. Emerging data suggest that immune cells, particularly innate immune cells, play an important role in de novo beige adipogenesis and beige fat thermogenesis in mature rodents. In previous studies we showed that administration of low levels of IL-4 in the first week of life to rat pups results in decreased adiposity and improved glucose tolerance in adulthood, suggesting that beige adipogenesis may be enhanced by neonatal IL-4 administration. Developing animals produce higher levels of IL-4 compared to mature animals and use a distinct pre-adipocyte compartment for adipogenesis. In this study, we analyze the effects of IL-4 on adipogenesis in the developing rat. We demonstrate that a short and transient IL-4 exposure in the neonate during postnatal days 1-6 induces acute beige adipogenesis in the inguinal white adipose tissue (iWAT) that is associated with the upregulation of Ucp1 (n=6). Concurrently, adipocyte maturation is decreased with Adipoq downregulated (n=6). Pre-adipocytes from 10 week old mature rats that had been treated with IL-4 as neonates were differentiated in vitro and also show a decrease in Adipoq compared to controls (n=6). These data demonstrate that neonatal IL-4 induces a long term decrease in the maturation potential of pre-adipocytes. Interestingly, these adult differentiated pre-adipocytes show no change in Ucp1 expression after neonatal IL-4 exposure compared to control (n=6). Thus, neonatal IL-4 induces only acute beige adipogenesis, but impairs adipocyte maturation long term. Phenotypically, neonatal IL-4 resulted in decreased iWAT (n=7) and decreased fasting blood glucose in 10 week old animals (n=6) compared to control. Our studies show that the neonatal period is critical for adipocyte development and may influence the later onset of obesity.

Disclosure
T. Ying: None. P. Seale: None. R.A. Simmons: None.

Funding
National Institutes of Health (DK114054)
1972-P: Adipose Tissue–Derived Exosomal MicroRNA Regulates Placental Glucose Uptake in Gestational Diabetes Mellitus Pregnancies
Authors: JAYABALAN NANTHINI , SCHOLZ-ROMERO KATHERIN , GUANZON DOMINIC , LAI ANDREW , MCINTYRE DAVID , LAPPAS MARTHA , SALOMON CARLOS 
Published: June 2020

Adipose tissue exosomal miRNAs (exomiRs) serve as a signalling molecule that is involved in conveying intercellular message signalling. In this study, we aimed to profile the adipose tissue exomiRs in patients with normal glucose tolerant (NGT) and gestational diabetes mellitus (GDM). Omentum were obtained from BMI-matched NGT (n=10) and GDM (n=10) women at delivery (&gt;37 weeks gestation). Isolated exosomes were characterised based on size distribution and protein enrichment. Total exosomal RNA was isolated by miRNeasy (Qiagen) according to manufacturer’s instructions. Illumina TrueSeq Small RNA kit was used to construct a small RNA library. Finally, the resulting sequencing FASTQ files were analysed using miRDeep2 to identify both known and novel miRNAs. A selected exomiR mimic was overexpressed in the human primary trophoblast (PHT) cells and its effect on glucose uptake was evaluated using 2-NBDG. We identified a total of 1209 miRNAs with 18 miRNAs were significantly differentially expressed in GDM exosomes. Comparatively, 12 miRNAs were upregulated while 6 were downregulated in the exosomes from GDM pregnancy compared to normal pregnancy. Consequently, has-miR-515-5p was selected to be investigated in further functional studies, following validation of its expression using real-time PCR. The QRT-PCR analysis of placental tissue showed a significant increase in the expression of GDM placenta compared to NGT placenta. In PHT cells, the overexpression of miR-515-5p significantly stimulated the glucose uptake (p&lt;0.0001) compared to control group. The proteomics analysis of miR-515-5p overexpressed PHT cells showed differential expression of proteins that are associated with glycolysis. These findings suggest adipose tissue exosomal miR515-5p mediated placental glucose uptake could contribute to an excessive placental nutrient transfer GDM, which could instigate consequences, such as fetal overgrowth.

Disclosure
N. Jayabalan: None. D. Guanzon: None. A. Lai: None. D. McIntyre: Other Relationship; Self; Novo Nordisk A/S. M. Lappas: None. C. Salomon: None.

Funding
Diabetes Australia; Fondo Nacional de Desarrollo Científico y Tecnológico (1170809)
198-LB: Pleiotropy Analysis of Adiposity, Glycemic, and Renal Traits in the Population Architecture Using Genomics in Epidemiology (PAGE) Consortium
Authors: HIGHLAND HEATHER M. , DOWNIE CAROLINA , DIMOS SOFIA F. , GRAFF MARIAELISA , POLFUS LINDA M. , DARST BURCU F. , BALDASSARI ANTOINE R.M. , SITLANI COLLEEN , HOWARD ANNIE GREEN , KOOPERBERG CHARLES L. , LOOS RUTH , MATISE TARA , MOTTL AMY K. , NORTH KARI E. , AVERY CHRISTY L. ,   THE PAGE CONSORIUM
Published: June 2020

A shared genetic susceptibility underlies diabetes, adiposity, and kidney phenotypes, yet few studies have leveraged this common genetic architecture in an attempt to clarify molecular functions, identify mechanistic common denominators, and prioritize variants for functional interrogation. We systematically interrogated evidence of a shared genetic architecture across adiposity (BMI [N=90,813], waist circumference[N=68,389], and waist to hip ratio [WHR, N=63,747]), type 2 diabetes (T2D, [N=98,686, Ncase=26,440], fasting glucose [FG, N=52,211], HbA1c [N=23,357], and fasting insulin [FI, N=48,395]), and kidney (eGFR [N=52,555] and chronic kidney disease [CKD, N=91,382, Ncase=10,883]) phenotypes in an ancestrally diverse study population (28% African American, 31% European ancestry, 28% Hispanic; 69% female; average age 56.9 (range 18-90)) within PAGE. We conducted a cross-trait meta-analysis using Adaptive Sum of Powered Score Tests (aSPU). We have identified 42 loci associated across these traits, (P&lt;5e-8), including one preliminary novel cross-trait association for rs200812701, a nonsynonymous variant in KIF4B p.Ala491Val that was associated with BMI, waist circumference, and HbA1c. rs200812701 is rare (minor allele frequency [MAF]&lt;0.1%) in all populations except Native Hawaiians (MAF=25%) and Asians (MAF=8%). Many of these loci are known for one trait, but the identification of shared genetic susceptibility for these loci is novel. For example, the PEPD locus is established for adiposity measures, namely WHR; however, this cross-trait association is driven more so by FI, T2D and eGFR. Our systematic interrogation of the shared genetic susceptibility underlying diabetes, adiposity, and kidney traits in an ancestrally diverse population has revealed novel loci and evidence of molecular functions and mechanistic common denominators underlying GWAS findings, demonstrating the utility of our approach.

Disclosure
H.M. Highland: None. C. Downie: None. S.F. Dimos: None. M. Graff: None. L.M. Polfus: None. B.F. Darst: None. A.R.M. Baldassari: None. C. Sitlani: None. A. Howard: None. C.L. Kooperberg: None. R. Loos: None. T. Matise: None. A.K. Mottl: None. K.E. North: None. C.L. Avery: Research Support; Self; Amgen.

Funding
American Diabetes Association (1-19-PDF-045 to H.M.M.); National Institutes of Health (T32HL007055, T32HL129982, R01HL142825)
1980-P: Broccoli Extract as a Supplement to Mitigate ER-Induced Inflammation in Adipocytes to Reduce Type 2 Diabetes Mellitus Risk
Authors: MURPHY ALICE , BARKER GUY , TRIPATHI GYANENDRA , MCTERNAN PHILIP G. 
Published: June 2020

Background: Nutrient excess during obesity can contribute to type 2 diabetes mellitus (T2DM) risk via endoplasmic reticulum (ER) stress within adipose tissue. Investigating ’Superfoods’ such as broccoli that contain nutrients which may be able to combat this disruption is therefore important to potentially reduce the risk of developing T2DM in obesity.
Methods: Differentiated human adipocytes (Chub-S7, n=6) were treated with a broccoli extract (BE; hybrid Brassica oleracea var. italic; 10ng/ml) alone or in combination with tunicamycin (Tun; 750ng/ml), an inducer of ER stress. ER stress genes (ATF4, ATF6 and CHOP) were measured at three time points (24hr, 48hr, 72hr, n=3) using qPCR. ER stress proteins (BiP, P-eIF2α and eIF2α) were measured at 18 time points (0hr - 72hr) using Western Blot.
Results: Tun increased ER stress gene expression 4.5-fold (p&lt;0.001), whilst BE+Tun reduced this expression by up to 64% (p&lt;0.001). Similarly, Tun increased ER stress proteins 9.5-fold (p&lt;0.05), whilst BE+Tun reduced expression by up to 94% (p&lt;0.05). Transcriptomic analysis also highlighted positive significant changes in the mevalonate pathway with the use of BE in treated adipocytes (P&lt;0,05), suggesting a possible mechanism of action.
Conclusion: These studies suggest that BE is able to alleviate ER stress in human adipocytes, possibly via mevalonate pathway activation, thus reducing the risk of subjects developing insulin resistance and T2DM. As such, there is the potential to develop a BE dietary supplement to reduce ER stress and reduce the impact of obesity on T2DM.

Disclosure
A. Murphy: None. G. Barker: None. G. Tripathi: None. P.G. McTernan: None.

Funding
Engineering and Physical Sciences Research Council
1996-P: Heightened Sweet-Taste Preference Is Associated with Greater Hypothalamic Response to Glucose and Longitudinal Weight Gain
Authors: YUNKER ALEXANDRA G. , ALVES JASMIN , ANGELO BRENDAN C. , DEFENDIS ALEXIS W. , LUO SHAN H. , PAGE KATHLEEN A. 
Published: June 2020

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking “sweets” can be associated with weight gain, but the influence of sweet taste preference (STP) on hypothalamic regulation of appetite is unknown. We tested the hypothesis that STP is associated with increased hypothalamic activation in response to glucose (a potential marker of obesity risk), and that greater STP and glucose-linked hypothalamic activation would predict greater weight gain. Forty-six (24 female) adults age 18-35 years completed the study. Height and weight were measured at baseline and 6-12 months later in a subset of 38. STP was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and ∼35 min after 75g glucose ingestion, and hypothalamic response to glucose was measured by calculating hypothalamic blood flow (BF) after minus before glucose ingestion. Linear regression was used to examine relationships between STP and the hypothalamic response to glucose and changes in BMI before and after adjusting for age, sex, BMI, mean cerebral BF, and baseline BMI. Baseline BMI was 27.61±5.13 kg/m2. STP scores ranged from 3% to 29.39% w/v. The hypothalamic response to glucose ranged from -14.64 to 15.63 ml/100g/min. Change in BMI ranged from -2.93 to 6.00 kg/m2. STP was positively associated with hypothalamic response to glucose (unadjusted: β=0.65, p&lt;0.0001; adjusted: β=0.29, p=0.01). Greater hypothalamic response to glucose was positively associated with increases in BMI (unadjusted: β=0.07, p=0.04; adjusted: β=0.09, p=0.07). STP was positively associated with increases in BMI (unadjusted: β=0.09, p=0.0004; adjusted: β=0.09, p=0.0002). Our results suggest that heightened STP is associated with a greater hypothalamic response to glucose which may relate to greater susceptibility for weight gain.

Disclosure
A.G. Yunker: None. J. Alves: None. B.C. Angelo: None. A.W. DeFendis: None. S.H. Luo: None. K.A. Page: None.

Funding
National Institutes of Health (R01DK102794)
1997-P: Bidirectional Regulation of Energy Homeostasis Mediated by Estrogen Receptor a and ß in the Medial Amygdala
Authors: YE HUI , HE YANLIN , IBRAHIMI LUCAS , SCHAUL SARAH , LUO PEI , CARRILLO-SÁENZ LESLIE , LAI PENGHUA , PATEL NIRALI , KOTA MAYA , DIXIT DEVIN , XU PINGWEN 
Published: June 2020

Compelling evidence has demonstrated that estradiol and estrogen receptor α/β (ERα/β) play key roles in the central regulation of energy balance and glucose homeostasis. Our previous research showed that ERα in the medial amygdala (ERαMeA) mediates estrogenic actions to stimulate physical activity, therefore promotes energy expenditure and prevents diet-induced obesity (DIO). Interestingly, another estrogen receptor, ERβ, is also highly expressed in the MeA. To test the metabolic functions of ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) during adulthood using AAV virus-mediated Cre-Lox site-specific recombination. We found that, when fed on a high-fat diet but not on a normal chow diet, compared to the control mice, both male and female ERβKOMeA mice showed decreased body weight gain and fat deposition, which were associated with increased energy expenditure. We further showed that half of the ERαMeA neurons co-express ERβ. In these ERα&β co-expressing MeA neurons, ERα agonist propyl pyrazole trio (PPT) induced ERα-dependent depolarization, while ERβ agonist diarypropionitrile (DPN) induced ERβ-dependent hyperpolarization. Finally, we showed that chemogenetic activation of ERαMeA or ERβMeA neurons induces a similar increase in energy expenditure. Collectively, our results support a model that, estrogen acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO, whereas activating ERαMeA decreases and activating ERβMeA increases body weight.

Disclosure
H. Ye: None. Y. He: None. L. Ibrahimi: None. S. Schaul: None. P. Luo: None. L. Carrillo-Sáenz: None. P. Lai: None. N. Patel: None. M. Kota: None. D. Dixit: None. P. Xu: None.

Funding
National Institutes of Health (5R00DK107008-04)