bluuebunny/crossref_metadata_2025_split huggingface dataset:
A UCP1 Near-Infrared Reporter System for Monitoring Adipose “Browning” In Vivo Using Photoacoustic Imaging
Authors: CHAN DERRYN XIN HUI , SUGII SHIGEKI , HAN WEIPING 
Published: June 2018

Obesity has reached pandemic proportions in the developed world. The discovery that white adipocytes have the capacity to undergo browning to become metabolically-active beige cells has generated significant interest in the field of metabolic medicine. However, the study of adipose tissue browning has been hampered by a lack of imaging modalities that permit longitudinal and non-invasive monitoring of this process. To this end, we designed near infra-red (NIR) fluorescence protein iRFP720-Ucp1 reporter construct, in which the expression of iRFP720 is driven by a mini UCP1 promoter. Non-invasive assessment of adipose beiging during adrenergic stimulation was performed by viral transduction of mouse white adipocytes, followed by multi-spectral optoacoustic imaging technology with ultrasound tomography (MSOT-US). We observed increased iRFP720 fluorescence coupled with attenuated lipid signals upon stimulation. As proof of concept, we validated our approach against the hybrid positron emission tomography combined with magnetic resonance (PET/MR) imaging modality, and quantified the extent of adipose browning by MRI-guided segmentation of PET signals. Notably, the browning extent detected by the iRFP720 reporter system with MSOT-US and the 18-FDG uptake in PET/MR are well correlated with Ucp1 induction. Together, these systems provide platforms for preclinical screening of compounds aimed to promote adipose browning and facilitate the translation of these discoveries into pharmacological treatments for obesity.

Disclosure
D. Chan: None. S. Sugii: Stock/Shareholder; Self; Celligenics. W. Han: None.
Maternal Dietary Manipulation Programs Offspring’s Metabolism
Authors: KANG MINSUNG , ANTIPENKO JESSICA P. , LIU XIAOBING , HABEGGER KIRK M. , TIMOTHY GARVEY W. 
Published: June 2018

There is emerging evidence supporting fetal metabolism is determined in utero, and the programmed metabolism persists into adulthood. Understanding how metabolic dysfunction is transmitted through generations will help identify the biological mechanisms underlying obesity and cardiometabolic disease, and provide insight regarding rational strategies for treatment and prevention.
Metabolic parameters were assessed in offspring from dams fed different diets for 4 weeks before pregnancy and during pregnancy and lactation; open standard (OSD), isocaloric low protein (LPD, 8% protein) and high-fat diets (HFD, 60% fat). After weaning, offspring had OSD.
Offspring from dams fed LPD showed 31% reduced birthweights compared to offspring from dams fed OSD, and the difference persisted into 6 months of age. At 3 and 6 months, they exhibited significantly smaller perigonadal fat pad than offspring from dams fed OSD. In addition, they showed significantly higher blood glucose concentration than offspring from dams fed OSD at birth (52.35mg/dl vs. 63.71 mg/dl). In case of offspring from dams fed HFD, they exhibited significantly higher body weights (5.99g vs. 6.56g) and blood glucose level at birth (52.35mg/dl vs. 64.64 mg/dl) compared to offspring from dams fed OSD. The difference of body weights continued to 3week-old at weaning, and they showed significantly impaired glucose tolerance compared to offspring from dams fed OSD at the same age.
Maternal dietary manipulation strongly influenced metabolic phenotypes such as birthweight, blood glucose concentration at birth and glucose tolerance, and the programed phenotypes persisted into adulthood. Therefore, maternal nutrition programs a glucose intolerant phenotype in offspring indicating that in utero stress augments diabetes risk not only childhood but also adulthood. We expect our findings in this study to help clarify the mechanism how the utero environment affects offspring’s metabolism, which would explain in part the intergenerational transmission of obesity.

Disclosure
M. Kang: None. J.P. Antipenko: None. X. Liu: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc. W. Garvey: Advisory Panel; Self; Novo Nordisk Inc., Merck & Co., Inc.. Research Support; Self; Sanofi, Pfizer Inc., Novo Nordisk Inc., AstraZeneca, Merck & Co., Inc., Elcelyx Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Eisai Inc..
Ablation of Galectin-1 Reduces Adipogenesis and Obesity
Authors: BAEK JUNGHWAN 
Published: June 2018

Galectin-1 is a member of the animal lectin family that contains a carbohydrate-recognition binding domain (CRD) that binds a B-galactoside. Many studies are reported about the role of galectin-1 in cancer and immune disorders. But, the role of galectin-1 in metabolic dysfunction is not fully understood. We were interested in the role of galectin-1 on metabolic diseases and investigated the mechanism how galectin-1 regulates adipocyte differentiation and high fat diet (HFD) induced obesity. The level of galectin-1 increased during adipocyte differentiation and was predominantly expressed in mouse fat tissues. Galectin-1 knockdown significantly reduced adipocyte differentiation in 3T3-L1 cells and also decreased the expression of peroxisome proliferator-activated receptor (PPAR)-γ, ccaat enhancer binding protein (C/EBP)-α. fatty acid binding protein (FABP) 4 and fatty acid synthase (FASN). When lactose was treated to inhibit function of extracellular galectin-1, there was no effect on adipocyte differentiation. After 10-week high-fat diet (60% fat), lgals1-/- mice had lower body weight and WAT mass than wild type (lgals1+/+) mice. The expression levels of lipogenic genes were significantly down-regulated in liver and gonadal WAT of lgals1-/- mice. In addition, lgals1-/- mice had elevated expression of genes involved in thermogenesis in inguinal WAT and BAT. These data suggest that galectin-1 is an important regulator of adipogenesis. We also suppose that galectin-1 might be potential therapeutic target in obesity and fat liver diseases and further study is needed for clinical application.

Disclosure
J. Baek: None.
Inhibition of Adipose Tissue Angiogenesis Prevents Rebound Weight Regain after Calorie Restriction Independent of Hypothalamic Melanocortin System in Obese Mice Fed a High-Fat Diet
Authors: LEE HYE-JIN , SONG MUN-GYU , HA NA-HEE , JIN BO-YEONG , CHOI SANG-HYUN , KIM DONG-HOON 
Published: June 2018

Prevention of rebound weight gain after dieting is essential to treat obesity. However, its attempts have been unsuccessful and the underlying mechanism remains unclear. In this study, we sought to investigate the role of adipose tissue (AT) vasculature in rebound weight gain after calorie restriction in obese mice fed a high-fat diet (HFD). Obese mice were randomly assigned to 4 groups including mice fed HFD ad libitum (CON), mice under 40% calorie restriction for 5 weeks (CR), 3 days of HFD ad libitum after CR (CRAL), or CRAL treated with TNP-470, an angiogenesis inhibitor (TNP). We compared parameters of energy balance, AT morphometry and remodeling, and hypothalamic neuropeptides gene expression among the groups. Rebound weight gain and food intake were significantly lower and the level of brown AT UCP-1 gene expression was higher in TNP group than CRAL group. Fat mass was significantly lower in TNP group than CRAL group and it was similar to CR group while lean mass was not different between TNP and CRAL groups. Notably, the CD31-positive area was not different in AT between CON, CR, and CRAL groups, indicating that AT vasculature was maintained independently of nutritional status. However, that tended to be lower in AT of TNP group compared to other groups, implicating that inhibition of AT vasculature might be crucial to suppress rebound weight gain after calorie restriction. Consistently, circulating leptin levels were significantly lower in TNP group than CRAL group. However, the pattern of hypothalamic neuropeptides gene expression was different from the changes in food intake among the groups, suggesting an existence of novel regulatory signals independent of melanocortin system. Taken together, these results suggested a critical role of AT vasculature in regulating rebound weight gain and hyperphagia after calorie restriction independent of hypothalamic melanocortin system.

Disclosure
H. Lee: None. M. Song: None. N. Ha: None. B. Jin: None. S. Choi: None. D. Kim: None.
Modified Mesenchymal Stromal Cells Promote Multiple Metabolic Benefits in Obese Diabetic Mice
Authors: DOMINGUES CLEYTON C. , KUNDU NABANITA , KROPOTOVA YANA , AHMADI NEEKI , SEN SABYASACHI 
Published: June 2018

Background: Mesenchymal stromal cells (MSCs) are multipotent cells that can home-in to the sites of inflammation. Therefore, antioxidant-upregulated MSCs delivered intra-peritoneally can home-in to local inflamed fat pockets which may reduce inflammation and improve glucose tolerance in diet-induced obese and diabetic mouse model.
Methods: GFP-containing adenoviral constructs were used to upregulate antioxidants Sod2 (mitochondrial) and Catalase (cytosolic) in human adipose-derived MSCs. Modified MSCs were delivered (IP) into mice subjected to 45% and 60% high-fat diet for 8-16 weeks.
Results: Glucose tolerance was improved at week 4 in the antioxidant upregulated MSC-receiving groups with concomitant reduction in hyperplasia in omental fat. A reduction in plasma levels of TNFa, an well-known inflammatory marker, was found for all treated animal groups in comparison to control (null-MSCs). RT-PCR analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000-fold and 10-100-fold, respectively) which was confirmed by Ucp1-staining and concomitant increases in down-stream genes such as Pgc1a and Prdm16 mRNA expression. Remarkably, the treatment showed a significant reduction in liver fat content (by histology) and triglyceride content measurement.
Conclusion: Delivery of Sod2 and Catalase upregulated MSCs improved glycemic control by reducing systemic inflammation, promotes browning of white adipose tissue and reverses hepatic lipid accumulation. These results indicate that antioxidant upregulated MSCs can help to improve glucose homeostasis, adipocyte energetics and hepatic lipid metabolism. Modified MSC therapy can be a promising therapy for type 2 diabetes, obesity and fatty liver disease.

Disclosure
C.C. Domingues: None. N. Kundu: None. Y. Kropotova: None. N. Ahmadi: None. S. Sen: None.
Loss of Insulin Actions on Arterial Smooth Muscle Cells May Enhance Unstable Atherosclerotic Plaque Formation
Authors: LI QIAN , FU JIALIN , PARK KYOUNGMIN , CHRISTIAN RASK-MADSEN , KING GEORGE L. 
Published: June 2018

Formation of unstable atherosclerotic plaque, a major cause of cardiovascular mortality, is accelerated in insulin resistance and diabetes. Previous studies have suggested that endothelial dysfunction and systemic hyperlipidemia due to loss of insulin actions can accelerated its formation. However, the mechanism for insulin resistance to accelerate the various pathologies of unstable plaque, such as decreases in VSMC and extra cellular matrix (ECM) and increased inflammatory cells, have not been defined. Since insulin actions on the vascular wall are diminished in insulin resistant states, we assessed the loss of insulin action in VSMC and its effect on the formation of atherosclerotic plaque. Insulin receptor (IR) was specifically deleted from VSMC by breeding SM22 a promoter Cre and IR Flox mice to produce SMIRKO mice which were mated with ApoE-/- mice to generate SMIRKO/ ApoE-/- mice. Cultured VSMC from SMIRKO/ApoE-/- mice showed decreased insulin signaling and stimulated proliferation by &gt;50%, but not to PDGF. Weight, blood pressure, glucose, and systemic insulin tolerance were comparable between ApoE-/- and SMIRKO/ApoE-/- mice; which were fed with normal chow to mimic pathophysiological hyperlipidemia encountered clinically. Surprisingly, SMIRKO/ ApoE-/- mice developed significantly more atherosclerotic aortic plaques (Sudan IV staining for lipid content) compared to ApoE-/- mice with parallel increases of macrophage content and inflammatory cytokines such as IL18 and ICAM1. In contrast, SMC as measured by SM22α staining was decreased with elevation of necrotic plaques (p&lt;0.05). Further, proliferative index of VSMC as measured by Ki67 staining and expression of hyaluronan synthase-2 were decreased. Thus, surprisingly, the loss of insulin’s specific actions on VSMC to increase proliferation increased inflammatory cell influx as observed in insulin resistance, may accelerated formation of unstable plaques in diabetes.

Disclosure
Q. Li: None. J. Fu: None. K. Park: None. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S. G.L. King: Research Support; Self; Sanofi-Aventis.
Differences in Energy Expenditure between Respiratory Chamber and Metabolic Ward in Inpatient Men and Women
Authors: ZHOU MEGAN S. , HOWARD REBECCA E. , RABEL ANTOINETTE , SEDMAK CAROLINE , CAI HONGYI , WALTER PETER J. , BRYCHTA ROBERT , FLETCHER LAURA , LEITNER BROOKS , GUO JUEN , SIKDER SHANAZ , COURVILLE AMBER B. , BERNSTEIN SHANNA , GREWAL SHIVRAJ , MUNIYAPPA RANGANATH , CHEN KONG Y. , HALL KEVIN 
Published: June 2018

We previously investigated 16 men with overweight or class I obesity who were admitted to a metabolic ward and engaged in 90 minutes of daily cycle ergometry at a fixed resistance. Subjects resided in a respiratory chamber for 2 days per week. The remaining days were spent in their inpatient rooms. Total expenditure was measured over 2 weeks via doubly labeled water (DLW). We found a surprisingly large (∼500 kcal/day) decrease in expenditure when subjects resided in the respiratory chamber as compared to the days spent in their rooms. Here, we attempted to reproduce this finding in non-exercising healthy volunteers.
Purpose: To measure differences in daily energy expenditure between days spent on a metabolic ward vs. days spent in a respiratory chamber.
Methods: 10 adults (2 M, 8 F) aged (mean ± SE) 34 ± 3.5 years with BMI 27.9 ± 2.3 kg/m2 completed a 7-day inpatient stay on the metabolic ward at the NIH Clinical Center. Two days were spent residing in a respiratory chamber. Study participants received a controlled diet and refrained from exercise. Temperature and clothing were kept constant. Energy expenditure on days spent on the ward was calculated using DLW over 6 days after accounting for the energy expended during the 2 respiratory chamber days.
Results: Average energy expenditure on the ward was 2122 ± 155 kcal/day, with an average of 1996±130 kcal/day expended during the two respiratory chamber days. Therefore, energy expenditure on the metabolic ward was 126 ± 55 kcal/day (p= 0.048) greater than in the respiratory chamber.
Conclusion: Participants expended ∼126 kcal/day more on the metabolic ward than in the respiratory chamber. This was a much smaller discrepancy than previously found in exercising men. Failure to reproduce our previous results may have been due to the lack of exercise, the inclusion of women, or the wider range of BMIs in the current study. Further studies are needed to investigate the determinants of energy expenditure differences between ward and respiratory chamber days.

Disclosure
M.S. Zhou: None. R.E. Howard: None. A. Rabel: None. C. Sedmak: None. H. Cai: None. P.J. Walter: None. R. Brychta: None. L. Fletcher: None. B. Leitner: None. J. Guo: None. S. Sikder: None. A.B. Courville: None. S. Bernstein: None. S. Grewal: None. R. Muniyappa: None. K.Y. Chen: None. K. Hall: None.
Sustained Improvement of Obesity in Hypogonadal Men with Type 2 Diabetes (T2DM) Receiving Long-Term Treatment with Injectable Testosterone Undecanoate (TU)—Real-Life Evidence from a Urological Registry Study
Authors: SAAD FARID , HAIDER KARIM S. , HAIDER AHMAD 
Published: June 2018

Background: Hypogonadism is highly prevalent in men with obesity as well as T2DM.
Methods: Of 805 hypogonadal men in a urological registry, 311 men (39%) had T2DM diagnosed and treated elsewhere. 141 received TU 1000 mg/12 weeks (T-group), 170 opted against treatment (CTRL). Mean changes over time between groups were compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction. Changes were adjusted for age, weight, waist circumference, HbA1c, blood pressure (BP), lipids to account for baseline differences between the two groups.
Results: Mean age:T-group: 61.8±5.3, CTRL: 63.5±4.9 years. Follow-up: mean: 7.5, median: 8 years. T-group: 89.4% were obese, 9.9% overweight, and 0.7% had normal weight. Weight decreased progressively from 113.4±13.9 to 90.7±8.6 kg at 10 years (p&lt;0.0001) with statistical significance vs. previous year for the first 9 years. CTRL: 70% were obese, 26.5% overweight, and 3.5% had normal weight. Weight remained stable. Estimated adjusted difference between groups: -25.7 kg (p&lt;0.0001). T-group: waist circumference decreased from 112.6±10.7 to 99.6±5.2 cm (p&lt;0.0001) with statistical significance vs. previous year for the first 9 years. CTRL: Waist circumference remained stable. Estimated adjusted difference between groups: -17.9 cm (p&lt;0.0001). T-group: BMI decreased from 36.3±4.4 to 29.3±2.7 kg/m2 at 10 years (p&lt;0.0001) with statistical significance vs. previous year for the first 9 years. CTRL: BMI remained stable. Estimated adjusted difference between groups: -8.3 kg/m2 (p&lt;0.0001). Since injections were administered in the doctor’s office and no patient dropped out, there was a 100% adherence to testosterone therapy (TTh).
Conclusions: Long-term TTh with TU in hypogonadal men with T2DM improved anthropometric measures compared to untreated controls.

Disclosure
F. Saad: Employee; Self; Bayer AG. Stock/Shareholder; Self; Bayer AG, Novo Nordisk A/S. K.S. Haider: Other Relationship; Self; Bayer AG. A. Haider: Research Support; Self; Bayer AG.
The CCR4-NOT Complex Maintains ß-Cell Identity through the Repression of ß-Cell Disallowed Genes
Authors: MOSTAFA DINA , TAKAHASHI AKINORI , YANAGIYA AKIKO , YAMAMOTO TADASHI 
Published: June 2018

Loss of β-cell identity, dedifferentiation and reprogramming are recognized as mechanisms of β-cell dysfunction in diabetes. Molecular β-cell identity is not only defined by the expression of signature functional β-cell specific genes but also the repression of several genes recently identified in β-cell research as β-cell disallowed genes. The molecular mechanisms involved in the repression of β-cell disallowed genes are largely unknown. Here, we show that the CCR4-NOT complex, a major deadenylase conserved in eukaryotes, is involved in post-transcriptional regulation of β-cell disallowed genes. β-cell specific depletion of CNOT3 (CNOT3βKO), a CCR4-NOT complex subunit, in mice promotes deceased insulin secretion, early impaired glucose tolerance and the development of overt diabetes at 12 weeks of age. CNOT3βKO islets display decreased insulin content and decreased glucose responsiveness. Furthermore, CNOT3 depleted ß cells exhibit ultrastructural abnormalities including: degranulated β cells, increased immature insulin granules and abnormal mitochondria. RNAseq and qRT-PCR analyses revealed that CNOT3βKO islets have decreased expression of β-cell functional genes: (Ins1, Ins2, MafA, Pcsk2 and Cpe) and increased expression of 9 of the 11 core β-cell disallowed genes: (Slc16A1, Ldha, Pdgfra, Cxcl12, Igfbp4, Oat, Maf, Smad3 and Cd302) and progenitor-like cells genes: (Nanog and Ngn3) supporting the loss of β-cell identity. Using the total RNAseq data, we assessed mRNA stability by calculating the relative amounts of introns and exons for a given mRNA. RNA immunoprecipitation revealed that the CCR4-NOT complex directly binds several upregulated stabilized β-cell disallowed genes: Slc16A1, Tgm2, Cat and Parp3 genes. The present data highlight deadenylation as a novel molecular mechanism regulating β-cell disallowed genes. Thus, we further propose that the CCR4-NOT complex is essential for maintaining β-cell identity by repressing β-cell disallowed genes.

Disclosure
D. Mostafa: None. A. Takahashi: None. A. Yanagiya: None. T. Yamamoto: None.
The Relationship of Acculturation to Cardiometabolic Risk Factors among U.S. South Asians—Findings from the MASALA Study
Authors: AL-SOFIANI MOHAMMED , LANGAN SUSAN J. , KANAYA ALKA M. , KANDULA NAMRATHA R. , NEEDHAM BELINDA , KIM CATHERINE , BECKER DIANE M. , VAIDYA DHANANJAY , GOLDEN SHERITA , LEE CLARE , KALYANI RITA RASTOGI 
Published: June 2018

Background: Immigration and the process of acculturation can lead to behavioral changes that exacerbate or reduce diabetes development. We investigated the association between acculturation strategies and cardiometabolic risk (CMR) factors among South Asian (SA) immigrants living in the U.S.
Methods: Participants (n=849) in the Mediators of Atherosclerosis in SA Living in America (MASALA) study were categorized into 3 acculturation strategy classes based on self-reported questionnaire responses: separation (preference for SA culture), assimilation (preference for U.S. culture), and integration (similar preference for SA and U.S. cultures). Adjusted linear regression models examined associations of acculturation strategies with fasting and 2 hour glucose, lipids, blood pressure, waist circumference (WC), and body composition.
Results: Overall, 22.4, 19.6, and 58% of men and 23.7, 26.2, and 50.1% of women were in separation, assimilation, and integration classes; respectively. Participants in the assimilation class had significantly lower levels of obesity, 2 hour glucose, insulin, HOMA-IR, triglycerides (TG), visceral fat, and higher HDL than those in the separation class (all p&lt;0.05). In sex-stratified analyses, after adjusting for education, income, other socioeconomic variables, physical activity, caloric intake, depression, smoking, and alcohol intake, women in the assimilation class continued to have significantly lower TG and higher HDL levels compared to women in the separation class [β (95% CI): -23.7 (-41.9, -5.5) and 7.5 (2.9, 12.1); respectively]. There was no significant association between acculturation and CMR factors in men.
Conclusion: SA women who employed an assimilation strategy had a more favorable CMR profile compared to women using a separation strategy. Future research should investigate the behavioral pathways linking acculturation strategies with CMR and potential incorporation into prevention interventions.

Disclosure
M. Al-Sofiani: None. S.J. Langan: None. A.M. Kanaya: None. N.R. Kandula: None. B. Needham: None. C. Kim: None. D.M. Becker: None. D. Vaidya: None. S. Golden: None. C. Lee: None. R. Rastogi Kalyani: None.