bluuebunny/crossref_metadata_2025_split huggingface dataset:
1991-P: Mammary Tumors Increase Diet-Induced Obesity and Insulin Resistance in Female MMTV-PyMT Mice
Authors: NOH HYE LIM , KANG HEE JOON , MERCADO-MATOS JOSE , FRIEDLINE RANDALL H. , SUK SUJIN , HU XIAODI , TRAN DUY A. , TAUER LAUREN A. , KO MIN-JI , CHOI JUNGEUN , LUONG THAVANVOTEY , TSUCHIDA YURAN , SHAW LESLIE M. , KIM JASON K. 
Published: June 2019

Diabetes and cancer share multiple risk factors including obesity and insulin resistance, but the potential relationship between these two major diseases is unknown. Here we examined the metabolic effects of high-fat diet (HFD) feeding in female MMTV-PyMT mice, a breast cancer model expressing the polyoma middle T antigen driven by the Mouse Mammary Tumor Virus promoter. Female PyMT and wild type (WT) mice were fed a HFD (55% fat by calories) for 4 weeks starting at 4∼5 weeks of age (n=10-12/group). During HFD, PyMT mice became more obese than WT mice with significant increases in both fat and lean mass (Figure 1; *P&lt;0.05). This was largely due to ∼5% and 30% decreases in energy expenditure and physical activity, respectively, in HFD-PyMT mice (Figure 2). Food intake did not differ between groups. Hyperinsulinemic-euglycemic clamps were performed to measure glucose metabolism in awake mice. HFD-PyMT mice showed increased insulin resistance with ∼25% decreases in glucose infusion rate and whole body glucose turnover compared to HFD-WT mice (Figure 3). Increased insulin resistance was due to significantly reduced glucose uptake in white adipose tissue (Figure 4).
In conclusion, these results demonstrate that tumor-bearing female PyMT mice developed increased obesity and insulin resistance after high-fat feeding, and our findings implicate an important relationship between obesity, cancer, and type 2 diabetes.

Disclosure
H. Noh: None. H. Kang: None. J. Mercado-Matos: None. R.H. Friedline: None. S. Suk: None. X. Hu: None. D.A. Tran: None. L.A. Tauer: None. M. Ko: None. J. Choi: None. T. Luong: None. Y. Tsuchida: None. L.M. Shaw: None. J.K. Kim: None.

Funding
National Institutes of Health (5U2C-DK093000)
20-LB: Endothelial Cell Metabolomics Identifies ?-glutamyl Cycle Alterations Associated with the 1q25 T2D-Specific Cardiovascular Locus
Authors: PIPINO CATERINA , SHAH HETAL , PARK KYOUNGMIN , MONTI STEFANO , MENDONCA CHRISTINE , KING GEORGE L. , PANDOLFI ASSUNTA , DORIA ALESSANDRO 
Published: June 2019

A variant on chromosome 1q25 (rs10911021) has been previously associated with coronary artery disease (CAD) in individuals with T2D. In human umbilical vein endothelial cells (HUVECs), the 1q25 risk allele (‘C’) was found to be associated with decreased expression of the adjacent gene GLUL encoding the enzyme glutamine synthase converting glutamate to glutamine. To further investigate the mechanisms through which the 1q25 locus modulates CAD risk in T2D, we performed a global metabolomics study (LC-MS, Metabolon) in 62 HUVECs (TT=11, CT=21, CC=30). Among 597 metabolites detected in HUVEC lysates, 23 attained p&lt;0.005 for association with the 1q25 risk allele. Through an unbiased hierarchical cluster analysis, these 23 metabolites could be subdivided into four clusters - two upregulated and two downregulated in carriers of the risk allele. The two upregulated clusters included a group of γ-glutamyl amino acids (γ-glutamylthreonine, γ-glutamylleucine, and γ-glutamylvaline) and a heterogeneous group of metabolites including isoleucylglycine and tyrosylglycine. The two downregulated clusters included a group of polyunsaturated fatty acid (PUFA) derivatives, such as DHA-choline and N-arachidonoyl taurine, and a cluster of several sphingomyelins. Consistent with the higher γ-glutamyl amino acids, the risk allele was associated with increased ophthalmate (p=0.04), a marker of γ-glutamyl cycle malfunction, and decreased S-lactoylglutathione (p=0.016), a possible sign of defective detoxification of the AGE-precursor methylglyoxal.
In summary, we have identified several metabolic pathways potentially mediating the 1q25 locus effect on CAD risk in T2D. These include impairment of the γ-glutamyl cycle, possibly increasing susceptibility to oxidative stress, and downregulation of PUFA derivatives and sphingomyelins. Further studies of these pathways may lead to the identification of novel therapeutic targets to reduce CAD risk in T2D.

Disclosure
C. Pipino: None. H. Shah: None. K. Park: None. S. Monti: None. C. Mendonca: None. G.L. King: Research Support; Self; Sanofi. A. Pandolfi: None. A. Doria: Research Support; Self; Sanofi-Aventis.

Funding
Sanofi-Aventis
2001-P: Thermoneutrality Dissociates Glucose Tolerance from Insulin Sensitivity in Rats
Authors: KELLER AMY C. , KNAUB LESLIE , HULL SARA E. , SCALZO REBECCA L. , WALKER LORI A. , REUSCH JANE E.B. 
Published: June 2019

Thermoneutrality (TN) has been used to induce weight gain in rodent models of obesity. We hypothesized that TN would potentiate high-fat diet (HFD) impairment of vascular reactivity, diminish vascular mitochondrial function, and induce insulin resistance. Male rats aged 5-7 weeks were housed at room temperature (RT=23 C) or TN (29 C) and fed a low-fat diet (LFD) or HFD for 10-16 weeks. Aortic vasomotion and mitochondrial respiration (Oroboros O2k) were measured at the end of the study. Intraperitoneal glucose and insulin tolerance tests (IP-GTT and IP-ITT) were done at baseline and endpoint. Animals housed at TN had impaired vasodilation regardless of diet (effect of temperature, p&lt;0.01). We also observed an elevated constriction response to phenylephrine in TN animals (interaction of temperature x concentration, p=0.023). Animals on HFD housed in both environments had diminished mechanical constriction (effect of diet, p=0.007). Animals housed at TN had elevated rates of both ADP-independent and dependent respiration (effect of temperature, p&lt;0.001 for both). Metabolic profiling revealed that TN lowered glucose tolerance (interaction of temperature x time p&lt;0.001). Fasting glucose was lower at endpoint in TN rats (interaction of time x temperature, p=0.004). Unexpectedly, glucose uptake improved in TN during an IP-ITT but worsened with RT (effect of temperature, p=0.023). IP-ITT insulin clearance in TN animals at endpoint was impaired (interaction of time x diet p=0.002). There was a significant effect of temperature on fat pad weight (p=0.034) with no effect on overall weight. In sum, TN provides a robust tool for inducing vascular dysfunction. A TN climate led to significant alterations in metabolism. Further experiments are underway to clarify potential mechanisms for the unexpected TN-mediated increased insulin sensitivity with concomitant glucose intolerance.

Disclosure
A.C. Keller: None. L. Knaub: None. S.E. Hull: None. R.L. Scalzo: None. L.A. Walker: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck & Co., Inc.

Funding
U.S. Department of Veterans Affairs (BX003185-01A2, BX002046, CX001532); National Institutes of Health (5T32HL007171)
2005-P: Transgenic Overexpression of Human Chimeric Intestinal Alkaline Phosphatase (IAP) Improves Plasma Lipid Profile and Attenuates Western Diet (WD)-Induced Atherosclerosis in LDLR-/- Mice
Authors: GHOSH SIDDHARTHA S. , WANG JING , YANNIE PAUL J. , SANDHU YASHNOOR K. , GHOSH SHOBHA 
Published: June 2019

IAP represents the first layer of the intestinal barrier and detoxifies bacterial endotoxin LPS in the gut lumen. Reduced levels of IAP are associated with diabetes and heart disease. We developed intestine specific IAP transgenic mice (IAPTg) and demonstrated attenuation of WD-induced intestinal barrier dysfunction and glucose intolerance. In this study, we crossed the IAPTg mice into LDLR-/- background to examine the effects on atherosclerosis. Panel A shows significant reduction in plasma total cholesterol (TC) and triglyceride (TG) in LDLR-/-IAPTg mice. There was a small but statistically non-significant improvement in glucose tolerance (Panel B). Enface analyses (Panel C) showed significant reduction in arch and total aortic lesions (Panel D). Expression of IAP was observed along the entire length of the GI tract including colon (Panel E). Expression of Muc-2, major protein of the mucin or the second layer of the intestinal barrier was enhanced in colon of IAPTg mice. Increased expression of GLP-1 was also noted in the ileum of IAPTg mice. These data suggest that in addition to limiting LPS-mediated intestinal inflammation, IAP also improves intestinal barrier function by increasing Muc-2 expression and IAP-modulated increase in ileal GLP-1 expression may contribute to the improved glucose tolerance.

Disclosure
S.S. Ghosh: None. J. Wang: None. P.J. Yannie: None. Y.K. Sandhu: None. S. Ghosh: None.

Funding
American Diabetes Association (1-16-IBS-105 to S.G.)
2008-P: BioChaperone Glucagon Exenatide (BC Glu Exe), a Stable Combination of Glucagon (Glu) and Exenatide (Exe) Achieved Larger Body Weight (BW) Loss than Exe Alone in DIO Mice
Authors: GAUDIER MARTIN , HAKIM SANA , MÉGRET CLAIRE , BEZAGU MARINE , FRANCOIS-HEUDE MARC , REGAIRAZ ANNE , MEIFFREN GRÉGORY , SOULA RÉMI , SOULA OLIVIER 
Published: June 2019

Combination of excessive food intake and lack of physical activity is associated with an increased risk of obesity and associated morbidity. GLP-1 Receptor Agonists (GLP-1 RA) are one of the few treatment options currently available, but with limited weight loss. A combination of Human Glu and GLP-1 RA is expected to provide a superior BW reduction than GLP-1 RA alone. GLP-1 RA acts in the brain to induce satiety while Glu has a lipolytic and thermogenic effect in liver and adipose tissues. BioChaperone (BC) proprietary technology allows the solubilization and stabilization of poorly soluble and/or unstable peptides at neutral pH and thus the combination of Glu and GLP-1 RA. A combination formulation of Glu and Exe (BC Glu Exe) was developed. Such combination is physically and chemically stable for at least 4 weeks at 37°C in cartridges. It was tested in vivo against reference Exe and vehicle in diet induced obese (DIO) male mice. Mice were dosed with a subcutaneous continuous infusion of vehicle, Exe or BC Glu Exe via osmotic minipumps. After 14 days, Exe and BC Glu Exe induced a BW loss of 10% and 25% respectively, compared to the vehicle. The BW loss was significantly more pronounced with BC Glu Exe than with Exe.
In conclusion, these results support the testing of BC Glu Exe in clinics as a treatment for obesity.

Disclosure
M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. S. Hakim: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. C. Mégret: Employee; Self; ADOCIA. M. Bezagu: None. M. Francois-Heude: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. A. Regairaz: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. R. Soula: Board Member; Self; Cellnovo. Employee; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. Employee; Self; ADOCIA. Stock/Shareholder; Spouse/Partner; ADOCIA. Stock/Shareholder; Self; ADOCIA.
2010-P: Increasing POMC Positive Neurons and Ameliorating the Brain Inflammation Played an Important Role in DJB Improving Glucose Homeostasis in Diabetic Rats
Authors: WANG HUAI-JIE , JIANG BIN , LI JIAN , WANG WEI-YU , LI NA , YAN QINGTAO , GAO ZHIQIN , QU MEI-HUA 
Published: June 2019

This study was focused on the effect of duodenal-jejunal bypass (DJB) on brain inflammation, activation brain insulin signaling and POMC positive neurons in type 2 diabetic (T2DM) rats. T2DM rats were induced by high-fat diet (HFD) and low dose streptozotocin (STZ) injection. Twelve T2DM rats were randomly divided into 2 groups, DJB group (T2DM-DJB, n=6) and T2DM group (T2DM-Sham, n=6). Six health Wistar rats were used as normal control rats (Wistar-Control, n=6). The results showed DJB group was significantly reduced the HOMA-IR and increased HOMA-ISI of T2DM rats 6 weeks after surgery. The Q-RT-PCR and Western-blot results showed DJB intervene significantly decreased the expression of inflammatory factors IL-6, TNF-α, IL-1β and NF-κB in the brain. Our data also showed that DJB activated the brain insulin by increasing the expression of insulin, IRS1 and IRS2 in the brain of T2DM rats. Immunohistochemical assay showed that DJB increased the number of POMC positive neurons in brain, and increased the expression of BDNF in neurons. Those results indicated that DJB might fulfill the antidiabetic effect by increasing POMC positive neurons and decreasing the brain inflammation in T2DM rats.

Disclosure
H. Wang: None. B. Jiang: None. J. Li: None. W. Wang: None. N. Li: None. Q. Yan: None. Z. Gao: None. M. Qu: None.

Funding
National Natural Science Foundation of China (81871892, 31671208, 81500798, 81471048); Shandong Province Natural Science Foundation (ZR2015HL128); Technology Development Plan of Weifang (2018YX027)
2013-P: Parkin Is Dispensable in Pancreatic Beta Cells and Adipocytes for Metabolic Homeostasis
Authors: PEARSON GEMMA , CORSA CALLIE , SOLEIMANPOUR SCOTT , MACDOUGALD ORMOND A. 
Published: June 2019

The E3 ligase parkin is a critical regulator of mitophagy and has been identified as a susceptibility gene for type 2 diabetes (T2D), but its role in metabolically active tissues to modulate the development of T2D is unknown. Pancreatic β-cells and adipocytes both rely heavily on mitochondrial function to regulate optimal glycemic control to prevent T2D, but the role of parkin to modulate β-cell or adipocyte mitochondrial quality control is unclear. Despite the reported importance of parkin to control mitophagy, here we report that parkin surprisingly is dispensable in both β-cells and adipocytes for glucose homeostasis during diet-induced insulin resistance. We observe that insulin secretion, β-cell formation, and islet architecture were preserved in parkin deficient β-cells and islets, suggesting parkin is not necessary for control of β-cell function and islet compensation for diet-induced obesity. While transient parkin deficiency mildly impaired mitochondrial turnover in β-cell lines, parkin deletion in primary β-cells yielded no deficits in mitochondrial clearance. In adipocyte-specific deletion models, lipid uptake and β-oxidation were increased in cultured cells, while adipose tissue morphology, glucose homeostasis, or the beige-to-white adipocyte transition were unaffected in vivo. In key metabolic tissues where mitochondrial dysfunction is implicated in the development of T2D, our studies unexpectedly demonstrate that parkin is not an essential regulator of glucose tolerance, whole-body energy metabolism, or mitochondrial quality control. These findings highlight a novel role for parkin-independent processes to maintain β-cell and adipocyte mitochondrial quality control with diet-induced obesity.

Disclosure
G. Pearson: None. C. Corsa: None. S. Soleimanpour: None. O.A. MacDougald: None.

Funding
American Diabetes Association (1-18-PDF-064 to C.C.); National Institutes of Health; JDRF
2017-P: Gut Microbes after Bariatric Surgery in Humans Improve Glucose Control in Mice without Fat Loss
Authors: ANHÊ FERNANDO FORATO , FOLEY KEVIN P. , BARRA NICOLE G. , DUGGAN BRITTANY M. , CAVALLARI JOSEPH F. , HENRIKSBO BRANDYN D. , CANI PATRICE D. , BIERTHO LAURENT , TCHERNOF ANDRE , MARETTE ANDRE , SCHERTZER JONATHAN D. 
Published: June 2019

Bariatric surgery (BS) is the most efficacious treatment against severe obesity and T2D. Among bariatric procedures, biliopancreatic diversion with duodenal switch (BPD-DS) can produce superior metabolic benefits compared with other surgical options. The mechanisms by which BPD-DS improve metabolic health are not well-understood, but there is evidence implicating the gut microbiota (GM) as contributor to changes in adiposity and consequently blood glucose control. We aimed to determine how the GM before and after BPD-DS alter host metabolism. Fecal samples from female patients subjected to BPD-DS were collected before (pre-surgery) and 12 months after surgery (post-surgery) and used to colonize female C57BL6NTac mice housed either in germ-free (GF) or SPF conditions. Oral glucose tolerance (OGT) was assessed in mice 3 and 7 weeks post-colonization. Three weeks after fecal microbiota transplantation (FMT), glucose tolerance was similar in GF mice receiving pre- and post-surgery fecal slurries. However, GF mice had lower glucose during OGT test 7 weeks after FMT derived from BPD-DS post-surgery compared to GF mice receiving pre-surgery fecal slurry. No changes in fat mass accretion were seen between pre- and post-surgery mice. SPF mice colonized with the fecal microbiota pre- and post-surgery showed no difference in glucose tolerance after 3 and 7 weeks of FMT. These data suggest that the GM after BPD-DS is an independent and transmissible contributor to improved host glucose control. Furthermore, while our data show that the mouse model (e.g., SPF vs. GF) dictates the glycemic response to FMT, exposure time (e.g., at least 7 weeks) is a key factor in microbe transmissible changes in glycemia.

Disclosure
F. Forato Anhê: None. K.P. Foley: None. N.G. Barra: None. B.M. Duggan: None. J.F. Cavallari: None. B.D. Henriksbo: None. P.D. Cani: Board Member; Self; A-Mansia Biotech. Consultant; Self; Biocodex, Pilèje, Valbiotis. Research Support; Self; Tate & Lyle. Stock/Shareholder; Self; A-Mansia Biotech, Enterosys. L. Biertho: None. A. Tchernof: Research Support; Self; Johnson & Johnson Medical Devices Companies, Medtronic, Pfizer Inc. A. Marette: Advisory Panel; Self; Plexus, Valbiotis. Consultant; Self; Danone Nutricia Research. J.D. Schertzer: None.

Funding
Canadian Institutes of Health Research; Diabetes Canada
2020-P: Comparable Disease Progression in GAN and AMLN Diet-Induced Obese Mouse Models of Biopsy-Confirmed Nonalcoholic Steatohepatitis
Authors: BOLAND BRANDON B. , HANSEN HENRIK H. , BOLAND MICHELLE , ORÓ DENISE , TØLBØL KIRSTINE SLOTH , VEIDAL SANNE , FEIGH MICHAEL , JELSING JACOB , VRANG NIELS , TREVASKIS JAMES 
Published: June 2019

Amylin Liver NASH (AMLN) diet-induced obese C57Bl/6J (DIO-NASH) and ob/ob (ob/ob-NASH) mouse models display clinical translatability with respect to metabolic and histopathological changes associated with nonalcoholic steatohepatitis (NASH). A recent FDA ban on trans-fats in foods has necessitated the development of a new NASH diet capable of promoting comparable disease, as AMLN diet contains trans-fat-containing Primex shortening. Here, we assessed the disease phenotype in C57Bl/6J and ob/ob mice fed a high-fat diet with a nutrient composition and caloric content comparable to the AMLN diet. Male ob/ob mice were fed AMLN diet (40% total fat kcal of which 18.5% were trans-fat kcal; 20% fructose; 2% cholesterol) for 16 weeks or a modified AMLN diet with Primex substituted by palm oil, termed Gubra Amylin NASH (GAN) diet, for up to 30 weeks. C57 mice were fed GAN diet for 28 weeks. In ob/ob-NASH mice, GAN diet was more obesogenic and adipogenic than the AMLN diet. GAN, but not AMLN, diet also impaired glucose tolerance in ob/ob-NASH mice versus chow-fed C57Bl/6J mice. Both diets promoted similar levels of steatosis, lobular inflammation and hepatocyte ballooning as well as similar fibrotic liver lesions and collagen-1a1 fractional area. Mild (stage F1) and moderate (stage F2) grade fibrosis was induced in DIO-NASH and ob/ob-NASH mice, respectively, when fed either diet for 16 weeks. When fed GAN diet for ≥24 weeks, a significant proportion of ob/ob-NASH mice developed advanced fibrosis (stage F3). The two diets also promoted overlapping liver transcriptome changes.
In conclusion, AMLN diet modification by substitution of Primex with palm oil results in a preserved NASH phenotype in C57 and ob/ob mice. Accordingly, the GAN diet induced clear metabolic and histopathological hallmarks of biopsy-confirmed NASH in both DIO-NASH and ob/ob-NASH mice, highlighting the suitability of these models for the characterization of novel drug therapies for NASH.

Disclosure
B.B. Boland: Employee; Self; Gubra, MedImmune. H.H. Hansen: None. M. Boland: Employee; Self; Gubra, MedImmune. D. Oró: None. K.S. Tølbøl: None. S. Veidal: None. M. Feigh: None. J. Jelsing: Stock/Shareholder; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Trevaskis: Employee; Self; Gilead Sciences, Inc., MedImmune. Stock/Shareholder; Self; AstraZeneca.
2021-P: STAT1 Represses Metabolic Intermediates Necessary to Store Fat
Authors: COX AARON , MASSCHELIN PETER , CHERNIS NATALIE , HARTIG SEAN M. 
Published: June 2019

Obesity associates with chronic low-grade inflammation that likely impinges on the metabolic functions of adipocytes and may partially explain the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). We recently demonstrated ectopic expression of the microRNA miR-30a in the subcutaneous fat pad of diabetic mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. Further, miR-30a directly inhibited STAT1, a major mediator of inflammatory signals such as interferon gamma (IFNγ). Despite the established dominance of STAT1 in the immune response and the importance of inflammation in the development of T2DM, the role of STAT1 in white adipocytes remains unknown. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. IFNγ treatment of human adipocytes diminished oxidative phosphorylation capacity, along with expression of mitochondrial proteins. STAT1 deletion in white adipocytes (STAT1 fKO) did not change body weight, but improved whole-body insulin sensitivity of diabetic mice. Transcriptome profiling by RNA-Seq suggested STAT1 fKO adipocytes engage GABPa and NFIA target genes that reflect oxidative phosphorylation specifically in the inguinal white adipose tissue (iWAT). Additional metabolomics profiling indicated the metabolic effects of STAT1 deletion in iWAT are associated with accelerated TCA cycle flux and aspartic acid generation, which provides intermediates to support lipid synthesis and histone modifications. These studies reveal important roles of inflammatory signals to suppress metabolism and epigenetic regulation in adipocytes that may underlie insulin resistance and T2DM.

Disclosure
A. Cox: None. P. Masschelin: None. N. Chernis: None. S.M. Hartig: None.

Funding
American Diabetes Association (1-18-IBS-105 to S.M.H.); National Institutes of Health (R01DK114356); Baylor College of Medicine (P30DK079638)