bluuebunny/crossref_metadata_2025_split huggingface dataset:
2007-P: Age-Dependent Metabolic Response to Erythropoietin in Mice
Authors: ROGERS HEATHER , NOGUCHI CONSTANCE T. 
Published: June 2019

Erythropoietin (EPO), the cytokine required for erythrocyte production, regulates glucose homeostasis and fat mass accumulation in animal models. For example, young (5-6 weeks) mice on high fat diet (HFD) treated with EPO for 5 weeks show a dose dependent increase in hematocrit and reduction in fat mass accumulation/weight gain. To assess potential age and sex dependent EPO metabolic response, C57/Bl6 mice beginning at 3 months, 4 months or 6 months of age were fed normal chow (NC) or high fat diet (HFD) and treated with EPO or saline for up to 6 weeks. After 3 weeks of EPO treatment, all mice exhibited the expected increase in hematocrit (hct up to 70%) that was accompanied by an improvement in glucose tolerance. Body weight gain was unchanged in the 3-month groups, while the 4- and 6-month males on HFD showed a reduced gain in body weight with 3-weeks of EPO treatment. Since earlier studies suggested an increased reduction in fat mass with extended EPO treatment, EPO treatment was continued for three more weeks. At 6 weeks EPO treatment, body weight gain was not affected in the 3-month groups on NC or HFD but was reduced in the 4- and 6-month groups on HFD in male and female mice. These differences in weight gain appear to be due to differences in fat accumulation. However, after 6 weeks EPO treatment, about 66% of the 3-month group, 70% of the 4-month group showed reduced hematocrit below baseline to low as 22% in the 3-month group and 11% in the 4-month group. Mice with the lowest hct showed the greatest impairment in glucose tolerance. In the 6-month group on HFD, EPO treatment for 6 weeks decreased body weight in both males and females. However, hct decreased in all 6-month mice treated with EPO for 6 weeks, falling as low as 15% and the improved glucose tolerance with EPO treatment seen at 3 weeks was no longer apparent. These data suggest an age dependent immune response at 6 weeks of human EPO treatment in mice and production of anti-human EPO antibodies with the potential to also reduce erythropoiesis and glucose tolerance associated with endogenous EPO.

Disclosure
H. Rogers: None. C.T. Noguchi: None.

Funding
National Institutes of Health
2018-P: Simultaneous Monitoring of Circulating Levels of Metabolic-Related Aging Biomarkers in Young and Elderly Mice
Authors: ZENG LING 
Published: June 2019

Aging is associated with a decline in lean muscle mass and development of metabolic dysfunction. Skeletal muscle-derived, exercise-induced “myokines” are believed to have anti-inflammatory effects and substantially regulate glucose and fatty acid metabolism. To better understand the linkage between aging associated metabolic dysfunctions and aberrant myokine signaling, we use the MILLIPLEX® map Mouse Myokine Panel and the Mouse Aging Panel (under development) to measure circulating myokine and aging related biomarkers in youth and elderly C57BL/6 mice (Youth: ∼8 weeks old, n=16; Elderly: ∼48 weeks old, n=16). Impaired regenerative capacity and reduction of myokine secretion are hallmarks of aged skeletal muscle. In the elderly group, the myokine SPARC concentrations were 40% that of the youth group and the myogenesis inhibitor GDF8 concentrations were 7-fold higher in the elderly vs. youth. Interestingly, a 21-fold higher level of EPO and a 3-fold higher level of OSTN were observed in the elderly vs. youth groups suggesting a possible compensation effect in these aged mice. We observed the novel type 2 diabetes associated chemokine fractalkine level is 604-fold higher in elderly vs. youth groups. In addition, 41-fold higher IL-6 and 2-fold higher CCL27 in elderly vs. youth coincide with the theory of aberrant glucose metabolism being associated with elevated adipocyte inflammation in elderly populations. Body composition change, and aberrant energy sensing are pervasive features of aging. We found the starvation hormone FGF-21 level was 23-fold higher in elderly mice vs. youth, while the satiety hormone leptin was 3-fold higher. In brief, we measured multiple novel myokines and geriatric related metabolic biomarkers using the MILLIPLEX® map quantitative immunoassay platform. Analytical validation revealed excellent assay performance well suited for biomarker monitoring in mouse models of age-related disease research.

Disclosure
L. Zeng: None.
2024-P: Protective Role of Lipocalin 2 in High-Fat Diet-Induced Gut Microbiota Dysbiosis
Authors: QIU XIAOXUE (SHERYL) , MACCHIETTO MARISSA , SHEN STEVE , CHEN XIAOLI 
Published: June 2019

Diet is the most important factor that shapes diversity in gut microbiome. However, what host factors are involved in dietary regulation of gut microbiota remains largely unknown. Lipocalin 2 (Lcn2) is expressed in intestine, and its expression is upregulated during acute intestinal inflammation. Herein, we investigated the role of Lcn2 in shaping gut microbiota during high-fat diet (HFD)-induced obesity. First, we showed that 12 weeks of HFD feeding led to a significant increase in Lcn2 protein levels in ileum and colon, but a decrease in Lcn2 levels in feces of C57BL/6J mice. This suggests that Lcn2 release into the gut lumen decreases following long-term HFD feeding. Second, we revealed a time course of HFD-induced changes in gut microbiota. Feces were collected from wild type (WT) and Lcn2 knockout (LKO) mice at 2, 4, 8 and 16 weeks of HFD feeding for DNA extraction and 16S sequencing. Compared to WT mice, LKO mice displayed a trend towards lower bacterial diversity (p=0.078) at 4 weeks but not 16 weeks of HFD feeding, suggesting that Lcn2 may have a protective role against gut microbiota dysbiosis during short-term HFD consumption. More interestingly, species richness (the number of bacterial species) was increased at 4 and 8 weeks of HFD feeding and then declined 16 weeks after HFD feeding in WT mice; this time-dependent change in the richness was not observed in LKO mice. Principal coordinate analysis indicates a difference in gut microbiota composition between WT and LKO mice when all time points were considered for the analysis. The heatmap shows that the abundance of short-chain fatty acid-producing bacteria such as Lachnospiraceae and Muribaculaceae was significantly decreased in HFD-fed LKO mice. Lastly, upon 16 weeks of HFD feeding, LKO mice had increased levels of STAT3 and NFκB phosphorylation in colon compared to WT mice, suggesting increased intestinal inflammation. We conclude that Lcn2 plays a protective role in HFD-induced intestinal inflammation and gut microbiota dysbiosis.

Disclosure
X. Qiu: None. M. Macchietto: None. S. Shen: None. X. Chen: None.
2039-P: Age-Related Dysfunction of Brown Adipose Progenitor Cells
Authors: GRAJA ANTONIA , GOHLKE SABRINA , SARAIVA LUIS , SCHULZ TIM J. 
Published: June 2019

Aging is a primary risk factor for the development of obesity and diabetes mellitus and is accompanied by impaired brown adipocyte formation. Deprivation of thermogenic capacity may contribute to an obesity-prone phenotype of aged individuals. To determine whether the age-related decline of brown adipogenesis is due to a cell-autonomous dysfunction of brown adipogenic cells, we isolated stem cells from brown adipose tissue of mice aged 2.5 or 25 months for characterization. While lipid accumulation capacity was unchanged, expression of brown adipocyte markers, such as Uncoupling protein-1 (Ucp1), were significantly reduced in aged cells after differentiation, suggesting that a cell-intrinsic defect is responsible for impaired brown adipogenesis during aging. We subsequently generated immortalized single stem cell clones from both age groups, which displayed a similar age-related defect. Transcriptomes generated from a total of 126 clones show that brown fat-derived stem cells from old mice more closely resemble stem cells isolated from white adipose tissue. Among the genetic pathways significantly altered in aged stem cells are changes to extracellular matrix function as well as cell-intrinsic pathways. Importantly, aged stem cells are characterized by an age-dependent induction of cellular senescence with increased expression of cell cycle inhibitors p16, p21 and p53. To further test the link between senescence and reduced brown adipogenic potential, we isolated brown adipogenic stem cells from a mouse model with conditional inactivation of p53. Confirming our hypothesis, p53-deficient stem cells displayed a marked increase in Ucp1-expression upon differentiation when compared to wild type stem cells. These data taken together suggest that aging of brown adipogenic stem cells may contribute to loss of brown adipocytes and that inhibition of cell cycle blockage may restore their ability to undergo full brown adipogenic differentiation.

Disclosure
A. Graja: None. S. Gohlke: None. L. Saraiva: None. T.J. Schulz: None.

Funding
German Center for Diabetes Research; German Research Foundation
204-OR: Advancing Our Understanding of the Relationships between Diabetes Distress and Depressive Symptoms with Biobehavioral Variables in Adolescents with Diabetes
Authors: ABUJARADEH HIBA , WONG JESSIE J. , HOOD KOREY K. 
Published: June 2019

In adolescents with diabetes, associations of depressive symptoms and diabetes distress (DD) with self-care behaviors and glycemic control vary considerably across studies, yet in adults, DD is a stronger predictor than depressive symptoms. This secondary data analysis compared the strength of the association of DD and depressive symptoms on bio-behavioral (HbA1c and average daily blood glucose monitoring checks [BGM]) and perceived global health among adolescents with diabetes.
Results: Data from 119 adolescents (75% T1D; diabetes duration of 4.8±4.5 years; HbA1c 8.7 ±2.3%; 62% female; mean age of 15.8±2.1 years; 36% Hispanic, 31% white) screened in clinic were analyzed. Teens completed the 2-item DD Scale (DDS2), the PHQ-9, and PROMIS Pediatric Global Health (PGH). Demographics, HbA1c, and BGM were obtained from medical chart review. Of the 119, 6% had severe depression (PHQ &gt;10) and 22% had moderate to severe DD. DD was significantly correlated with HbA1c and BGM (r=.27, -.32;p=.004, .002; respectively); and both DD and PHQ were significantly correlated with the PGH (r=.43, -.57;ps&lt;.001; respectively). In the regression models that included both DD and PHQ along with demographic and clinical covariates, DD was a significant predictor of HbA1c (ß= .31, partial r=.27, p=.004) and BGM (ß= -.24, partial r=-.23, p=.03). PHQ was not a significant predictor of either, but was a significant predictor of PGH (ß=-.6, partial r=-.47, p&lt;.001). Type of diabetes was not a significant covariate.
Conclusion: DD had stronger associations with diabetes biobehavioral variables than depressive symptoms. Considering the outcomes are diabetes-specific, this is not surprising. However, it shows that simply screening for depression may miss an important aspect of the psychosocial health of adolescents with diabetes. Appropriate intervention should follow positive screens of DD to improve adolescents’ diabetes-related variables.

Disclosure
H. Abujaradeh: None. J.J. Wong: None. K.K. Hood: Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Johnson & Johnson Diabetes Institute.
2045-P: Lipid-Induced Mitochondrial Dysfunction Interferes with Retinoic Acid Signaling in Hepatocytes
Authors: KARMAKAR ESHANI , DAS NABANITA , MUKHOPADHYAY SATINATH , ROY SIB SANKAR 
Published: June 2019

Insulin Resistance (IR) plays a key role in pathogenesis of type 2 diabetes. NAFLD, considered by some as the hepatic manifestation of IR, leads to NASH, cirrhosis and rarely hepatocellular carcinoma. Hepatic Cirrhosis secondary to NAFLD is an emerging public health tsunami. IR is known to impair lipid induced hepatic Retinoid metabolism. Lecithin: Retinol Acyl Transferase (Lrat) plays a crucial role in retinoid homeostasis. Studies have shown the involvement of all-trans Retinoic Acid (atRA) in mitochondrial biogenesis; it functions mainly through PPAR-α and RXR. We identified overexpression of LRAT in liver of HFD-fed rats, hepG2 and huh7 cell lines. Lipid (Palmitic acid-PA) induced over expression of Lrat was associated with a significant reduction in RA production; thereby impairing PPAR-α mediated fatty acid oxidation (FAO) and fat accumulation in hepatocytes. PA induced overexpression of hepatic Lrat was accompanied by excess lipid influx into the mitochondria resulting in impaired mitochondrial biogenesis and bioenergetics, characterized by loss of membrane potential, elevated ROS generation and impaired FAO. Knockdown of Lrat gene restored reduced levels of PPARα resulting from overexpression of Lrat upon PA treatment. Silencing of hepatic Lrat abrogated neutral fat accumulation in PA treated liver tissue and cell lines. Lipid induced mitochondrial dysfunction and resulting elevation in ROS levels was associated with increased mitochondrial fragmentation and decreased membrane potential; Lrat silencing reversed this process. Taken together our study unravels a novel role of PA induced Lrat overexpression in neutral fat accumulation in the liver that may potentially lead to development of NAFLD and NASH in the short term and cirrhosis and rarely, HCC in the long term. This brings to the fore Lrat silencing as a future drug target to prevent and/or treat fat accumulation in the liver in setting of Insulin Resistance.

Disclosure
E. Karmakar: None. N. Das: None. S. Mukhopadhyay: None. S. Roy: None.
205-LB: Use of Internet and Mobile Technology for Health Communications in the Jackson Heart Study
Authors: ANUGU PRAMOD R. , VALLE KAREN A. , WINTERS KAREN , CORREA ADOLFO 
Published: June 2019

The availability of internet and/or mobile phone technology (IMT) provides an opportunity to explore more practical approaches to collect and disseminate information related to diabetes prevention and control in cohort studies. However, the extent of use of IMT in cohort studies of high-risk populations is unclear. In the Jackson Heart Study (JHS), a community-based cohort study of cardiovascular disease among African Americans with an increased prevalence of diabetes, we evaluated the prevalence and demographic correlates of IMT use. As part of annual follow-up telephone interviews of JHS participants in 2017-2018, we conducted a survey on IMT use and examined prevalence and demographic correlates of IMT use. Of 3,810 JHS participants in annual follow-up interviews, 2,564 (67.3%) completed the IMT use survey, of whom 2,262 (88.2%) reported IMT use. Compared to non-users, IMT users were more likely to be men (37% vs. 26%), younger (mean age 70 vs. 81years), and to have attained high school or more years of education (89% vs. 57%) and middle-affluent income status (91% vs.78%) (Table 1). For a majority of JHS participants, it may be feasible to use IMT to conduct intensive interviews and pilot diabetes-related communications. For participants with more limited use of IMT, standard methods will continue to be needed and novel methods developed to capture and disseminate information on diabetes prevention and control.

Disclosure
P.R. Anugu: None. K.A. Valle: None. K. Winters: None. A. Correa: None.

Funding
Jackson State University (HHSN268201800013I); Tougaloo College (HHSN268201800014I); Mississippi State Department of Health (HHSN268201800015I); University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, HHSN268201800012I); National Heart, Lung, and Blood Institute; National Institute for Minority Health and Health Disparities
2054-P: Endothelial Dysfunction, Inflammation, and Oxidative Stress Urinary Biomarkers in Obese Children from Alabama
Authors: SELVARAJU VAITHINATHAN , AYINE PRISCILLA , PARRA EMILY P. , BROWN MICHAEL , JEGANATHAN RAMESH B. , THANGIAH GEETHA 
Published: June 2019

Obesity is a state of chronic low-level inflammation closely associated with the oxidative stress. Childhood obesity has been related to endothelial dysfunction, inflammation and oxidative stress markers individually. The aim of this study was to determine the association of biomarkers of the inflammation, oxidative stress and endothelial dysfunction in urine samples of healthy and obese children. Thirty healthy and thirty overweight/obese elementary school children aged between 6 to 10 years from Alabama participated in this study. Anthropometric measurements were measured using WHO recommendations. Urine samples were analyzed for biomarkers of low-grade inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), α-1-acid glycoprotein (AGP); oxidative stress such as 8-isoprostane, 8-hydroxy-2'-deoxyguanosine (8-OHdG); and endothelin-1 (ET-1). Linear regression analysis was performed to analyze the association between the parameters. The overweight/obese children have significantly increased levels of IL-6, CRP, ET1 and 8-isoprostane compared to normal weight. CRP, IL-6, AGP and 8-isoprostane have significant positive association with at least one of the obesity measures except the ET-1 and 8-OHdG. ET-1 is significantly positively correlated with IL-6 and 8-isoprostane. The increased urinary IL-6 and 8-isoprostane can be used as a non-invasive benchmark to monitor childhood obesity.

Disclosure
V. Selvaraju: None. P. Ayine: None. E.P. Parra: None. M. Brown: None. R.B. Jeganathan: None. G. Thangiah: None.

Funding
National Institute of Food and Agriculture
2057-P: HDL-Cholesterol Concentration Independently Predicts Future Accumulation of Intra-abdominal Fat in Japanese Americans
Authors: SONG SUN OK , HWANG YOU CHEOL , KAHN STEVEN E. , LEONETTI DONNA L. , FUJIMOTO WILFRED Y. , BOYKO EDWARD J. 
Published: June 2019

Background: Both intra-abdominal fat (IAF) and HDL cholesterol (HDL-C) are known to be associated with cardiometabolic health problems, with an inverse correlation between them. However, there is little information about the association between HDL-C concentration with future accumulation of IAF. We conducted a prospective study to evaluate whether baseline HDL-C concentration was associated with the accumulation of CT-measured intra-abdominal fat (IAF) over 5 years.
Methods: All participants were Japanese-American men and women between the ages of 34 to 74 years. HDL-C concentration and CT-measurements of IAF, abdominal (SCF) and thigh (TF) subcutaneous fat cross-sectional areas were evaluated at baseline and 5 year follow-up visits. Data were analyzed to determine the association between HDL-C and future 5-year accumulation of IAF.
Results: A total of 545 subjects with and without diabetes (296 men, 249 women, and mean age 53.6±11.4 and 54.0±12.0 years, respectively) were included. The mean (SD) HDL-C concentration was 1.3 mmol/L (0.4) in men and 1.7 mmol/L (0.4) in women and mean (SD) IAF was 102 cm2 (53.8) in men and 74.5 cm2 (46.8) in women. Baseline HDL-C concentration was inversely associated with Δ IAF over 5 years using multivariable regression analysis 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: These results demonstrate that HDL-C concentration predicts significantly future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in nondiabetic Japanese-American men and women.

Disclosure
S. Song: None. Y. Hwang: 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.)
2065-P: Effects of Obesity on Productivity in the Australian Population: A Life Table Modelling Study
Authors: MENON KIRTHI ARAVIND , ZOMER ELLA , LIEW DANNY , COURTEN BARBORA DE 
Published: June 2019

Background: The prevalence of obesity has tripled over the last 40 years, which represents a growing public health concern. Other than exerting a major health impact, the economic consequences of obesity are also significant. The cost of obesity in Australia in 2010 was estimated to be close to AUD $57 billion, including both direct and indirect costs. Absenteeism and presenteeism result in reduced or loss of work productivity, which significantly impacts the economy. The present study sought to estimate the loss of productivity due to obesity over the next 10 years among Australians.
Methods: Prevalence, incidence, mortality, and absenteeism data were obtained from published sources. Life table models were created to estimate the productivity of Australians aged 17-69 years, with follow-up for 10 years or until age 70 years. Productivity was measured in terms of productivity adjusted life years (PALYs) lived. The life table was constructed for the current cohort of Australians of working age with obesity (including incident cases) and then repeated for the same cohort assuming they were not obese. The differences in outcomes between the two modelled analyses reflected the impact of obesity on productivity. All outcomes were discounted by 5% per annum.
Results: Obesity resulted in over 54,000 excess deaths, and a loss of 285,000 (discounted) PALYs. If the economic value of each PALY was assumed to be equivalent to the Australian gross domestic product per equivalent full-time worker, which in 2015 was AUD $192,000, then the loss of PALYs attributable to obesity would equate to a loss of AUD $55 billion to the Australian economy.
Conclusions: The results support the need to implement measures, strategies and ultimately policies to manage and control the growing epidemic of obesity.

Disclosure
K. Aravind Menon: None. E. Zomer: Consultant; Self; Amgen Inc., AstraZeneca, Pfizer Inc., Shire. D. Liew: Advisory Panel; Self; AstraZeneca, Bayer AG. Research Support; Self; AbbVie Inc., AstraZeneca, Bristol-Myers Squibb Company, CSL Behring, Pfizer Inc. B. de Courten: None.
2083-P: Monogenic Obesity Mutations Lead to Less Weight Loss after Bariatric Surgery: A 6-Year Follow-Up Study
Authors: HU CHENG 
Published: June 2019

Objectives: Bariatric surgery is emerging as the most effective treatment option for patients with obesity. Hypothalamic arcuate nucleus plays an important role in metabolic homeostasis. However, the influence of mutations related to the feeding center on weight loss after bariatric surgery is still unclear. We aimed to diagnose monogenic obesity by whole-exome sequencing (WES) and explore whether monogenic mutations influence the effectiveness of bariatric surgery.
Methods: We collected obese patients aged 15 to 55 with a BMI &gt;28 kg/m2 and who underwent laparoscopic sleeve gastrectomy from March 2011 to June 2017 in Shanghai. Data related to weight loss and metabolic characteristics preoperatively and postoperatively were collected, including fasting blood glucose (FBG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides. WES was performed in obese patients using genomic DNA from whole blood samples.
Results: We investigated the proportion of 131 obese adults with one mutation as high as to 8.4% and then evaluated the association between these mutations and weight loss. Mutation carriers had less weight loss over both short-term and long-term periods. Survival analyses indicated it was harder to attain the goal of 20% weight loss for mutation carriers (Plog-rank=0.001; Pbreslow&lt;0.001), and the difference remained significant with a Cox regression model. Improvement in FBG, HDL cholesterol and triglycerides postoperatively were observed in both groups, while there were significant differences between the two groups.
Conclusions: Our data indicated that 8.4% of obesity cases were caused by change in genetics, and mutations had negative effects on the efficacy of bariatric surgery.

Disclosure
C. Hu: None.