bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary Animal and Saturated Fat Predict Future Visceral Fat Accumulation in Japanese Americans
Authors: HAYASHI TOMOSHIGE , SATO KYOKO , LEONETTI DONNA L. , KAHN STEVEN E. , UEHARA SHINICHIRO , FUJIMOTO WILFRED Y. , BOYKO EDWARD J. 
Published: June 2018

Both diet and visceral adiposity play key roles in cardiometabolic disease. However, the association between dietary fat and subsequent visceral fat accumulation is not known. Thus, we prospectively examined future visceral fat accumulation in relation to dietary intake of animal and plant fats, or saturated and polyunsaturated fats in 312 nondiabetic Japanese-American men and women. Visceral adiposity was measured as intra-abdominal fat (IAF) area at the umbilicus by computed tomography at baseline and 10-11 years. Detailed dietary information was assessed at baseline using a food frequency questionnaire and 24-hour recall. Insulin sensitivity was evaluated by homeostasis model assessment for insulin resistance (HOMA-IR) and insulin response by the insulinogenic index (IGI) [Δinsulin/Δglucose (30-0 minutes)]. After adjustment for baseline IAF, age, sex, smoking habits (non-smokers, past-smokers, current smokers), physical activity, alcohol consumption, HOMA-IR, IGI, total protein intake, and total carbohydrate intake in multiple linear regression models, baseline log transformed animal fat intake [coefficient=15.319 (P=0.002)], but not plant fat intake [0.163 (P=0.270)], was associated with future IAF change. In the model that included saturated and polyunsaturated fat substituted for animal and plant fat intake, saturated fat was associated with future IAF change in both men [0.892 (P=0.030)] and women [1.121 (P=0.022)], but a statistically significant interaction was present between sex and polyunsaturated fat, such that polyunsaturated fat intake was inversely associated with future IAF change in men [-1.290 (P=0.003)], but not women [-0.058 (P=0.905)].
In conclusion, in both men and women, higher intake of animal fat and saturated fat, not plant fat, precede more visceral fat accumulation, while in men only, higher polyunsaturated fat intake precedes less visceral fat accumulation.

Disclosure
T. Hayashi: None. K. Sato: None. D.L. Leonetti: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. S. Uehara: None. W.Y. Fujimoto: None. E.J. Boyko: None.
APPL2 Promotes Inflammation in Mouse Liver by Negative Regulation of Adiponectin Signaling
Authors: RYU JIYOON 
Published: June 2018

Adiponectin is an insulin sensitizer that exerts antidiabetes and anti-inflammation functions. Adiponectin signaling is negatively regulated by the adaptor protein APPL2 in cells, yet the in vivo roles of APPL2 remains largely unknown. In this study, we show that liver-specific knockout of APPL2 improved insulin sensitivity and enhanced adiponectin signaling in high fat diet (HFD)-fed mice. The liver-specific APPL2 knockout mice (APPL2LKO) had less macrophage infiltration in liver tissues compared with their wild type controls and were resistant to LPS-induced expression of inflammatory genes such as IL-6, IL-1α, MCP-1, and TNF-α. Pretreatment of macrophage Raw264.7 cells with conditioned media from primary hepatocytes of APPL2LKO mice attenuated LPS-stimulated expression of inflammatory genes and the migration of the cells. The anti-inflammatory effect of APPL2 knockout was significantly reduced in adiponectin and liver-specific APPL2 double knockout mice (AdiponectinKO/APPL2LKO). Taken together, our results show that APPL2 promotes inflammation in mouse liver and the protein exerts a pro-inflammatory role by antagonizing adiponectin signaling.

Disclosure
J. Ryu: None.
The Transcription Factor ETV5 Regulates Adipogenesis through PPARg Signaling Pathway
Authors: MAO ZHUO 
Published: June 2018

ETV5 is a member of PEA3 subfamily of E26 transformation-specific (ETS) transcription factors, characterized by the conserved DNA binding domain, ETS domain. Recently, a series of genomic-wide association studies (GWAS) found that ETV5 is associated with obesity. ETV5 knockout mice have lower fat mass and resistant to diet induced obesity, suggesting it was involved in the adipogenesis. In our study, we showed that ETV5 was expressed in the nucleus of adipocyte. Its expression level was altered according to different nutrient status. In order to exclude other tissues’ effect, we examine its biological function in preadipocyte 3T3-L1 cells. We found that the protein level but not the mRNA level of ETV5 was significantly elevated during adipogenesis. We utilized lentivirus to successfully knockdown ETV5 in 3T3-L1 cells. Deficiency of ETV5 resulted in reduced number and smaller size of adipocytes showed by oil red O staining. The major genetic changes involved in the impaired adipogenesis was defective PPAR signaling. Rosiglitazone stimulation of 3T3-L1 could restore adipogenesis caused by ETV5 deficiency. Dual luciferase assay found that ETV5 potently enhanced PPRE activity. These results suggest ETV5 is an important regulator of adipogenesis in early stage and a potential target for the treatment of obesity.

Disclosure
Z. Mao: None.
The Vagus Nerve Mediates Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias
Authors: RENO CANDACE M. , SKINNER ALLIE J. , BAYLES JUSTIN , FISHER SIMON J. 
Published: June 2018

Severe hypoglycemia causes fatal cardiac arrhythmias. The extent to which the parasympathetic nervous system regulates hypoglycemia-induced fatal arrhythmias remains unknown. To investigate the role of vagal innervation in regulating arrhythmias during severe hypoglycemia, Sprague Dawley rats underwent vagotomy (left vagus nerve transection adjacent to the carotid artery; n = 15) or sham surgery (control; n = 13). One week after surgery, all rats underwent hyperinsulinemic (0.2 U/kg/min) severe hypoglycemic (10-15 mg/dl) clamps with electrocardiogram recordings. Rats with vagotomy had increased heart rate at baseline and throughout the clamp, indicating successful vagotomy. Glucose infusion rates during hypoglycemia were increased 1.7-fold in rats with vagotomy, but epinephrine values were similar between the groups. Vagotomy resulted in fewer cardiac arrhythmias including a 12-fold decrease in 2nd degree heart block. Reduction in arrhythmias was associated with a 7-fold decrease in severe hypoglycemia-induced mortality in rats with vagotomy (7%) compared to controls (46%).
In summary, vagal transection reduces mortality and cardiac arrhythmias during severe hypoglycemia. Since vagal innervation mediates severe hypoglycemia-induced sudden death, targeting the parasympathetic nervous system may be a logical approach to prevent sudden death for at-risk people with insulin treated diabetes.

Disclosure
C.M. Reno: None. A.J. Skinner: None. J. Bayles: None. S.J. Fisher: None.
Sennoside A Improves Mitochondrial Function of Large Intestine in Diet-Induced Obese Mice to Preserve GLP-1 Expression through Induction of Short-Chain Fatty Acids
Authors: LE JIAMEI , YE JIANPING , SUN YONGNING 
Published: June 2018

Objective: Sennoside A (SA) is a bioactive component of Chinese herbal medicines with an activity of irritant laxative. However, its activity remains unknown in the regulation of GLP-1 expression. Here, we investigated the possibility in high-fat-diet (HFD) induce obesity (DIO) mice.
Methods: SA was administrated in DIO mice through dietary supplementation for 8 weeks. In the study, energy balance and insulin sensitivity were monitored. GLP-1 was determined in plasma and colon tissue. Mitochondria were examined in structure by transmission electron microscopy and in function with Seahorse XF24 in the colon tissue. Gut microflora was examined using fecal DNA and the diversity of gut microbiota was analyzed by Miseq sequencing. The fecal short chain fatty acids (SCFAs) were examined by GC (gas chromatograph).
Results: There was an increase in cell necrosis in the epithelial layer of mucosa of DIO mice, which was observed with reduction of plasma GLP-1 and mRNA expression in the colon tissue. Mitochondria exhibited an increase in size and membrane rupture in the epithelial cells. An elevation in the complex I activity, and a fall in the complex II activity were observed in the mitochondria, suggesting an imbalance of the complex I/II in the cells. The short chain fatty acids were decreased in abundance along with the dysbiosis in the colon of DIO mice. All of those alterations were corrected by SA in DIO mice along with control of obesity and insulin resistance.
Conclusion: The data suggested that SA may improve GLP-1 expression in colon through restoration of mitochondrial function and structure in the epithelia cells of mucosal. The effect may be related to restoration of gut microflora/SCFAs axis.

Disclosure
J. Le: None. J. Ye: None. Y. Sun: None.
Early Life Exposure to Antibiotic Alters Energy Balance during Chronic High-Fat Feeding in Adult Male and Female Mice
Authors: NOH HYE LIM , SUK SUJIN , FRIEDLINE RANDALL H. , INASHIMA KUNIKAZU , TRAN DUY A. , KIM ALLISON M. , KIM SOOYOUNG , JEONG SANGEUN , UONG CECILIA , OZKAN BERK A. , KASINA VISHAL , KNOWLES KATHERINE P. , PEREZ-PEREZ GUILLERMO , LEE KI WON , BLASER MARTIN J. , KIM JASON K. 
Published: June 2018

Gut microbiota are affected by antibiotics and may modulate host energy metabolism. Male and female C57BL/6J mice (n=5∼11/group) were exposed to low-dose penicillin (LDP) via maternal drinking water from birth to 4 weeks (w) of age, and chronic changes in energy balance were examined using metabolic cages. Through 8w of age (Chow), LDP and Control mice had comparable fat mass, but male and female LDP mice showed significantly increased O2 consumption rates without changes in food intake and activity (Figure). At 9w of age, mice were given a high-fat diet (HFD; 45% fat by calories), and they began gaining adiposity with female LDP mice showing ∼40% lower fat mass than Controls. After 8w of HFD, male LDP group showed significantly elevated O2 consumption rates compared to Controls. Male LDP mice also showed marked reductions in food intake and activity, but these effects were no longer observed after 12w of HFD. In contrast, female LDP group had reduced O2 consumption rates compared to Controls after 4 and 8w of HFD without changes in food intake and activity.

In conclusion, these results indicate that early life exposure to penicillin modulates energy balance in young and mature mice, suggesting an important role of altered populations of gut microbiota in diet-induced obesity. Our findings also identify important gender-selective effects of early life antibiotic exposure on energy balance in mature mice.

Disclosure
H. Noh: None. S. Suk: None. R.H. Friedline: None. K. Inashima: None. D.A. Tran: None. A.M. Kim: None. S. Kim: None. S. Jeong: None. C. Uong: None. B.A. Ozkan: None. V. Kasina: None. K.P. Knowles: None. G. Perez-Perez: None. K. Lee: None. M.J. Blaser: None. J.K. Kim: None.
Genome-Wide and Abdominal Imaging Data Characterizes Common Alleles Associated with Higher BMI and Subcutaneous Fat but Less Liver Fat and Lower Risk of Type 2 Diabetes
Authors: YAGHOOTKAR HANIEH , JI YINGJIE , YIORKAS ANDRIANOS M. , FRAU FRANCESCA , MOOK-KANAMORI DENNIS , MUTSERT RENÉE DE , TYRRELL JESSICA , JONES SAMUEL E. , BEAUMONT ROBERT , WOOD ANDREW R. , THOMAS LOUISE , ALLEBRANDT KARLA V. , STEFAN NORBERT , STAIGER HARALD , PEARSON EWAN , BLAKEMORE ALEX I. , BELL JIMMY D. , FRAYLING TIMOTHY M. 
Published: June 2018

Genetic studies have identified “favourable adiposity” variants - where the allele associated with higher adiposity is associated with lower risk of type 2 diabetes. We took a novel approach to find more of these alleles and find the underlying mechanisms.
We first performed a genome wide association study (GWAS) of body fat percentage using 451000 individuals from UK Biobank. Second, we used published genetic data in a multivariate test to find alleles associated with higher adiposity but a “favourable” metabolic phenotype: higher HDL-C, adiponectin, sex hormone binding globulin, but lower triglycerides, fasting insulin and alanine transaminase. Third, we used abdominal imaging data from 4 studies to define the adiposity phenotype in more detail.
We identified 620 variants associated with body fat percentage (p&lt;5x10-8). Fourteen alleles had a “favourable adiposity” phenotype, including 7 previously known variants (in/near PPARG, LYPLAL1, GRB14, IRS1, PEPD, FAM13A and ANKRD55), 5 known to be associated with a relevant trait (TRIB1, KLF14/MKLN1, DNAH10, VEGFA/C6orf223 and AEBP2/PDE3A) and 2 novel variants (MAFF and CITED2). Carrying 10 additional "favourable adiposity" allele was associated with higher BMI (0.63 kg/m2, p = 4x10-45) but lower risk of type 2 diabetes (odds ratio: 0.60, p = 4x10-44, 14371 cases), lower risk of heart disease (0.82, p = 3x10-14, 37741 cases) and lower risk of hypertension (0.82, p = 1x10-33, 241691 cases). Using MRI/CT scans of abdominal fat from UK Biobank (N = 5000), NEO (2236), TÜF (900), and a published GWAS (10557), carrying more “favourable adiposity” alleles was associated with higher subcutaneous fat (p = 1x10-12) but lower liver fat (p = 1x10-7). These effects were similar when we removed the 7 known “favourable adiposity” variants.
“Favourable adiposity” alleles associated with higher BMI but lower risk of type 2 diabetes are characterized by higher subcutaneous but lower liver fat.

Disclosure
H. Yaghootkar: None. Y. Ji: None. A.M. Yiorkas: None. F. Frau: None. D. Mook-Kanamori: None. R. de Mutsert: None. J. Tyrrell: None. S.E. Jones: None. R. Beaumont: None. A.R. Wood: None. L. Thomas: None. K.V. Allebrandt: None. N. Stefan: Consultant; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, OmniaMed Ltd.. H. Staiger: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company. A.I. Blakemore: None. J.D. Bell: None. T.M. Frayling: None.
Carvedilol Prevents Counterregulatory Failure in Recurrently Hypoglycemic Rats
Authors: FARHAT RAWAD , SU GONG , CHAN OWEN 
Published: June 2018

We showed previously that recurring activation of β2-adrenergic receptors in the ventromedial hypothalamus (VMH) leads to the development of counterregulatory failure, in part by increasing local lactate levels. The current study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent the development of counterregulatory failure and improve hypoglycemia awareness (HA) in recurrently hypoglycemic (RH) rats. Sprague-Dawley rats (n=6-10 per group) underwent surgery for the implantation of vascular catheters and intracranial guide cannulas that targeted the VMH. These animals then received either 3 bouts of insulin-induced hypoglycemia (RH) over the course of 3 days or they received 3 injections of saline (Controls). A subgroup of RH rats was treated with carvedilol (3mg/kg QID; IP) beginning one day prior to the start of RH and continuing through to the last episode of hypoglycemia. Following the last bout of hypoglycemia, the animals underwent a hypoglycemic clamp with microdialysis to evaluate changes in central lactate and hormone levels. Compared to controls, RH increased VMH lactate by 1.7-fold (P&lt;0.03) and this was associated with an impaired counterregulatory response to hypoglycemia (glucagon and epinephrine responses were reduced by ∼45% and ∼73%, respectively, P&lt;0.04), as expected. Treatment of RH animals with carvedilol restored VMH lactate levels and improved the counterregulatory responses to hypoglycemia. To assess whether carvedilol improved HA, we treated rats that were made “hypoglycemia unaware” with repeated 2-deoxyglucose (2DG; 200mg/kg, SQ) injections with carvedilol and measured food intake in response to insulin-induced hypoglycemia as a surrogate marker for HA. Compared to Controls, 2DG reduced food intake in response to hypoglycemia and treatment with carvedilol increased food intake in 2DG rats (P&lt;0.01). We conclude that carvedilol may be a useful therapeutic strategy to prevent counterregulatory failure and improve HA in RH rats.

Disclosure
R. Farhat: None. G. Su: None. O. Chan: None.
Diet-Dependent Sex Differences in the Response to Bariatric Surgery
Authors: HUTCH CHELSEA , STELMAK DARIA , SINGER KANAKADURGA , SANDOVAL DARLEEN A. 
Published: June 2018

Despite the well-known efficacy of bariatric surgery in reducing body mass and improving metabolic outcomes, the mechanisms underlying these dramatic effects are not fully understood. Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic pre-clinical studies have focused exclusively on males. Premenopausal women have a reduced risk for obesity-associated co-morbidities and enhanced lipid metabolism. Although both sexes lose weight and benefit metabolically after bariatric surgery, clear physiological sex differences in metabolism suggest the mechanistic pathway to those outcomes are dependent upon sex and hormone status. The goal of this study was to determine the impact of diet- and surgery-induced weight loss on sex differences in glucose regulation and hepatic lipid metabolism. Male and female mice were fed a 60% high-fat (HF) diet 12 weeks before undergoing either vertical sleeve gastrectomy (VSG) or sham surgery. After surgery, mice either remained on a HF diet or were switched to a standard chow diet. Both males and females decreased fat-mass after VSG, yet males showed further body mass loss on a chow diet. Both sexes improved fasting glucose and oral glucose tolerance on a HF diet after VSG, while only males showed further benefit from surgery and chow diet. Despite continued HF diet feeding, male but not female mice show significant improvements in hepatic triglyceride levels after VSG relative to their sham surgery counterparts. However, when mice were switched to a low-calorie chow diet both males and females reduced hepatic triglycerides after VSG. Furthermore, removing female gonadal hormones, via ovariectomy, did not impact hepatic triglyceride levels after VSG. Overall, these data suggest that the impact of surgery on hepatic triglycerides is diet-dependent in females and support the hypothesis that males and females achieve similar metabolic outcome, at least within the liver, via distinct mechanisms.

Disclosure
C. Hutch: None. D. Stelmak: None. K. Singer: None. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC..
Combination Linagliptin and Empagliflozin Therapy Improves Diastolic Function in Female Diabetic db/db Mice
Authors: HABIBI JAVAD , AROOR ANNAYYA R. , KLEIN THOMAS , MAYOUX ERIC , DEMARCO VINCENT 
Published: June 2018

We recently reported that linagliptin (LINA) and empagliflozin (EMPA) monotherapies exhibit favorable effects in the heart, vasculature and kidneys in murine models of prediabetes and diabetes. Herein, we extend those studies by testing whether these two drugs used in combination improve diastolic function in diabetic female db/db mice. Eleven week old db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks (dbE10, dbL10). Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA (dbE10/L5) or EMPA added to LINA (dbL10/E5)). One group received LINA and EMPA combination therapy for the entire 10 week test period (dbL10/E10). One group was untreated (DbC). Glycemia, cardiac function, fibrosis and hypertrophy were examined by HbA1c, tissue Doppler ultrasound and histology. With the exception of LINA monotherapy, HbA1c was reduced in all other treated groups (p&lt;0.05). Compared to lean mice on background strain (CkC), myocardial wall motion during diastole was impaired in untreated db/db mice, indicated by increased E/E’ ratio (LV filling pressure), and this was improved with mono- and add-on therapies. Myocardial fibrosis and hypertrophy were improved with mono- and add-on therapies.
In summary, the combination of LINA and EMPA appeared to be as cardioprotective as monotherapies of each drug.# weeks on E or LType of therapyDiastolic FunctionGlycemiaCardiac RemodelingE, EMPA L, LINAE/E’ RatioHbA1c %Intersititial Fibrosis (AGSI)Cardiomyocyte cross sectional area (μm2)CkCuntreated18 ± 34.3 ± 0.2---368 ± 33DbCuntreated56 ± 3*11.0 ±0.6*4.9 ± 0.6533 ± 34†db E10mono38 ± 3*†5.9±0.2*†2.8 ± 0.2†433 ± 15†dbL10mono36 ± 2*†10.8±0.5*2.8 ± 0.2†411 ± 11†dbE10/L5L added to E35 ± 4*†6.5±0.2*†3.2 ± 0.2†421 ± 26†dbL10/E5E added to L34 ± 2*†6.9±0.3*†2.8 ± 0.1†358 ±12†dbL10/E10combo44 ± 6*†6.1±0.2*†3.2 ± 0.1†430 ± 21†*p&lt;0.vs CkC †p&lt;0.vs DbC

Disclosure
J. Habibi: None. A.R. Aroor: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. E. Mayoux: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Global Prevalence of Type 2 Diabetes over the Next Ten Years (2018-2028)
Authors: KAISER AMY BRADSHAW , ZHANG NICOLE , DER PLUIJM WOUTER VAN 
Published: June 2018

Objective: We aimed to estimate the global prevalence of type 2 diabetes over the next ten years, taking into account trends in obesity. Our analysis includes estimates for 45 countries representing almost 90% of the world population. We defined a prevalent case as anyone living with type 2 diabetes, irrespective of whether it has been formally diagnosed or not and excluded type 1 diabetes cases.
Methods: We performed a global systematic search of published studies and other data sources that reported the prevalence of type 2 diabetes, as well as any factors that may change its risk or prognosis over time or between countries. Our analysis is based on critically-appraised literature and database evidence that reports the total prevalence of type 2 diabetes. From the results of this search, we appraised and selected country-specific estimates to project up to national totals. These estimates were adjusted to account for historical or future trends in risk, as well as relevant differences between countries when extrapolations were made. Our model includes country-specific obesity prevalence to incorporate the impact of obesity on diabetes trends.
Results: We estimate that in 2018 there are more than 500 million prevalent cases of type 2 diabetes worldwide and the prevalence is comparable between high- and low-income countries. The prevalence will increase in all countries covered over the projection period, but the greatest growth will be experienced in lower-income countries.

Disclosure
A. Bradshaw Kaiser: None. N. Zhang: None.