bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Adipocyte Fatty Acid Binding Protein in the Development of Liver Fibrosis
Authors: WU XIAOPING , SHU LINGLING , LAM KAREN S. , XU AIMIN , HOO RLC 
Published: June 2018

Liver fibrosis is the result of chronic liver injury and the first step toward the development of liver cirrhosis and hepatic carcinoma. Under the stress of damage factors, quiescent hepatic stellate cells (qHSCs) trans-differentiate into myofibroblast-like cells, and take the main role of extracellular matrix secretion contributing to the development of liver fibrosis. In recent clinical study, circulating level of A-FABP, was found to positively correlate with the stages of liver fibrosis and liver cirrhosis. Here, we investigate the role of A-FABP in the development of liver fibrosis. A-FABP knockout (A-FABP KO) mice and their wild type (WT) littermates were subjected to bile duct ligation (BDL) for two weeks to induce liver fibrosis. Plasma and hepatic A-FABP were significantly elevated in BDL treated WT mice. Liver sinusoidal endothelial cell (LSEC) was identified as the major cellular source of hepatic A-FABP in response to BDL. In the BDL treated groups, comparing to the WT mice, A-FABP KO mice showed significantly reduced collagen formation and HSC activation which were accompanied by an attenuated induction of hepatic expression of transforming growth factor beta 1 (TGFβ1), a central regulator in hepatic fibrogenesis. As the LSECs and HSCs are closely attached to each other, we hypothesize that LSECs-derived A-FABP may act in a paracrine manner to stimulate the expression of TGFβ1 in HSCs. Our in vitro study demonstrated that treatment of recombinant A-FABP protein (rA-FABP) significantly induced the expression of TGFβ1 in primary HSCs. Mechanistically, BDL induces the release of A-FABP from LSECs which stimulates the TGFβ1 gene transcription through enhancing the activator protein-1 (AP-1) activity on its promoter via upregulating the phosphorylation of c-Jun, a component of AP-1.
In conclusion, A-FABP contributes to the development of liver fibrosis via enhancing the expression of TGFβ1 in HSCs.

Disclosure
X. Wu: None. L. Shu: None. K.S. Lam: None. A. Xu: None. R. Hoo: None.
cGMP-Dependent Protein Kinase I (cGKI) Modulates Human Hepatic Stellate Cell Activation
Authors: FRANKO ANDRAS , KOVAROVA MARKETA , WAGNER ROBERT , WEIGERT CORA , FEIL ROBERT , FEIL SUSANNE , HAERING HANS-ULRICH , LUTZ STEFAN Z. , PETER ANDREAS 
Published: June 2018

Background: Nonalcoholic fatty liver disease and hepatic insulin resistance precede diabetes and may further develop into nonalcoholic steatohepatitis and liver fibrosis/cirrhosis. The activation of hepatic stellate cells (HSC), which is characterized by the loss of retinyl-ester stores, plays a crucial role in the pathophysiology of this process. Since cGMP-dependent protein kinase I (cGKI) deficient (cGKI-KO) mice displayed hepatic insulin resistance and disturbed glucose metabolism, as well as, cGKI is only detected in HSC but not in hepatocytes, we hypothesized that cGKI modulates HSC activation and its metabolic consequences.
Methods: First, retinol storage and gene expression were studied in cGKI-KO mice. Second, we investigated the effects of cGKI-silencing on gene expression and cellular activation in the human stellate cell line LX2. Finally, cGKI expression was investigated in human liver biopsies covering a wide range of liver fat content.
Results: Retinyl-ester level in the liver of cGKI-KO mice was lower compared to wild type animals, which was associated with increased inflammatory gene expression. Activation of LX2 cells showed increased α-smooth muscle actin and matrix metalloproteinase 2 expression, which was augmented by silencing cGKI. On the other hand, activation of LX2 cells by TGFβ suppressed cGKI expression. Furthermore, we detected a negative correlation between cGKI mRNA and liver fat content in human biopsies.
Conclusions: The lower mRNA level of cGKI either in TGFβ activated LX2 cells or in liver biopsies with high fat content suggest that cGKI function might be impaired during HSC activation. Furthermore, the higher expression of inflammatory genes and low retinyl-ester levels in cGKI-KO mice as well as the higher levels of activation markers in cGKI-silenced LX2 cells indicate that cGKI inhibits HSC activation. Since cGKI is a downstream target of nitric oxide (NO), it is conceivable that NO may exert protective effects inhibiting liver fibrosis via cGKI.

Disclosure
A. Franko: None. M. Kovarova: None. R. Wagner: None. C. Weigert: None. R. Feil: None. S. Feil: None. H. Haering: None. S.Z. Lutz: None. A. Peter: None.
Short-Term Exercise Improves Hepatic Insulin Extraction in Individuals with Nonalcoholic Fatty Liver Disease
Authors: HARI ADITHYA , FEALY CIARAN E. , KIRWAN JOHN P. 
Published: June 2018

Nonalcoholic fatty liver disease (NAFLD), the hepatic component of insulin resistance syndrome, is pathophysiologically associated with lower hepatic insulin clearance, lower fat oxidation and increased carbohydrate oxidation in a post-absorptive state. Aerobic exercise is purported to be beneficial in NAFLD. To better understand the mechanisms through which short-term, moderate intensity aerobic exercise training could exert these benefits, 13 obese, sedentary adults (age: 58±3.4 years, BMI: 34.3±1.1 kg/m2; means±SEM) with NAFLD (&gt;5% Intra-hepatic lipid content assessed by 1H MR spectroscopy) were recruited into a 7-day exercise training program (treadmill walking for 60 mins, 5 days per week, at 80-85% maximum heart rate). Participants maintained their normal dietary patterns. Pre- and post-intervention assessments included a 75-gm OGTT, CT scans, VO2max and indirect calorimetry. Insulin sensitivity (ISI) was estimated using Soonthorpun model. Hepatic Insulin Extraction (HIE) was calculated as the molar difference in AUCs for insulin and C-peptide (HIE=1-(AUCInsulin÷AUCC-Pep)). The intervention yielded an ∼9% increase in VO2max and HIE (P&lt;0.01). Whole-body insulin sensitivity increased by ∼43% (P&lt;0.05). There was a significant increase in basal fat oxidation (pre vs. post: 47±6 vs. 65±6 mg/min, P&lt;0.05) and decrease in basal carbohydrate oxidation (160±20 vs. 112±15 mg/min, P&lt;0.05). After the intervention, HIE was positively correlated with adiponectin (r=0.56, P&lt;0.05) and negatively correlated with TNF-α (r=-0.78, P&lt;0.001). The change in ISI was negatively correlated with change in subcutaneous abdominal fat depot (r=-0.55, P=0.05). These data suggest that exercise may quickly reverse the pathophysiology of NAFLD by improving
HIE and fasting substrate oxidation. The cardio-metabolic benefit of exercise in individuals with NAFLD is potentially mediated through changes in HIE.

Disclosure
A. Hari: None. C.E. Fealy: None. J.P. Kirwan: None.
Insulin Signaling in Adipocytes Controls Systemic Insulin Sensitivity through the 5-LO-LTB4 Axis
Authors: HOSOOKA TETSUYA , OGAWA WATARU 
Published: June 2018

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis has been unclear. To provide insight into the role of insulin action in adipocytes, we generated mice that lack 3'-phosphoinositide-dependent kinase1 (PDK1) specifically in adipocytes (A-PDK1KO mice). These mice manifest impairment of metabolic actions of insulin in adipose tissue and a reduction in adipose tissue mass. The mice developed insulin resistance, glucose intolerance, and hepatic steatosis, all of which were markedly attenuated by additional ablation of FoxO1 specifically in adipocytes without an effect on adipose tissue mass, indicating that the PDK1-FoxO1 axis in adipocytes plays an important role in systemic metabolic homeostasis through a mechanism independent of the regulation of adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammation in adipose tissue differed between A-PDK1KO mice and adipocyte-specific PDK1/FoxO1 deficient mice (A-PDK1/FoxO1KO mice), indicating that those factors did not account for the difference in metabolic phenotypes of the two genotypes of mice. Microarray and lipidomics analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissues as well as the expression of 5-lipoxygenase (5-LO), a rate limiting enzyme for LTB4 production, in adipose tissues were increased and normalized in A-PDK1KO and A-PDK1/FoxO1KO mice, respectively. Administration of a 5-LO inhibitor reduced plasma levels of LTB4 and ameliorated insulin resistance and glucose intolerance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through downregulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. These results thus indicate that insulin signaling via the PDK1-FoxO1 pathway negatively regulates the production of LTB4 through the suppression of 5-LO in adipocytes and thereby maintains systemic insulin sensitivity.

Disclosure
T. Hosooka: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. W. Ogawa: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Abbott.
Impact of Type 1 Diabetes on 24-Hour Energy Expenditure and Metabolic Flexibility
Authors: CARNERO ELVIS A. , CORBIN KAREN D. , BOCK CHRISTOPHER P. , SMITH STEVEN R. , PRATLEY RICHARD E. 
Published: June 2018

Type 1 diabetes (T1D) is associated with an increase in resting metabolic rate, but the impact of T1D on other components of 24-hour energy expenditure (EE) and metabolic flexibility (MF) is not known. We measured 24-hour EE, its components and substrate oxidation rates in 11 patients with T1D and 12 nondiabetic, age and BMI matched controls (HC) using whole room calorimetry. MF was defined as the respiratory quotient (RQ) kinetic response after ingesting a standard high CHO breakfast. Briefly, the kinetics between the lowest RQ pre-breakfast and the highest RQ after breakfast were analyzed by a simple linear regression between time (1-minute resolution) and RQ units (RQUnits). Subjects with T1D had marginally higher 24-hour EE and higher 24-hour non-exercise EE, but sleeping EE and basal EE were not significantly different (Table 1). There were no differences in 24-h respiratory quotient (RQ) or sleeping RQ, but MF during the breakfast meal was significantly lower in T1D vs. HC (p=0.042). Among patients with T1D, MF was related to the glycemic response to breakfast. These data suggest that T1D is characterized by alterations in EE and MF. These results have implications for glycemic and weight management among patients with T1D.

Disclosure
E.A. Carnero: None. K.D. Corbin: None. C.P. Bock: None. S.R. Smith: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc..
Relating Disinhibited Eating Behaviors to Resting State Functional Connectivity in Young Children
Authors: SHAPIRO ALLISON L.B. , JOHNSON SUSAN L. , MOHL BRIANNE , WILKENING GRETA , LEGGET KRISTINA T. , DABELEA DANA , TREGELLAS JASON R. 
Published: June 2018

The prevalence of obesity among children in the United States is alarming, with recent work implicating disinhibited eating behaviors (DEBs) as a potential pathway toward obesity development. DEBs have been documented among young children, and are associated with longitudinal weight gain. However, the underlying neurobiology of DEBs in young, healthy weight children, prior to obesity development, remains unknown. This study investigated the relationship between DEBs and intrinsic neuronal connectivity in young children. We tested the hypothesis that greater DEBs would be positively associated with higher neuronal connectivity in the default mode network (DMN) and the salience network, and lower connectivity in the executive control network. The Eating in the Absence of Hunger paradigm was implemented to measure DEBs, with post-lunch calories consumed from highly palatable foods used as our main predictor. Resting state functional magnetic resonance imaging was used to examine neuronal connectivity within the networks of interest. Eighteen typically developing, healthy weight children (mean age = 5.8 years; BMI z-score = -0.6) were included in this analytic sample. Independent component analysis was used to isolate brain networks of interest. Associations between calories consumed and the three networks of interest were examined with second-level general linear models. A significant positive association was observed between calories consumed and functional connectivity in anterior cingulate cortex, a major anterior DMN hub (ACC; x=-6, y=14, z=41; t=5.23; p &lt; 0.01, corrected). No other associations were significant. While preliminary, our results are consistent with previous studies in adults relating both DEBs and obesity status to altered neuronal response in the ACC. Our data suggest that aspects of the neurobiology of DEB are detectable in young, healthy weight children, providing a potential tool to better understand the development of obesity in this population.

Disclosure
A.L.B. Shapiro: None. S.L. Johnson: None. B. Mohl: None. G. Wilkening: None. K.T. Legget: None. D. Dabelea: None. J.R. Tregellas: None.
Sensory Innervation of the Pancreatic Islet
Authors: MAKHMUTOVA MADINA , WEITZ JONATHAN , DIAZ RAYNER RODRIGUEZ , ALMACA JOANA , BERNAL-MIZRACHI ERNESTO , CAICEDO ALEJANDRO 
Published: June 2018

Sensory innervation of viscera is an important component for proper maintenance of body homeostasis. Visceral stimuli are detected by free nerve endings of the vagus nerve and are transmitted to the hindbrain via sensory neurons. However, the signals that activate vagal sensory neurons in the periphery are not known. The objective of this study is to identify and characterize the population of vagal sensory neurons that innervates the pancreas. Using immunohistochemistry for sensory neuronal marker substance P, we show that sensory innervation targets islet periphery. Upon islet damage (in NOD model or following streptozotocin (STZ) treatment), density of islet sensory innervation increases. Expression of the immediate early gene c-Fos, shows that hindbrain neurons in the nucleus of the solitary tract (NTS) respond to severe islet inflammation induced by STZ. We assessed response profile of pancreatic sensory neurons using in-vivo calcium imaging of mouse vagal sensory ganglion (nodose). This method allows us to monitor in real time the response profile of sensory neurons and identify pancreas-specific subpopulations by chemical stimulation of the exteriorized pancreas. We have identified sensory neurons that respond to pancreatic application of serotonin (5HT) and cholecystokinin (CCK). The observed response profile suggests that these neuronal populations are tuned to sense differentially endocrine and exocrine pancreas. While endocrine sensory neurons are sensing local 5HT that is co-released with insulin, exocrine neurons sense CCK a hormone that stimulates release of digestive enzymes. Altogether our data suggest that pancreatic sensory neurons could be important regulators of pancreatic physiology. By taking a snapshot of endocrine and exocrine pancreatic microenvironments and sending this information to the brain, sensory neurons might trigger feedback loops and help the organ to be tuned to physiological needs.

Disclosure
M. Makhmutova: None. J. Weitz: None. R. Rodriguez Diaz: None. J. Almaca: None. E. Bernal-Mizrachi: None. A. Caicedo: None.
Westernized Diet–Induced Insulin Resistance in Mice Is Associated with Focal Duodenal Hyperplasia
Authors: GHOSH SOUMITRA , RUBINO FRANCESCO , WISMANN PERNILLE , RIGBOLT KRISTOFFER , RAJAGOPALAN HARITH , MAGGS DAVID 
Published: June 2018

Westernized diet (WD; high fat and sugar) induces an insulin resistant state associated with obesity and type 2 diabetes (T2D). Duodenal exclusion surgery in obese T2D patients implicates the duodenum as a key GI region involved in insulin resistance. To identify adaptive changes of pathophysiological relevance, detailed analyses of the GI tract was undertaken following exposure of mice to WD. Metabolic indices and stereological characteristics of the whole gut, mucosal surface and transcriptome were investigated in C57BI/6J male mice fed either chow (lean) or WD (60% fat; 20% sugar) for 7 or 13 weeks (10 mice/cohort). Compared to lean, WD gained more weight and had higher plasma glucose, insulin and total cholesterol (Table) with differences greater at 13 vs. 7 weeks. Unlike other intestinal segments, focal hyperplasia was observed in the duodenum with increased weight and surface area (∼40%). The hyperplastic duodenum was characterized by increased chromogranin-A staining of enteroendocrine (EE) cells. Transcriptomic analysis revealed differences between WD and lean groups (both 7 and 13 weeks) with enrichment for genes involved in lipid and glucose metabolism. Exposure to WD induces adaptive responses in duodenal mucosa, EE cell population, and transcriptome. These findings suggest a potential role of the duodenum in insulin resistance and may explain the insulin-sensitizing effect of duodenal exclusion.

Disclosure
S. Ghosh: Consultant; Self; Fractyl Laboratories, Inc. F. Rubino: Advisory Panel; Self; Fractyl Laboratories, Inc.. Consultant; Self; Fractyl Laboratories, Inc., Ethicon US, LLC.. Speaker's Bureau; Self; Ethicon US, LLC.. Consultant; Self; Medtronic. Advisory Panel; Self; GI Dynamics Inc.. Consultant; Self; GI Dynamics Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Ethicon US, LLC.. P. Wismann: None. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. H. Rajagopalan: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Board Member; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc. D. Maggs: Stock/Shareholder; Self; Fractyl Laboratories, Inc.. Employee; Self; Fractyl Laboratories, Inc.. Stock/Shareholder; Spouse/Partner; Gelesis. Employee; Spouse/Partner; Gelesis.
The Sarcoplasmic Reticulum Calcium ATPase Pump Is a Major Regulator of Whole–Body Glucose Metabolism
Authors: MARIA ZAHRA , CAMPOLO ALLISON , GRAY SHANELL SHOOP , HARTSON STEVEN , LACOMBE VERONIQUE 
Published: June 2018

The heart is a very active metabolic organ which exerts endocrine effects by secreting natriuretic peptides. However, its role in the regulation of whole-body metabolism has received scarce attention. Therefore, we hypothesized that cardiac-specific overexpression of the sarcoplasmic reticulum calcium ATPase (SERCA) pump, which tightly regulates cytosolic calcium, modulates whole-body glucose homeostasis during healthy and diabetic states. Diabetes was induced by streptozotocin injections in wild type (WT) and transgenic (TG) mice overexpressing the SERCA pump in the heart (n=4-10/group). Translocation of glucose transporters (GLUTs) was measured in insulin-sensitive tissues using a photolabeled biotinylation assay. The cardiac secretome function was analyzed by mass spectrometry. We reported that blood glucose concentration was lower in diabetic TG mice compared to diabetic WT mice (p=0.023). Cell surface GLUT-4 and -8 protein content was downregulated in the heart of WT diabetic vs. healthy mice (by 56% and 71%, p=0.01 and p&lt;0.001, respectively), which was rescued in TG diabetic mice. In addition, diabetes induced a downregulation of cell surface GLUT4 trafficking in skeletal muscle, and white and brown adipose tissue of WT mice (by 79%, 68% and 74%, respectively, P&lt;0.05), which was restored in TG diabetic mice. We further identified 28 and 32 candidate proteins that have a high probability (i.e., &gt; 95%) of being secreted by the ventricle and atria of TG mice, respectively. Of these, 13 and 10 potentially secreted proteins by the atria and ventricle, respectively, were involved in metabolic processes.
In conclusion, these data suggest that cardiac-specific SERCA overexpression rescued hyperglycemia by improving glucose transport in insulin-sensitive tissues of diabetic TG mice. Insights gained from this study could identify the SERCA pump and its secreted proteins as novel pharmacological targets to regulate glucose homeostasis in diabetic patients.

Disclosure
Z. Maria: None. A. Campolo: None. S. Shoop Gray: None. S. Hartson: None. V. Lacombe: None.
Coadministration of GLP-1 and Y2R Receptor Agonists Synergize to Promote Muscle Glucose Uptake and Induce Diabetic Remission
Authors: BOLAND BRANDON , HOWARD VICTOR G. , BEATON MICHELLE , WILL SARAH , OLDHAM STEPHANIE , TREVASKIS JAMES , RHODES CHRISTOPHER J. , GRIMSBY JOE 
Published: June 2018

One proposed mechanism for the effects of bariatric surgery is the enhanced postprandial release of enteroendocrine L-cell hormones, such as PYY and GLP-1. Four week co-administration of Fc-conjugated GLP-1R and Y2R-selective agonists induced weight loss, reduced %HbA1c, and improved glucose tolerance in DIO and KS db/db mice compared to vehicle or monotherapy control groups. To assess the impact of this combination on glucose control, a hyperinsulinemic/euglycemic clamp was performed in KS db/db mice following two week treatment with vehicle or co-administration of GLP-1/Y2R agonists. A vehicle-treated group weight-matched to combination-treated mice was also assessed. Compared to KS db/db vehicle animals, combination-treated mice exhibited a 16-fold greater glucose infusion rate compared to only 4-fold in weight-matched controls. Glucose uptake was increased 4-fold in the skeletal muscle of combination-treated animals, but was unaltered in adipose or brain. Weight-matched controls did not exhibit increased glucose uptake in any tissue. To better characerize the mechanism of Fc-GLP-1/Fc-Y2R action on peripheral glucose metabolism, lean mice were acutely administered Fc-GLP-1 and/or Fc-Y2R, and then sacrificed to assess brain c-Fos activation. Compared to monotherapies, combination administration led to additive c-Fos activation in hindbrain regions. Strikingly, whereas monotherapy had no effect on the PVH, combination administration led to a synergistic 2-fold increase in c-Fos immunoreactivity. These findings implicate a neuronal population in the PVH as a putative driver of the antidiabetic efficacy observed following co-administration of GLP-1R and Y2R selective peptides, and may represent a novel mechanism to improve insulin sensitivity and skeletal muscle glucose uptake.

Disclosure
B. Boland: Employee; Self; MedImmune. V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Regeneron Pharmaceuticals, Inc., AstraZeneca. M. Beaton: Employee; Self; MedImmune. Employee; Spouse/Partner; MedImmune. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. C.J. Rhodes: Stock/Shareholder; Self; AstraZeneca. J. Grimsby: Employee; Self; AstraZeneca.