bluuebunny/crossref_metadata_2025_split huggingface dataset:
1141-P: Short-Chain Fatty Acid Acetate Increases TNF-a-Induced MCP-1 Production in Monocytes via the ACSL-1/MAPK/NF-?B Axis: Significance for Inflammation and Insulin Resistance
Authors: AHMAD RASHEED , ALROUB AREEJ ABU , ALRASHED FATEMA , AL-SAYYAR AMNAH , AKHTER NADEEM , KOCHUMON SHIHAB P. , ALMULLA FAHD , SINDHU SARDAR T. 
Published: June 2021

Short-chain fatty acids (SCFAs) are formed as by-products of dietary fiber metabolism by gut bacteria and have multiple immunomodulatory functions in different cells involved in the inflammatory and immune responses. In general, the anti-inflammatory role of SCFAs is well documented. Here, we investigated whether SCFAs could modulate the TNF-α-mediated induction of chemokine MCP-1 (also known as CCL2) in monocytes/macrophages; and if so, which mechanisms were involved. Monocytic cells were exposed to SCFAs including acetate, propionate, and butyrate, with or without TNF-α, and the release of MCP-1 was measured. We found that none of the SCFAs suppressed TNF-α-induced MCP-1 release in monocytes. However, challenge with acetate in combination with TNF-α resulted in substantially greater MCP-1 release from monocytic cells than challenge with TNF-α alone, indicating synergistic effects. Interestingly, such effects of acetate were not seen in macrophages. Synergistic upregulation of MCP-1 was mediated through the activation of acyl-CoA synthetase 1 (ACSL1). Acetate/TNFα induced phosphorylation of p38, ERK1/2, and NF-κB was observed during the secretion of MCP-1. Acetate/TNF-α mediated synergistic expression of MCP-1 was significantly reduced by the inhibition of p38 MAPK, ERK1/2 and NF-κB signaling pathways. Furthermore, inhibition of the ACSL1 activity also attenuates the TNF-α-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. ACSL1 inhibition led to a lower induction of NF-κB/AP-1 activity in response to co-stimulation with acetate and TNF-α.
In conclusion, these data support the proinflammatory, rather than anti-inflammatory, effects of acetate on TNF-α-mediated MCP-1 expression in monocytes involving the ACSL1/MAPK/NF-kB axis. These findings point to the differential effects of SCFA acetate in the settings of obesity and metabolic inflammation/insulin resistance.

Disclosure
R. Ahmad: None. A. Abu alroub: None. F. Alrashed: None. A. Al-sayyar: None. N. Akhter: None. S. P. Kochumon: None. F. Almulla: None. S. T. Sindhu: None.
1149-P: A Comparison between One Month vs. Two Months on a High-Fat Diet on the Impact on Glucose Metabolism in Male and Female Liver Androgen Receptor Knockout Mice
Authors: OSEI-NTANSAH ADJOA , OLIVER TRINITEE R. , FALZARANO CLAIRE , LOFTON TAYLOR , ANDRISSE STANLEY 
Published: June 2021

Previous research has indicated that a lipid-independent pathogenic mechanism plays a role in androgen-induced hepatic insulin resistance where liver androgen receptors may play a role in modulating disease. Consequently, this study aims to investigate the pathophysiology of high fat diet (HFD) induced dysglycemia and hepatic insulin resistance in male and female liver androgen receptor knockout (LivARKO) mice. We performed insulin tolerance tests (ITT), glucose tolerance tests (GTT), and pyruvate tolerance tests (PTT) on LivARKO male and female mice fed a high fat diet (HFD) or a control diet (CD) (from Research Diets Inc) during months 1 or 2 after starting the diet. Two-months on the CD showed significantly enhanced glucose tolerance (EGT) compared to 1-month on CD in both male and female LivARKO mice. This EGT phenotype was the same and equally as significant in males vs. females. Two-months on CD showed impaired insulin sensitivity (IIS) compared to 1-month on CD in male and female LivARKO mice. This IIS was significantly greater in female mice. Two-months on the CD displayed enhanced pyruvate tolerance compared to 1-month on the CD in male and female LivARKO mice. Two-months compared to 1-month on HFD displayed no significant difference in glucose tolerance in male and female LivARKO mice. Two-months on HFD showed impaired insulin sensitivity compared to 1-month in female but not male LivARKO mice. Pyruvate tolerance was not changed from 1- to 2-months on HFD in male or female LivARKO mice. In the CD mice, we see EGT but IIS. This suggests that insulin action is decreased. The enhanced pyruvate tolerance in CD mice suggests that the control diet lowers gluconeogenesis. Why the control diet is altering glucose metabolism from 1-2 months is still a question to be investigated.
In conclusion, we show that 1- vs. 2-months on HFD showed no change in glucose metabolism in male and a slight change in female LivARKO mice.

Disclosure
A. Osei-ntansah: None. T. R. Oliver: None. C. Falzarano: None. T. Lofton: None. S. Andrisse: None.

Funding
National Science Foundation (HRD-1931045); Robert Wood Johnson Foundation
116-OR: Lipocalin-Type Prostaglandin D2 Synthase Depletion Induces Adipose Tissue Dysfunction in Response to High-Fat Diet
Authors: SRIVASTAVA ANKITA , PALAIA THOMAS , HALL CHRIS , LEE JENNY , STEVENSON MATTHEW , RAGOLIA LOUIS 
Published: June 2021

Adipose tissue dysfunction is the primary defect in obesity which contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease and some cancers. Previous study from our lab implicated the role of lipocalin-type prostaglandin D2 synthase (L-PGDS) in glucose intolerance and atherosclerosis. Our lab also showed the development of NAFLD in L-PGDS knockout mice on both low fat and high fat diet. In the present study, we examined the role of L-PGDS in adipose tissue in response to high fat diet. We found decreased expression of L-PGDS in visceral and subcutaneous white adipose tissue (WAT) of C57BL/6 mice after 12 weeks on high fat diet (HFD). Our study showed increased fat content in L-PGDS KO mice as compared to control C57BL/6 mice after 14 weeks on HFD. Histological analysis showed hypertrophied adipocytes in visceral WAT of L-PGDS KO mice as compared to control mice. Furthermore, we found increased expression of the lipogenesis genes LXRα, SREBP-1c and FAS in visceral WAT of L-PGDS KO mice after 14 weeks on HFD. L-PGDS KO mice showed reduced gene expression of adiponectin and PPARγ in visceral WAT on HFD. The plasma adiponectin level was also decreased in L-PGDS KO mice. We conclude that absence of L-PGDS has a deleterious effect on adipose tissue functioning which further reduces insulin sensitivity in adipose tissue. Thus, our study suggests L-PGDS as a novel therapeutic target for the treatment of obesity-associated metabolic syndrome.

Disclosure
A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.

Funding
American Heart Association (15GRNT22420001); George Link, Jr. Foundation Inc. (3500-7294)
1161-P: NOD1-JNK1 Axis Plays a Causal Role in Palmitate-Induced ß-Cell Dysfunction
Authors: YUNG JUSTIN HOU MING , IVOVIC ALEKSANDAR , CLARK ISABEL , LI FIONA , LIN BRIAN , TAN YAO , GIACCA ADRIA 
Published: June 2021

Chronic elevation of free fatty acids (FFA) in obesity may cause ß-cell dysfunction leading to type 2 diabetes (T2D). Recent studies have focused on innate immunity receptors due to evidence implicating inflammation in obesity-induced T2D. While several of these receptors have been implicated in FFA-induced ß-cell dysfunction, the nucleotide-binding oligomerization domain (NOD) receptors have not been investigated. Our previous work showed that whole-body NOD1-null mice were protected from palmitate-induced ß-cell dysfunction in vivo. This may be due to lack of NOD1 in ß-cells and/or macrophages infiltrating islets. Also, islets of whole-body NOD1-null and JNK1-null mice were protected from ß-cell dysfunction induced by palmitate but not oleate in vitro, suggesting NOD1 activation is likely in ß-cells, is specific to saturated FFA and may cause ß-cell dysfunction via JNK1. Thus, we hypothesized that ß-cell NOD1 mediates palmitate-induced ß-cell dysfunction in vivo, and that JNK1 is downstream of NOD1 activation. Addition of an ethyl group on palmitate reduces toxicity of unbound palmitate, thus ethylpalmitate (EtPAL) was used. Ethyl esterases in mouse plasma hydrolyze EtPAL into palmitate and ethanol. ß-cell specific NOD1-null (ßKO) mice (using Ins1- and RIP-Cre) and their controls were infused with EtPAL or ethanol vehicle (Veh) for 48 hours, followed by a hyperglycemic clamp to evaluate ß-cell function in vivo from the disposition index (DI). Islets of JNK1-null and wildtype (WT) mice were isolated and treated with a NOD1 activator to investigate the NOD1-JNK1 axis. As expected, EtPAL infusion elevated plasma FFA. EtPAL decreased DI in control mice, while EtPAL-infused ßKO mice had similar DI to Veh-infused mice. Further, the NOD1 activator reduced insulin secretion in WT islets but not in JNK1-null islets. These data implicate ß-cell NOD1-JNK1 axis in palmitate-induced ß-cell dysfunction and reveal a novel pathway that could be targeted for manipulation in order to preserve ß-cell function.

Disclosure
J. Yung: None. A. Ivovic: None. I. Clark: None. F. Li: None. B. Lin: None. Y. Tan: None. A. Giacca: None.

Funding
Canadian Institutes of Health Research (CIHR50748)
1162-P: Proinsulin as a Biomarker for Beta-Cell Function in a Diverse Cohort
Authors: COUCH CATHARINE , GOWER BARBARA , PICCININI FRANCESCA 
Published: June 2021

Declining beta-cell function is a key component in the development of type 2 diabetes (T2D). Early in disease progression, first-phase insulin secretion deteriorates, precipitating impaired glucose tolerance. Markers for early beta-cell decline could assist in identifying individuals at risk for disease progression, particularly among demographic groups at elevated risk for T2D. This study was designed to test the hypothesis that proinsulin concentrations would be inversely associated with first-phase beta-cell function, as reflected in the Disposition Index (DI), in a diverse cohort of young individuals without T2D. Participants were 117 men and women of African-American and European-American descent aged 19-45 years with normal glucose tolerance. An oral-glucose tolerance test (OGTT) was used to measure proinsulin concentrations and assess beta-cell function. Mathematical modeling was used to estimate insulin sensitivity (Si) and indices of beta-cell function specific to basal, first-phase, second-phase, and total insulin secretion (PhiB, PhiD, PhiS, PhiTot, respectively). First-phase DI (DId) was calculated as Si x PhiD and second-phase DI (DIs) as Si x PhiS. Proinsulin concentrations were normalized for C-peptide. Fasting and 2-h proinsulin concentrations were inversely associated with DId (r=-0.21, p=0.02 and r=-0.22, p=0.01, respectively). Neither fasting nor 2-h proinsulin concentrations were significantly associated with DIs. African-Americans, who as a group have an elevated prevalence of T2D, had 25% higher concentrations of fasting proinsulin and 18% higher concentrations of 2-h proinsulin compared to EA (p=0.001 and p=0.01, respectively). Proinsulin may be a practical biomarker for first-phase beta-cell function that could assist in identification of individuals at risk for T2D who would benefit from interventions to prevent deterioration of glucose metabolism.

Disclosure
C. Couch: None. B. Gower: Advisory Panel; Self; Abbott. F. Piccinini: Employee; Self; Medtronic.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096388); Nutrition Obesity Research Center (P30DK056336); Diabetes Research Center (P30DK079626); National Heart, Lung, and Blood Institute (T32HL105349)
1164-P: A Zebrafish Nonalcoholic Fatty Liver Disease Model Links Liver Inflammation with Pancreatic Inflammation and Hyperglycemia
Authors: IBRAHIM SARA , HAIDER ISRA , KULKARNI ABHISHEK , DOYCHEVA ILIANA , MIRMIRA RAGHAVENDRA G. , SIMS EMILY K. , ANDERSON RYAN 
Published: June 2021

The spectrum of nonalcoholic liver disease (NAFLD) ranges from simple steatosis to steatohepatitis with the latter having the potential to irreversibly progress to cirrhosis. Compared with the general population, NAFLD is more frequently seen in patients with type 2 diabetes (T2D), and conversely, NAFLD is associated with increased incidence of T2D. Existing rodent models of NAFLD focus narrowly on certain stages of liver damage and insufficiently encompass all metabolic changes, limiting their utility.
The aims of this study were to develop a new model of NAFLD in young zebrafish and use it to probe the associations between liver inflammation and pancreatic islet function. We examined hepatopancreatic inflammation under three conditions: (1) in a zebrafish line (fabp10-CETI-PIC3) in which liver-specific expression of pro-inflammatory cytokines IL-1β, TNFα, and IFN-γ was induced by doxycycline treatment (M1); (2) in wild-type zebrafish fed a high-fat diet (M2); and (3) in a combination of these models (M3). All three conditions showed increased expression of inflammatory cytokines compared to Tg(fabp10:cre) control larvae, and when compared to controls, all three showed increased macrophage infiltration in the liver. Strikingly, staining with CellRox Deep Red to assess reactive oxygen species (ROS)-mediated stress in the liver revealed a 2-fold increase in the M3 combination model, but not in either M1 or M2. Further, although all models showed hyperglycemia, decreased insulin transcription without β cell death, and ROS accumulation in the pancreas, only the M3 condition demonstrated a significant increase in macrophage infiltration of the pancreatic islets as compared to controls. In sum, our novel zebrafish model of liver steatosis and steatohepatitis is a promising model in which to study the intricate associations between NAFLD and T2D, and may serve as an amenable platform for screening novel pharmaceutical interventions.

Disclosure
S. Ibrahim: None. I. Haider: None. A. Kulkarni: None. I. Doycheva: None. R. G. Mirmira: Advisory Panel; Self; Hibercell Inc., Sigilon Therapeutics, Inc., Veralox Therapeutics, Employee; Spouse/Partner; Beta Bionics, Inc. E. K. Sims: None. R. Anderson: None.
117-LB: Glucokinase Activator Dorzagliatin (HMS5552) Regulates GLP-1 Release in T2D Patients and Is Synergistic with Sitagliptin and Empagliflozin in Optimizing Beta-Cell Function
Authors: CHEN LI , ZHANG JIAYI , YANG RONG , FENG LINGGE , MEDICINE HUA 
Published: June 2021

Glucokinase (GK) is a glucose sensor and plays a central role in glucose homeostasis through regulation of threshold of hormone release from α and β cell that controls blood glucose set point. Based on this concept, Dorzagliatin as a glucose sensitizer for the treatment of diabetes has completed pivotal registration trial in China with desirable outcome. GLP-1 is an important hormone involved in β cell secretory function and such plays an important role in glucose homeostasis. It has been debated over the last decade on whether GK is involved in GLP-1 secretion. The dominant reports support the GLP-1 secretory organ is intestine L cell and the secreted hormone traveled to pancreas regulating β cell secreting function. Others suggested β cell regulates GLP-1 secretion from α cell through paracrine and is mediated through GLP-1 receptor on β cell.
Here we report that a glucokinase activator Dorzagliatin stimulates GLP-1 release in T2D patients and is synergistic with Sitagliptin, a DDP-IV inhibitor, to increase circulating active GLP-1 in T2D patients with AUEC0-4h of 94.9% over Dorzagliatin. Increase of total GLP-1 was observed in the Dorzagliatin treatment with AUEC0-4h increase of 103.6% and Cmax increase of 141% compared with Dorzagliatin in combination with Sitagliptin. The effect on β cell function is also seen in patients taking Dorzagliatin together with Sitagliptin and Empagliflozin, a SGLT-2 inhibitor, in the OGTT study with increased C-peptide secretion AUEC0-4h of 46.6% (p &lt; 0.01) and 20.4%, Cmax of 52.5% (p &lt; 0.01) and 22%, respectively. Furthermore, the C-peptide secretion increased in combination treatment with AUEC0-4h of 30.3% (p &lt; 0.05) and Cmax of 31%(p &lt; 0.01), compared with Empagliflozin alone. In both combination studies with Sitagliptin and Empagliflozin, reduction of glucose AUEC0-4h is 33.1% and 37.6% with reduction glucose Cmax of 13.9% and 27.8% over Sitagliptin and Empagliflozin alone.

Disclosure
L. Chen: Board Member; Self; Hua Medicine. J. Zhang: Employee; Self; Hua Medicine. R. Yang: Employee; Self; Hua Medicine. L. Feng: Employee; Self; Hua Medicine. Hua medicine: n/a.
1176-P: Effects of GLP-1 Therapy on GDF15 Expression in Hepatocytes of MAFLD
Authors: GAN LU , LIN BEISI , XU WEN , YAN JINHUA , SU YANNA , CHEN YALAN , YANG DAIZHI , LIANG HUA , XU FEN 
Published: June 2021

To explore the effects of glucagon-like peptide-1 therapy (GLP-1) on the expression of growth different factor 15 (GDF15) in hepatocytes of metabolic dysfunction-associated fatty liver disease (MAFLD). Patients with MAFLD and type 2 diabetes mellitus received a 26-week therapy of liraglutide, sitagliptin, or insulin glargine, respectively. The level of serum GDF15, intrahepatic lipid (IHL) and body mass index (BMI) were collected at baseline and week 26. C57BL/6J mice challenged with a high-fat diet (HFD) for 12 weeks were treated with GLP-1 receptor agonist exenatide (GLP-1 group) or normal saline by intraperitoneal injection for 8 weeks (HFD group). Another group with a chow diet was designed as normal control. Human HepG2 cells were incubated in medium containing 300 μM sodium palmitate (PA) and treated with Exendin-4 0nM, 1 nM, 20 nM, 100 nM, respectively. A total of 25 patients were analyzed (liraglutide group, 9; insulin glargine group, 8 and sitagliptin group, 8). The level of serum GDF15 increased significantly in the liraglutide group (742±279pg/mL vs. 920±265pg/mL, P=0.015), and IHL and BMI decreased significantly (18.3±7.4% vs. 12.2±5.5%, P=0.004; 29.0±2.2kg/m2 vs. 27.8±1.9 kg/m2, P= 0.01, respectively). No significant changes in the level of serum GDF15 were observed in the sitagliptin and insulin glargine groups after 26-week therapy. Furthermore, negative correlation was found between the change in serum GDF15 and IHL by in the liraglutide group (r=-0.676, P=0.045). Hepatic steatosis and inflammation in the liver, which were improved markedly in the HFD group, reduced in GLP-1 group. Relative mRNA levels of GDF15 in liver tissue of mice were remarkably higher in the GLP-1 group than those in HFD group and control group (P&lt;0.05). In addition, Exendin-4 alleviated lipid deposition in HepG2 cells, which induced by PA, and elevate the expression and secretion of GDF15 in a dose-dependent manner (P&lt;0.05). GLP-1 can alleviates hepatic steatosis of MAFLD and up-regulate the expression and secretion of GDF15.

Disclosure
L. Gan: None. B. Lin: None. W. Xu: None. J. Yan: None. Y. Su: None. Y. Chen: None. D. Yang: None. H. Liang: None. F. Xu: None.
1180-P: Short-Term Low-Protein Diet Ameliorates Metabolic Dysfunction in Diabetic Lipodystrophic Mice
Authors: MUNOZ MARCOS D. , MCCANN MAXIMILIAN A. , KIM PHILIP , LIEW CHONG WEE 
Published: June 2021

Long-term ad libitum dietary restriction such as low-protein diet (LPD) improves metabolic health and extend the life spans of mice and possibly human. However, most studies conducted thus far have mainly focused on preventive rather than the treatment potential of LP diets. To determine whether dietary protein or caloric restriction could be used to treat preexisting metabolic symptoms, particularly in a more severely affected mouse model, we subjected hyperglycemic lipodystrophic IRFKO (adipose-specific insulin receptor knockout) mice to LPD (5.1% kcal from protein). Interestingly, postprandial blood glucose (BG) values of the IRFKO mice began to improve 10 days after the introduction of LPD. The IRFKO mice became normoglycemic 2 weeks after the onset of the LPD treatment. Activation of adaptive thermogenesis in brown (BAT) and beige adipose tissues promotes energy expenditure (EE) and utilization of BG and triglyceride (TG). A LPD has been previously shown to promote EE via the sympathetic nervous system (SNS). Consistent with previous study, we observed that a LPD acutely and sustainably upregulates EE in both the WT and IRFKO mice. This is likely due to LPD dramatically improves BAT functions by transforming the whitened unilocular lipid droplet BAT in the IRFKO mice into normal looking brown multi-locular lipid droplet BAT within 1 week of LPD treatment. This is further supported by significant increase in thermogenic markers expression in the BAT after LPD. Besides thermogenic markers, we also observed a time-dependent regulation of gene markers for fatty acid transport, oxidation and glucose metabolism in BAT after LPD. Together with changes in blood chemistry in the IRFKO mice, we think that glucose and lipid-lowering effects of LPD is the consequence of continuous activation of EE leading to utilization and depletion of systemic thermogenic fuels. Taken together, our data suggest that short-term LPD could be a potential strategy for the treatment of metabolic syndrome.

Disclosure
M. D. Munoz: None. M. A. Mccann: None. P. Kim: None. C. Liew: None.
1185-P: Erythrocyte Eicosapentaenoic and Docosahexaenoic Acid Are Reliable Biomarkers of Dietary Intake in Women of African Ancestry: The Federal Women's Study
Authors: COURVILLE AMBER B. , YANG SHANNA , MABUNDO LILIAN , CRAVALHO CELESTE K. , MATTA SAMANTHA , VILLALOBOS-PEREZ ALFREDO , DAWSON JOSHUA M. , LICHTENSTEIN ALICE H. , SUMNER ANNE E. , CHUNG STEPHANIE T. 
Published: June 2021

To formulate precision nutrition prescriptions, it is essential to understand the relationship between dietary assessment, ethnicity and cardiometabolic disease. Erythrocyte (RBC) fatty acid (FA) profiles reflect long-term dietary fat intake but have not been rigorously compared with short-term FA intake in women of African ancestry who have paradoxically low triglycerides with high fat intake. We compared the type of dietary fat consumed (proportion of total fat) using food records with fasting RBC FA (mol%) determined by gas chromatography in 130 female, healthy, federal employees without diabetes (12% African Immigrants (AI), 47% African Americans (AA), 41% White Americans (WA)); mean age 43+10 y and BMI 30 + 6 kg/m2). Diet quality and home prepared meals were similar across ethnicities. AI reported the lowest energy intake. Regardless of absolute energy intake, macronutrient distributions were similar. Fat intake differed by ethnicity; WA had the highest saturated FA (SFA) and lowest eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and omega-3 index (EPA + DHA), while AI and AA had similar SFA, EPA and DHA intake. AI women had the highest RBC DHA and omega-3 index. Associations between FA intake and RBC profiles were significant for DHA (r=0.3, p&lt;0.01), EPA (r=0.2, p&lt;0.05) and the omega-3 index (r=0.2, p&lt;0.01). Overall, RBC EPA and DHA were reliable biomarkers of dietary intake in women of African ancestry, consistent with data in predominantly white populations. These findings support the combined use of food records and RBC profiles for comprehensive dietary assessments. As RBC SFA and monounsaturated FA reflect both endogenous and exogenous sources, the discrepancies between intake and RBC profiles could reflect ethnic variations in nutrient metabolism. To enable precision nutrition prescriptions, exploration of population-specific biomarkers in concert with dietary assessment is needed.

Disclosure
A. B. Courville: None. S. T. Chung: None. S. Yang: None. L. Mabundo: None. C. K. Cravalho: None. S. Matta: None. A. Villalobos-perez: None. J. M. Dawson: None. A. H. Lichtenstein: None. A. E. Sumner: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases