bluuebunny/crossref_metadata_2025_split huggingface dataset:
189-LB: Maternal Pharmacological Activation of PPAR-gamma or PPAR-alpha Differentially Affects Adiposity and Energy Metabolism in the Offspring of Rats Born to Mothers Subjected to Caloric Restriction during Pregnancy
Authors: VERONESI VANESSA B. , SANTOS-SILVA JUNIA C. , SOUZA DAILSON N. , JORDÃO TEIXEIRA CAIO , HECHT FERNANDA B. , TOBAR NATALIA , RODRIGUES PIOLI MARIANA , ANHE GABRIEL F. 
Published: June 2019

Aims: Rats born to mothers subjected to caloric restriction (CR) during pregnancy and lactation exhibit reduced birth weight and adiposity in adult life. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play important roles in adipocytes differentiation. The aim of our study is to evaluate if antenatal exposition PPAR-gamma (Pioglitazone) or PPAR-alpha (Gemfibrozil) activators are able to affect energy metabolism in the offspring born from rats subjected to RC during pregnancy and lactation.
Methods: Wistar rats were kept under CR from the 11th day of pregnancy until the 21st day after delivery. Pioglitazone (10mg/kg) or Gemfibrozil (90mg/kg) were offered during the period of CR (offspring were CR+Pio and CR+Gem, respectively). Adult female offspring were subjected to indirect calorimetry, thermal infra-red imaging of BAT, VLDL production assay and DEXA for body composition.
Results: The body weight in adult CR+Gem, but not in CR+Pio, was higher than that of offspring born to CR mother. CR+Pio had reduced energy expenditure (EE) and higher relative weight of the perigonadal and retroperitoneal fat pads. On the other hand, adult CR+Gem had no changes in EE and visceral adiposity when compared to RC but presented increased whole-body adiposity as revealed by DEXA analysis. Although hepatic triglycerides (TG) or VLDL production were not altered in offspring born to CR mothers and in CR+Pio, these parameters were downregulated in RC+Gem. Both RC+Pio and RC+Gem had reduced temperature of the interscapular brown adipose tissue when compared to CR.
Conclusion: Maternal activation of PPAR-gamma increases visceral adiposity and reduces EE in the offspring born to mothers subjected to CR during pregnancy. Maternal activation of PPAR-alpha instead, increased body weight and reduced hepatic steatosis of the offspring born to mother exposed to CR.

Disclosure
V.B. Veronesi: None. J.C. Santos-Silva: None. D.N. Souza: None. C.J. Teixeira: None. F.B. Hecht: None. N. Tobar: None. M. Rodrigues Pioli: None. G.F. Anhe: None.

Funding
Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo
1892-P: Hepatic Agpat5 Regulates Plasma Insulin in Obesity
Authors: ST. CLAIR SAMANTHA L. , BELISLE SABRINA L. , LEYVA JAIMES FERNANDA B. , LI ZHONGGANG , PARKS BRIAN 
Published: June 2019

There is increasing need to understand the molecular mechanisms contributing to obesity and type 2 diabetes. Agpat5, 1-acylglycerol-3-phosphate O-acyltransferase 5, is a lipid acyltransferase that esterifies the SN2 position of lysophospholipids to produce phospholipids. We previously identified Agpat5 within a genome-wide significant quantitative trait locus (QTL) associated with plasma insulin levels after high fat feeding in a mouse genetic reference population. We validated the effect of Agpat5, showing in multiple mouse models that treatment with Agpat5 antisense oligonucleotide (ASO) reduces plasma insulin after high-fat feeding. To investigate the hepatic role of Agpat5, we developed a liver-specific Agpat5 knockout mouse model. After 12 weeks of high-fat feeding, liver-specific Agpat5 knockout mice have significantly reduced fasting plasma insulin relative to control mice. Additionally, liver-specific Agpat5 knockout mice have significantly reduced hepatic triglycerides and are protected from hepatic steatosis. Investigating the effect of Agpat5 on hepatic insulin resistance, we found that loss of Agpat5 improves insulin signaling and reduces Foxo1 protein levels. Our studies suggest that hepatic Agpat5 may serve as a link between lipid metabolism and insulin signaling to regulate plasma insulin in obesity. Thus, drug therapies targeting Agpat5 could be developed to treat type 2 diabetes in obese populations.

Disclosure
S.L. St. Clair: None. S.L. Belisle: None. F.B. Leyva Jaimes: None. Z. Li: None. B. Parks: None.

Funding
National Institutes of Health
1893-P: Impact of Lean Hepatic Volume on Hepatic Insulin Resistance in Human NAFLD
Authors: IGARASHI HIROYUKI , SHIGIYAMA FUMIKA , HIRUMA SHIGENORI , HIROSE TAKAHISA , KUMASHIRO NAOKI 
Published: June 2019

Hepatic insulin resistance (H-IR) is a major pathogenesis of type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD). Due to pandemic obesity, in addition to reducing toxic lipids in the liver, searching for other factors that may regulate hepatic insulin sensitivity (H-IS) is inevitable in humans with NAFLD. To find such factors, we performed comprehensive assessment in the patients with NAFLD (n=36) aged 47.4±12.3, BMI 29.4±4.7 kg/m2, DM/non-DM 23/13, HbA1c 6.7±1.0% (mean±SD). We assessed putative biomarkers in blood and urine, body composition, tissue lipid content by 1H-MRS, tissue IS by hyperinsulinemic euglycemic clamp, hepatic histological scores and gene expressions using biopsies, and life styles. Furthermore, we developed a new magnetic resonance imaging analytic method that can exactly evaluate the whole liver volume, whole hepatic lipid volume, and whole hepatic lean volume. We performed single regression analysis between H-IS assessed by clamped % suppression of endogenous glucose production and all evaluated indices. As results, existence of diabetes, fasting plasma glucose, and HbA1c showed significant negative correlation with H-IS, while plasma adiponectin, muscle IS and adipose tissue IS showed significant positive correlation with H-IS. Interestingly, whole liver volume (cm3/m2) and lean hepatic volume (cm3/m2) corrected by body surface area showed negative correlation with H-IS (β=-0.02, -0.03 and p&lt;0.05, &lt;0.01, respectively), specifically in patients with T2DM. Finally, multiple regression analysis confirmed that lean hepatic volume is a negative factor for the H-IS (β=-0.02, p&lt;0.05).
Conclusion: Through comprehensive assessment including our new whole hepatic volume evaluation, we first demonstrated that lean hepatic volume strongly associates with H-IR specifically in patients with T2DM. Not only hepatic volume control but quality control supported by adiponectin or other insulin-targeted organs is necessary for H-IS in humans with NAFLD.

Disclosure
H. Igarashi: None. F. Shigiyama: None. S. Hiruma: None. T. Hirose: None. N. Kumashiro: Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.

Funding
Japan Society for the Promotion of Science (26702032, JP17H02180)
1896-P: Effect of PNPLA3 I148M Genotypes on Palmitate-Induced Hepatic Inflammation and Apoptosis
Authors: CHEN YUNZHI , LIANG HUA , YAN XUE MEI , XU XIAO 
Published: June 2019

Background: GWAS has revealed that rs738409 C&gt;G patatin-like phospholipase domain-containing 3(PNPLA3) is strongly associated with nonalcoholic fatty liver disease(NAFLD), but the mechanism remains obscure. Our study aims to investigate differences in mechanism for genotypes of PNPLA3 I148M in palmitate-induced inflammation and apoptosis.
Method: We constructed point mutation PNPLA3 148 I/I,148 I/M 148 M/M HepG2 cell lines via CRISPR-associated (Cas) 9 system. Cells were exposed to palmitate to induce lipid accumulation. Oil red O staining was used to explore the lipid deposition. Levels of inflammatory and apoptotic factors were determined by real-time PCR and western blotting.
Result: Lipid accumulation was remarkably increased in cells induced by PA, it is remarkably higher in 148M/M cell than in 148I/I HepG2 cell (P&lt;0.05 PA vs. BSA). Expression of apoptotic and inflammatory markers BIP, p-PERK, CHOP, p-JNK increased significantly in 148M/M and 148I/M hepG2 cells (P&lt;0.05). Compared with 148I/I cells, The mRNA expression of TNF-α and IL-8 was higher in 148M/M hepG2 cells induced by palmitate.
Conclusion: Different genotypes of PNPLA3 I148M have different effects on PA-induced lipid deposition, PNPLA3 148M may play an important role in pathogenesis of NAFLD through ER stress CHOP and IRE1α-JNK pathway.

Disclosure
Y. Chen: None. H. Liang: None. X. Yan: None. X. Xu: None.
1903-P: Protective Effects of Linagliptin on Hepatic Steatosis in Mice Treated with Dual Inhibitor for Insulin Receptor and IGF-1 Receptor
Authors: OKUYAMA TOMOKO , SHIRAKAWA JUN , TERAUCHI YASUO 
Published: June 2019

We previously reported that systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by administration of OSI-906 (linstinib), a dual IR/IGF1R inhibitor, for a week induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In this study, we investigated the effects of a DPP-4 inhibitor linagliptin on hepatic steatosis in OSI-906-terated mice (OSI mice). Eight-week-old C57BL/6 mice were administrated 45 mg/kg of OSI-906 or vehicle with or without 3 mg/kg of linagliptin for 7 days. Linagliptin did not influence on hyperinsulinemia elicited by OSI-906. On the other hand, linagliptin reduced plasma triglyceride levels in OSI mice. Linagliptin also improved OSI-906-induced hepatic steatosis without changes in visceral fat atrophy. Hepatic gluconeogenic gene expressions, such as G6Pase, PEPCK and PGC-1α, were elevated by the administration of OSI-906, and linagliptin had no significant effect on those gene expressions. OSI-906-induced hepatic steatosis showed no significant changes in gene expressions of fatty acid synthesis or inflammation, such as SREBP-1c, TNF-α and IL-6. We also performed hepatic quantitative proteomic and phosphoproteomic analysis in OSI-906- or linagliptin-treated mice. Linagliptin significantly upregulated 3 proteins and significantly downregulated 7 proteins in the liver of OSI mice (fold change &gt;1.5, p&lt;0.05). The phosphorylation of 102 proteins and 191 proteins were up- and down-regulated by linagliptin in OSI mice. Proteomic analysis indicated Mup20, Cyp2b10, Perilipin-2, and Sirt2 were modulated in the process of amelioration of hepatic steatosis by linagliptin. Taken together, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism, except for gluconeogenesis, lipogenesis, or inflammation, suggesting the potential action of DPP-4 inhibitors for the treatment of hepatic steatosis under insulin resistant conditions.

Disclosure
T. Okuyama: None. J. Shirakawa: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.
1909-P: The Platelet-Derived Growth Factor a—An Additional Pathophysiological Factor in Hepatic Steatosis and Fibrosis Development Both in Patients with Hepatitis C and Patients with Prediabetes
Authors: BLASLOV KRISTINA , MALES VISNJA KOKIC , KOKIC SLAVEN , KRULJAC IVAN 
Published: June 2019

Insulin resistance (IR) represents one of the key regulatory mechanisms in the development of non - alcoholic fatty liver disease. It is a common hepatocyte injury in hepatitis C virus (HCV) infection and type 2 diabetes mellitus (T2DM). Higher plasma platelet-derived growth factor A (PDGF- A) concentration is associated with increased hepatic steatosis and fibrosis in T2DM. PDGFs are key regulators of the connective tissue formation and potent mitogens for hepatic stellate cells. We investigated whether there is an association between PDGF-A serum concentration, IR and HCV mediated hepatic steatosis and fibrosis. This cross-sectional study comprised 90 nondiabetic participants aged 47.11±1.54 years divided into 3 groups: HCV negative group with IR (HCV-/IR-, N=12), HCV positive group without IR (HCV+/IR-, N=34), HCV positive group with IR (HCV+/IR+, N=44). The fasting PDGF-A concentration was determined by enzyme-linked immunoadsorbent assay. Homeostatic Model Assessment of IR score over 1.64 was categorised as IR. Fibrosis and steatosis were evaluated by elastography. Steatosis severity accessed by Controlled Attenuation Parameter (p&lt;0.001) had the mean value of 15.9 kPa in the HCV+/IR+ (p&lt;0.001) revealing the highest value in HCV-/IR+ (296.5 dB/m) group. The PDGF-A concentration correlated positively with steatosis (r=0.341, p=0.007) and fibrosis (r=0.264, p=0.071). Both IR positive groups had higher PDGF-A compared to HCV+/IR- group (p=0.006). In accordance with more pronounced steatosis, the HCV-/IR+ group revealed the highest PDGF-A. Concentration of PDGF-A is associated with the severity of hepatic steatosis in HCV and non-HCV patients with IR; i.e., that PDGF-A could represent one of the key regulatory mechanisms in the pathway from hepatic steatosis towards fibrosis. These results provide better understanding of pathways that regulate fibrosis.

Disclosure
K. Blaslov: None. V. Kokic Males: None. S. Kokic: None. I. Kruljac: None.
1919-P: Regulation and Function of Bone Marrow Adipocytes in Osteogenesis and Hematopoiesis
Authors: ZHANG ZENGDI , HUANG ZAN , RUAN HAI-BIN 
Published: June 2019

In the bone marrow stroma, skeletal stem cells (SSCs) and their derived stromal cells, osteoblasts and bone marrow adipocytes (BMAs) provide the niche microenvironment to support the self-renewal and differentiation of hematopoietic stem cells (HSCs). However, it’s still largely mysterious how the bone-fat balance is disrupted and whether marrow adiposity contributes to the skewed differentiation of HSCs toward myeloid over lymphoid cells. Here we showed that the O-linked β-N-acetylglucosamine (O-GlcNAc) modification on intracellular proteins determined the adipogenic vs. osteogenic differentiation of SSCs. Conditional deletion of O-GlcNAc transferase (OGT) in Osx1+ cells promoted BMA formation while impaired osteoblast development and bone ossification, which resulted in defective B cell development. To determine the role of BM adipokines in hematopoiesis, we selectively ablated Kit ligand (Kitl) in Osx1+ and Adipoq+ lineages. Both Osx1-Kitl KO and Adipoq-Kitl KO mice lost myeloid progenitors in BM and developed macrocytic anemia. Collectively, our data identified protein O-GlcNAcylation as a novel regulator of SSCs differentiation and demonstrated that BMAs are functionally essential for unperturbed hematopoiesis.

Disclosure
Z. Zhang: None. Z. Huang: None. H. Ruan: None.

Funding
National Institutes of Health
1930-P: Heterogeneity of Skeletal Muscle (SM) Insulin Resistance (IR) in Type 1 Diabetes (T1D)
Authors: WILLIAMS KATHERINE V. , SHAY CHRISTINA M. , PRICE JULIE , ORCHARD TREVOR J. , KELLEY DAVID 
Published: June 2019

In addition to a severe deficiency of insulin secretory capacity, systemic IR has also been identified as contributing to the pathophysiology of T1D. This study was undertaken to examine the contribution of SM, the major site for insulin-stimulated glucose uptake, to the IR of T1D, and more specifically, the role of impaired glucose transport. During euglycemic insulin infusion, dynamic PET imaging of SM was done using [18F]fluorodeoxyglucose (FDG), the metabolism of which is restricted to transport/phosphorylation. PET images were co-registered with calf MRI to assess and compare FDG uptake (Patlak K) in soleus (SO) SM (largely oxidative, type 1 fiber) and in tibialis anterior (TA) SM (largely glycolytic, type 2 fiber) to determine the respective severity of IR in these two types of SM. Systemic IR was assessed as glucose disposal rate (GDR) during the clamps. Participants (n=10) with T1D with no evidence of coronary artery or renal disease were recruited from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset T1D. Mean HbA1c in T1D was 7.6±1.3%. Nondiabetic healthy controls (n=13) of comparable age (40.4 years) and BMI (24.1 kg/m2) as the T1D group (43.1 years, 24.3 kg/m2) were studied. Systemic IR was evident in T1D, with GDR reduced by ∼25% (4.95 vs. 6.60 mg/kg-FFM, p=0.06). SM IR was clearly present in oxidative SO SM in T1DM, as values for K were reduced by nearly 50% (0.0075 vs. 0.0126 mL/cm3-minutes, p&lt;0.01). Yet intriguingly, there was no evidence of IR in the glycolytic muscle TA in T1D (0.0077 vs. 0.0087 mL/cm3-minutes); K was not different in either muscle group in T1D, though K for SO was greater than in TA in controls. Systemic GDR correlated with both SO (r=0.59, p=0.003) and TA (0.54, p=0.007) FDG uptake (K). Our findings confirm systemic IR in T1D, indicate the contribution of impaired glucose transport/phosphorylation within SM to IR in T1D, and raise the novel hypothesis that SM IR in T1DM predominately involves oxidative type SM.

Disclosure
K.V. Williams: None. C.M. Shay: None. J. Price: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. D. Kelley: Consultant; Self; Kallyope, Regeneron Pharmaceuticals, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc.

Funding
National Institutes of Health (DK071487)
1936-P: Muscle Ischemia Impairs Insulin-Mediated Microvascular Recruitment
Authors: WANG NASUI , LIU ZHENQI 
Published: June 2019

Diabetes predisposes patients to peripheral artery disease (PAD). Muscle microvasculature plays a critical role in maintaining muscle function and health by delivering oxygen, nutrients and hormones to myocytes. Insulin dilates precapillary arterioles to increase muscle perfusion. To define the impact of ischemia to muscle microvascular perfusion and microvascular response to insulin, adult male rats were subject to hind limb ischemic surgery. Total hind limb blood flow was determined using laser Doppler blood flowmetry and muscle microvascular blood volume (MBV) measured using contrast-enhanced ultrasound in both the ischemic (left) and control (right) hind limb. Ischemic to control limb (I/C) ratios were calculated. Hyperinsulinemic euglycemia clamps were performed to determine microvascular responses to insulin. Hind limb ischemic surgery decreased total limb blood flow by ∼70% immediately, from a pre-surgical I/C ratio of 1.10 ± 0.07 to 0.34 ± 0.06. The I/C ratios then progressively increased to 0.45 ± 0.08, 0.54 ± 0.06, 0.67 ± 0.11, and 0.74± 0.11 on postsurgical day 3, 7, 14 and 21 respectively. Similarly, ischemic surgery decreased MBV promptly from a pre-surgical I/C ratio of 1.01 ± 0.04 to 0.39 ± 0.06. MBV I/C ratios completely recovered on day 3 (1.11 ± 0.09) and remained stable afterwards. Insulin induced similar increases in muscle MBV in both legs before surgery (I/C ratio 1.14 ± 0.16) but the increase was much less in ischemic leg on day 3 (I/C ratio 0.63 ± 0.15). Microvascular insulin responses fully recovered on day 7 (I/C ratio 0.97± 0.25). We conclude that hind limb ischemia is associated with decreased total blood flow, muscle microvascular perfusion as well as microvascular responses to insulin. While the recovery in muscle microvascular perfusion precedes that of total limb blood flow, recovery in muscle microvascular response to insulin is delayed. These changes may contribute to muscle injury in patients with diabetes and the muscle microvasculature is potentially a therapeutic target for PAD.

Disclosure
N. Wang: None. Z. Liu: None.

Funding
American Diabetes Association (1-17-ICTS-059 to Z.L.); National Institutes of Health (R01DK102359)
1938-P: GLP-1 Receptor Agonist Ameliorates Intramyocellular Lipid Deposition without Weight Loss by Activating AMPK
Authors: XU FEN , CAO HUANYI , CHEN ZONGLAN , GU HUIMIN , GUO WANRONG , LIN BEISI , WENG JIANPING 
Published: June 2019

Objective: Ectopic deposition of lipids is closely related with type 2 diabetes (T2D). Whether and how GLP-1 receptor agonists (GLP-1 RAs) ameliorate lipid deposition in skeletal muscle remain unknown. Here, we investigate the effect of GLP-1 RA exenatide on intramyocellular lipid deposition of skeletal muscle in T2D models and whether this process depends on weight loss.
Methods: ob/ob mice and diet-induced obese (DIO) mice were treated with exenatide, leptin or saline control i.p. for four weeks. Systemic phenotypic evaluations were carried out during and after the intervention. An in vitro model used palmitate-treated myoblast C2C12 cells. The expression of key enzymes involved in lipid metabolism was assessed in skeletal muscle of ob/ob mice and DIO mice.
Results: In ob/ob mice, body weight and fat mass were not improved by four-week exenatide treatment. However, intramyocellular lipid deposition and lipid profiles were still modestly ameliorated by exenatide. In DIO mice, body weight, lipid profiles and intramyocellular lipid were all remarkably alleviated by exenatide but not by leptin. In skeletal muscle of these two models, activated AMPK signaling pathway, stimulated lipid oxidative enzymes and improved insulin signaling pathway were observed by exenatide treatment. In vitro, exendin-4 activated AMPK signaling pathway and promoted lipid metabolism to improve lipid accumulation in palmitate-treated myoblast C2C12 cells, and inhibiting AMPK abolished this effect.
Conclusion: Exenatide ameliorates intramyocellular lipid deposition before the weight loss effect appears in ob/ob mice. While both body weight and intramyocellular lipid are alleviated remarkably at the same time by exenatide in DIO mice. Thus, the effect of exenatide on ameliorating intramyocellular lipid deposition could be independent on weight loss by activating AMPK signaling pathway.

Disclosure
F. Xu: None. H. Cao: None. Z. Chen: None. H. Gu: None. W. Guo: None. B. Lin: None. J. Weng: None.