bluuebunny/crossref_metadata_2025_split huggingface dataset:
1831-P: Activating AMPK Mediates FGF1 Protection from NAFLD in Diabetic Mice
Authors: LIN QIAN , CAI GENXIANG , LIU ZHENGSHUAI , LI JINGYA , LI JIA , WINTERGERST KUPPER A. , EPSTEIN PAUL N. , CAI LU , LI YU , TAN YI 
Published: June 2020

Fibroblast growth factor 1 (FGF1) demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic (T2D) and obese mice by uncertain mechanism. This study investigated the therapeutic activity and mechanism of a non-mitagenic FGF1 variant (FGF1ΔHBS) against NAFLD. FGF1ΔHBS administration was effective in 9-month old db/db mice with established NAFLD; liver weight, lipid deposition and inflammation declined and liver function improved. FGF1ΔHBS reduced oxidative stress by nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1ΔHBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of AMP-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1ΔHBS. In palmitate treated hepatic cells, siRNA knockdown of Nrf2 abolished only FGF1ΔHBS anti-oxidative actions but not lipid metabolism improvement. In contrast, AMPK inhibition by pharmacological agents or siRNA abolished both FGF1ΔHBS benefits on oxidative stress and lipid metabolism that was FGF receptor 4 (FGFR4) dependent. Further support of these in vitro findings is that liver specific AMPK knockout abolished therapeutic effects of FGF1ΔHBS against high-fat-high-sugar diet-induced hepatic steatosis. These findings indicate that FGF1ΔHBS is effective in late stage NAFLD and acts by activation of AMPK via hepatocyte FGFR4.

Disclosure
Q. Lin: None. G. Cai: None. Z. Liu: None. J. Li: None. J. Li: None. K.A. Wintergerst: None. P.N. Epstein: None. L. Cai: None. Y. Li: None. Y. Tan: None.

Funding
American Diabetes Association (1-13-JF-53 to Y.T.), (1-18-IBS-082 to L.C.)
1856-P: Hepatic Insulin Clearance Is Not Driven by Liver Fat but by Systemic Inflammation: A Mendelian Randomization Study
Authors: LAMPRINOU APOSTOLIA , MACHANN JÜRGEN , SCHICK FRITZ , ECKSTEIN SABINE S. , MAN CHIARA DALLA , VISENTIN ROBERTO , STEFAN NORBERT , BIRKENFELD ANDREAS L. , PETER ANDREAS , HAERING HANS-ULRICH , FRITSCHE ANDREAS , HENI MARTIN , WAGNER ROBERT 
Published: June 2020

Introduction: Type 2 diabetes is not only associated with insulin resistance but also with decreased insulin clearance. Insulin is mostly eliminated from portal blood during the first pass through the liver. The magnitude of this effect is closely related to systemic insulin sensitivity. As insulin resistance is often accompanied by fatty liver, we here investigated whether there is a causal link between liver fat and hepatic insulin clearance (IC).
Methods: We computed IC using data from oral glucose tolerance tests in 3391 non diabetic individuals and the oral C-peptide and Insulin Minimal Models. Liver fat was quantified by 1H-MR-spectroscopy in 1211 participants. We performed Mendelian randomization analyses to test for causal determination of IC by liver fat and potentially related traits using established single nucleotide polymorphisms (liver fat: 115 SNPs, alanine-aminotransferase: 155 SNPs, insulin sensitivity: 37 SNPs, C-reactive protein: 193 SNPs).
Results: IC associated inversely with liver fat content (β=-0.1±0.03, p&lt;0.003) and insulin sensitivity (β=0.6±0.03, p &lt; 0.0001). Both liver fat content and IC were independently associated with insulin sensitivity (β=-0.2±0.03 and β=0.1±0.02 respectively, both p &lt; 0.0001). Neither liver fat content nor alanine-aminotransferase were causally linked to IC (p=0.6 and 0.2, respectively), as indicated by the Mendelian randomization. On the other hand, both genetically determined insulin sensitivity and C-reactive protein levels influenced IC (β=0.3±0.1, p=0.04 and β=0.1±0.07, p=0.03, respectively).
Conclusion: This study supports the hypothesis that systemic effects such as inflammatory activity and/or genetic factors determining insulin resistance might modulate insulin extraction in the liver.

Disclosure
A. Lamprinou: None. J. Machann: None. F. Schick: None. S.S. Eckstein: None. C. Dalla Man: Research Support; Self; Sanofi-Aventis Deutschland GmbH. R. Visentin: None. N. Stefan: None. A.L. Birkenfeld: None. A. Peter: None. H. Haering: None. A. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company.

Funding
German Center of Diabetes Research (01GI0925)
1866-P: Adipocyte Hypertrophy Is Associated with Increased Dietary Fatty Acid Storage in Adipose Tissue and Reduced Postprandial Hepatic Fatty Acid Uptake and Esterification in Humans
Authors: YE RUN ZHOU , PHOENIX SERGE , NOLL CHRISTOPHE , MONTASTIER EMILIE , FRISCH FRÉDÉRIQUE , BOUFFARD LUCIE , AMRANI MEHDI , TURCOTTE ERIC E. , CARPENTIER ANDRÉ C. 
Published: June 2020

Introduction: Excessive exposure of lean tissues to nonesterified fatty acids (NEFA) leads to insulin resistance (IR). Adipocyte hypertrophy is associated with IR and increase in adipose tissue intracellular triglyceride lipolysis and in NEFA levels, that may contribute to hepatic steatosis and IR. The effect of adipocyte hypertrophy on postprandial hepatic NEFA flux and metabolism and dietary fatty acids (DFA) storage in adipose tissues has not been studied, however.
Methods: In 28 healthy adult subjects, fat cell size (FCS) was determined via histomorphologic analysis of abdominal subcutaneous fat tissue. Adipose tissue DFA storage was measured using oral administration of 18FTHA with positron emission tomography (PET). Postprandial hepatic NEFA uptake, oxidation, and esterification were determined using intravenous 11C-palmitate with dynamic PET acquisition.
Results: As expected, FCS was correlated positively with fasting glycemia (ρ=0.44, P-value=0.029), homeostasis model assessment-estimated insulin resistance (HOMA-IR) (ρ=0.43, P-value=0.049), and hepatic fat content from CT radiodensity (ρ=0.32, P-value=0.10). FCS was correlated positively with DFA storage in intra-abdominal adipose tissues (ρ=0.48, P-value=0.022) and negatively with postprandial hepatic NEFA uptake (ρ=-0.42, P-value=0.027) and esterification (ρ=-0.58, P-value=0.0080).
Conclusion: Adipocyte hypertrophy is associated with increased DFA storage in intra-abdominal adipose tissues and reduced postprandial hepatic NEFA uptake and esterification, despite being associated with greater hepatic fat content, fasting glycemia and HOMA-IR. Adipocyte hypertrophy is thus associated with adipose tissue metabolic adaptation that limits the exposure of the liver to fatty acids in the postprandial period.

Disclosure
R. Ye: None. S. Phoenix: None. C. Noll: None. E. Montastier: None. F. Frisch: None. L. Bouffard: None. M. Amrani: None. E.E. Turcotte: None. A.C. Carpentier: Advisory Panel; Self; HLS Therapeutics, Inc.

Funding
Canadian Institutes of Health Research (MOP53094); Centre de recherche du CHUS; Centre d’imagerie moléculaire de Sherbrooke; Faculté de médecine et des sciences de la santé de l’Université de Sherbrooke
1888-P: Activation of Myocardial Mitochondrial Akt1 Remotely Modulated Body Composition and Adiposity through LXR/RXR Signaling
Authors: CHEN YU-HAN , TA ALBERT , TOM EMILY , CHEN YUMAY , WANG PING H. 
Published: June 2020

Insulin resistance contributed to the development of type 2 diabetes (T2D) and is a major risk factor for diabetic cardiomyopathy (DCM). We have previously reported that insulin resistance led to impaired Akt1 translocation into myocardial mitochondria in DCM. To study the role of mitochondrial Akt1 in DCM, we have generated two cardiac-specific inducible Cre-lox transgenic mice models that expresses (1) a mitochondria-targeting dominant negative Akt (CAMDAKT) or (2) a mitochondria-targeting constitutively active Akt (CAMCAKT) upon Tamoxifen induction (T). T-CAMDAKT mice showed LV dysfunction with increased heart failure markers, while T-CAMCAKT mice restored LV dysfunction to normal in the T2D model. In a T2D model induced by high fat/high fructose diet with relative insulin deficiency, T-CAMCAKT mice showed lower body fat mass (16.6% vs. 26.5%, p&lt;0.001) and higher body lean mass (77.1% vs. 68.1%, p&lt;0.001). To study the mechanism underlying the changes of body composition, we performed transcriptomic profiling and analysis in gonadal white adipose tissues (WAT) by bulk RNA sequencing. When compared to the control T2D mice, 544 genes were upregulated and 1077 genes were downregulated in the WAT of T-CAMCAKT T2D mice. The result indicated enhanced lipid catabolism, triglyceride catabolism, HDL assembly, and downregulated critical nuclear transcription. Pathway analysis revealed the Liver X receptor/Retinoid X receptor signaling was activated in WAT of T-CAMCAKT mice as compared to the controls. This was accompanied by increased fatty acid oxidation and apolipoproteins expression. These findings suggest that impaired mitochondrial Akt signaling in DCM could remotely increase adiposity by reducing lipid catabolism in WAT through modulating LXR/RXR signaling.

Disclosure
Y. Chen: None. A. Ta: None. E. Tom: None. Y. Chen: None. P.H. Wang: Board Member; Self; Dianavi.

Funding
National Institutes of Health (R01HL096987)
1900-P: HNF1A Deficiency Leads to Perturbed Glucagon Secretion in Humans
Authors: SAPONARO CHIARA , ACOSTA-MONTALVO ANA , ANGUELOVA LIA , THEVENET JULIEN , CHIRAL MAGALI , PASQUETTI GIANNI , PIRON ANTHONY , CNOP MIRIAM , GMYR VALERY , PREHN JOCHEN , KERR-CONTE JULIE A. , PATTOU FRANCOIS , PONTOGLIO MARCO , OWEN KATHARINE R. , SPILIOTIS IOANNIS , BONNER CAROLINE 
Published: June 2020

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). Carriers are normoglycemic in childhood, but with age, they develop hyperglycemia associated with insulin secretory defects and beta cell dysfunction. Although endogenous glucose production has been reported, glucagon in HNF1A-MODY has been less explored. Patients respond well to low dose sulfonylureas such as gliclazide, which increases insulin secretion independent of glucose but may predispose to hypoglycemia. We aimed to investigate whether low dose gliclazide had an effect on glucagon secretion in HNF1A-MODY. Additionally, we explored the potential of GLP-1 to normalize hormone secretion using in vivo and in vitro models of HNF1A deficiency. A 75g oral glucose tolerance test was performed in 7 MODY patients before and 72h after stopping gliclazide. Glucose rise was greater off gliclazide (p=0.003), while c-peptide and glucagon levels were similar between the groups. When adjusting for glucose levels during the OGTT, the change from baseline glucagon levels (Δ glucagon/glucose ratio) showed a significant decrease in those taking gliclazide (p=0.048), while there was no difference in Δ c-peptide/glucose ratio. Hnf1a-/- mice compared to WT mice are hyperglycemic, have decreased plasma insulin levels and hyperglucagonemia that was not suppressed after a glucose challenge (p=0.008). Furthermore, induction of the HNF1A variant Pro291fsInsC in rat INS1 cells reduced insulin and increased glucagon secretion, both of which were improved by GLP-1 treatment. Using the TIGER database we found HNF1A to be heterogeneously expressed in human islets, and siHNF1A reduced insulin secretion at high glucose. Collectively, these findings indicate that HNF1A is also essential for the regulation of glucagon secretion and glucose homeostasis. The mechanism by which GLP-1 normalizes insulin and glucagon secretion needs further investigation but could contribute to a better understanding of treatment response in HNF1A-MODY.

Disclosure
C. Saponaro: None. A. Acosta-Montalvo: None. L. Anguelova: None. J. Thevenet: None. M. Chiral: None. G. Pasquetti: None. A. Piron: None. M. Cnop: None. V. Gmyr: None. J. Prehn: None. J.A. Kerr-Conte: None. F. Pattou: None. M. Pontoglio: None. K.R. Owen: None. I. Spiliotis: None. C. Bonner: None.

Funding
European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme; Oxford Health Sciences Research Committee (1233)
1901-P: Individual and Longitudinal Effects of Gastric Bypass Surgery on the Circulating Proteome
Authors: THOMAS CECILIA E. , HÄUSSLER RAGNA S. , HONG MUN-GWAN , RAVERDY VIOLETA , DALE MATILDA , CANOUIL MICKAËL , MAZZONI GIANLUCA , VIÑUELA ANA , FROGUEL PHILIPPE , BRUNAK SØREN , SCHWENK JOCHEN M. ,   THE IMI DIRECT CONSORTIUM
Published: June 2020

Roux-en-Y gastric bypass surgery (RYGB) has been effective for inducing weight-loss and remission of diabetes in obese persons. Nonetheless, the response to RYGB and resulting improvements in glycemic control are heterogeneous and not well understood. To gain molecular insights into how individuals respond to RYGB, we monitored the longitudinal effects of RYGB surgery via circulating proteins. We quantified 368 proteins using multiplexed and sensitive immunoassays (Olink) in sera collected from 146 obese persons with T2D (BMI &gt; 35 kg/m2) prior to, and at one and three months after surgery. We observed an overall longitudinal change in circulating levels for ∼50% of the proteins (FDR &lt; 0.01). This included a post-RYGB increase in levels of GH, IGFBP-2, NT-proBNP, REGA1 and MMP-3, as well as a decrease in levels of SSC4D, SERPINA12, GIF, FBP1, CES1. To deconvolute the inter-individual heterogeneity of the circulating proteomes and protein-related longitudinal dynamics, we clustered the total of ∼44,000 protein profiles into 10 response patterns. Just 8% (28/368) of the proteins’ levels changed in a common manner across the majority of individuals, as these were grouped into 3 or fewer clusters. Among these were proteins related to adipogenesis (LEP, DLK1, GH), white adipocyte differentiation (LEP, FABP4), as well as innate immunity (CHIT1, PTX3, CSTB). However, out of these 28 proteins, only levels of VSIG2 were significantly associated (FDR &lt; 0.01) with diabetes remission at 12 months (HbA1c &lt; 6.5%, no diabetes medication). Overall, our results suggest a wide-reaching, individual-specific, but predominantly short-term impact of RYGB surgery on the circulating proteome. Current investigations examine how genetic variance and mRNA expression in adipose and liver tissue influence the donors’ circulating proteomes in order to explain the observed heterogeneity and its impact on a person’s molecular homeostasis.

Disclosure
C.E. Thomas: None. R.S. Häussler: None. M. Hong: None. V. Raverdy: None. M. Dale: None. M. Canouil: None. G. Mazzoni: None. A. Viñuela: None. P. Froguel: None. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Self; Lundbeck, Novo Nordisk A/S. J.M. Schwenk: None.

Funding
Innovative Medicines Initiative Joint Undertaking (115317); European Union’s Seventh Framework Programme (FP7/2007-2013); Conseil Regional Nord-Pas-de-Calais; European Commission (FEDER 12003944); European Genomic Institute for Diabetes (ANR-10-LABX-46); Foundation Coeur et Arteres (R15112EE); Fonds hospitalier d’aide a l’emergence et a la structuration des activities et des equipes de recherche 2015 (CHRU Lille, France)
1912-P: Bariatric Surgery Downregulates Glucocorticoid Signaling in Mice
Authors: AKALESTOU ELINA , NORIEGA LIVIA LOPEZ , CHRISTAKIS IOANNIS , LECLERC ISABELLE , RUTTER GUY A. 
Published: June 2020

Background: Glucocorticoids (GC) produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. GC activation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss.
Aim: To investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice.
Methods: Fourteen lean mice and twelve HFD mice underwent Vertical Sleeve Gastrectomy (VSG) (n=7-8) or sham (n=5-6) surgery. Glucose and insulin tolerance tests were performed four weeks post operatively. Liver, gut and adipose tissue were harvested from fed mice and analysed using Quantitative real-time PCR (qRT-PCR) and Western Blot (WB).
Results: VSG did not cause excess weight loss in lean mice when compared to sham operated mice (p=0.37). However, both lean and HFD VSG mice displayed significantly improved glucose and insulin tolerance (p&lt;0.001). Of note, qPCR and Western blotting analysis on mouse liver demonstrated a significant lowering of 11β-HSD1 levels 4 and 12 weeks after VSG (p&lt;0.01). Additionally, in lean mice, 11β-HSD1 expression was also lowered in omental adipose tissue (p=0.01) and GR expression was inhibited in liver and ileum at the transcript level (p&lt;0.05).
Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoid activation physiologically and in the obese state, irrespective of weight loss. The reduction in glucocorticoid signalling may represent an additional contribution to the health benefits of bariatric surgery. These findings point towards a physiologically-relevant gut-adrenal axis.

Disclosure
E. Akalestou: None. L. Lopez Noriega: None. I. Christakis: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.

Funding
Rosetrees Foundation (M825); British Society for Neuroendocrinology; Society for Endocrinology (19ES001); UK Wellcome Trust (212625/Z/18/Z); Medical Research Council UK (MR/R022259/1); European Union (115881)
1922-P: Type 2 Adipocyte Subpopulation Mediates Obesity-Associated Inflammation in a PPARγ Dependent Pathway
Authors: HUANG JUN , SHARMA RITA , LEE KEVIN Y. 
Published: June 2020

Recent studies have shown that heterogeneity among adipocytes exists within a single WAT depot. Our lab has uncovered three developmentally distinct subpopulations of WAT adipocytes distinguished by the expression of these genes: Wilms’ Tumor 1 (Wt1) (Type 1), Transgelin (Tagln) (Type 2), and Myxovirus 1 (Mx1) (Type 3). Utilizing Cre transgenic mice, transcription of which is directed by the promoters of these marker genes, lineage tracing analysis showed that these three preadipocyte subpopulations independently gave rise to adipocytes in vivo, and differentially contribute to the adipose tissue depots. This study extends these findings to investigate the role of Type 2 adipocytes during obesity. The number of Type 2 preadipocytes and adipocytes was not significantly altered by high fat diet induced obesity. However, greater than 80% of recruited macrophages, organized into crown-like structures were found in direct contact with Type 2 adipocytes, suggesting increased apoptosis of this adipocyte subpopulation. Furthermore, treatment of Type 2 adipocytes with the inflammatory cytokine TNFα promoted a 15% increase apoptosis specifically in Type 2 adipocytes, with no effects on other adipocytes. RNA-seq analysis of Type 2 adipocytes revealed a global downregulation of 102 of 298 known PPARγ regulated genes in Type 2 adipocytes. Although PPARγ mRNA was not altered, the protein level of PPARγ was reduced by 60% in Type 2 vs. control adipocytes. Pre-treatment of Type 2 adipocytes with the PPARγ agonist, rosiglitazone reduces TNFα-induced apoptosis in this subpopulation to similar levels found in control adipocytes, suggesting that reduced PPARγ activity in Type 2 adipocytes may, at least in part, regulates obesity-associated inflammation. Thus, further investigation of the physiological role of these adipocyte subpopulations are promising avenues of study to develop novel treatment strategies to combat diabetes and other disorders associated with the obesity epidemic.

Disclosure
J. Huang: None. R. Sharma: None. K.Y. Lee: None.

Funding
Ohio University
1927-P: Protective Role of DNAJB3 Cochaperone against Obesity-Induced Insulin Resistance and Diabetes
Authors: DEHBI MOHAMMED , DIANE ABDOULAYE , SCOGGIN SHANE , BENSMAIL ILHAM , KHATTAB NAMAT , RAMALINGAM LATHA , EFOTTE ALIYAH , MOUSTAID-MOUSSA NAIMA 
Published: June 2020

The last decade has witnessed a dramatic increase in the prevalence of obesity and type 2 diabetes (T2D) in some Middle Eastern countries. In the GCC countries, over 35% and 20% develop obesity and T2D, respectively. Of extreme concern, the disease starts affecting the population at a relatively younger age (∼40 years), and vulnerable individuals manifest severe insulin resistance (IR). We previously showed that subjects with obesity and T2D among the Kuwaiti population have reduced expression of DNAJB3 that was associated with increased metabolic stress and poor clinical outcomes. Furthermore, physical exercise was effective in restoring the normal expression of DNAJB3 with the concomitant metabolic improvements. These observations suggest a therapeutic value of DNAJB3 against obesity-associated metabolic diseases. To gain further insights into this protective role, we generated mice lacking DNAJB3 using CRISPR/Cas9 approach, and challenged them with high fat diet (HFD). We also determined the in vitro effects of DNAJB3 overexpression/knockdown in modulating metabolic stress, mitochondrial and glucose homeostasis in C2C12 cells. Accordingly, DNAJB3 KO mice showed increased body weight and fat mass in response to HFD, compared to wild type. In addition, DNAJB3 KO mice on HFD exhibited increased glucose intolerance. Moreover, overexpression of DNAJB3 prevented the activation of both JNK and IKK in response to palmitate and inflammatory cytokines, respectively; while it promoted the PI3K/AKT pathway and both basal and insulin-stimulated glucose uptake. These observations were consistent with DNAJB3 knockdown experiments. Mechanistically, we showed a significant effect of DNAJB3 on enhancing Glut4 translocation and stimulating expression of key mitochondrial markers including PPARγ, PGC1α and OXPHOS. Together, these data indicate an important physiological role of DNAJB3 in obesity-induced IR and T2D and warrant further in vivo animal and clinical investigations.

Disclosure
M. Dehbi: None. A. Diane: None. S. Scoggin: None. I. Bensmail: None. N. Khattab: None. L. Ramalingam: None. A. Efotte: None. N. Moustaid-Moussa: None.

Funding
Qatar Biomedical Research Institute (IGP 2014-001)