TY  - JOUR
A1  - Werno, Martin Witold
A1  - Wilhelmi, Ilka
A1  - Kuropka, Benno
A1  - Ebert, Franziska
A1  - Freund, Christian
A1  - Schürmann, Annette
T1  - The GTPase ARFRP1 affects lipid droplet protein composition and triglyceride release from intracellular storage of intestinal Caco-2 cells
JF  - Biochemical and biophysical research communications
N2  - Intestinal release of dietary triglycerides via chylomicrons is the major contributor to elevated postprandial triglyceride levels. Dietary lipids can be transiently stored in cytosolic lipid droplets (LDs) located in intestinal enterocytes for later release. ADP ribosylation factor-related protein 1 (ARFRP1) participates in processes of LD growth in adipocytes and in lipidation of lipoproteins in liver and intestine. This study aims to explore the impact of ARFRP1 on LD organization and its interplay with chylomicron-mediated triglyceride release in intestinal-like Caco-2 cells. Suppression of Arfrp1 reduced release of intracellularly derived triglycerides (0.69-fold) and increased the abundance of transitional endoplasmic reticulum ATPase TERA/VCP, fatty acid synthase-associated factor 2 (FAF2) and perilipin 2 (Plin2) at the LD surface. Furthermore, TERA/VCP and FAF2 co-occurred more frequently with ATGL at LDs, suggesting a reduced adipocyte triglyceride lipase (ATGL)-mediated lipolysis. Accordingly, inhibition of lipolysis reduced lipid release from intracellular storage pools by the same magnitude as Arfrp1 depletion. Thus, the lack of Arfrp1 increases the abundance of lipolysis-modulating enzymes TERA/VCP, FAF2 and Plin2 at LDs, which might decrease lipolysis and reduce availability of fatty acids for triglyceride synthesis and their release via chylomicrons. (C) 2018 The Authors. Published by Elsevier Inc.
KW  - Chylomicron
KW  - Lipid droplet proteome
KW  - Triglyceride secretion
KW  - Lipolysis
Y1  - 2018
U6  - https://doi.org/10.1016/j.bbrc.2018.10.092
SN  - 0006-291X
SN  - 1090-2104
VL  - 506
IS  - 1
SP  - 259
EP  - 265
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - JOUR
A1  - Gancheva, Sofiya
A1  - Ouni, Meriem
A1  - Jelenik, Tomas
A1  - Koliaki, Chrysi
A1  - Szendroedi, Julia
A1  - Toledo, Frederico G. S.
A1  - Markgraf, Daniel Frank
A1  - Pesta, Dominik H.
A1  - Mastrototaro, Lucia
A1  - De Filippo, Elisabetta
A1  - Herder, Christian
A1  - Jähnert, Markus
A1  - Weiss, Jürgen
A1  - Strassburger, Klaus
A1  - Schlensak, Matthias
A1  - Schürmann, Annette
A1  - Roden, Michael
T1  - Dynamic changes of muscle insulin sensitivity after metabolic surgery
JF  - Nature Communications
N2  - The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio. Persistent elevation of intramyocellular lipid intermediates, likely resulting from unrestrained adipose tissue lipolysis, accompanies the lack of rapid changes in insulin sensitivity. Simultaneously, alterations in skeletal muscle expression of genes involved in calcium/lipid metabolism and mitochondrial function associate with subsequent distinct DNA methylation patterns at 52 weeks after surgery. Thus, initial unfavorable metabolic changes including insulin resistance of adipose tissue and skeletal muscle precede epigenetic modifications of genes involved in muscle energy metabolism and the long-term improvement of insulin sensitivity.
Y1  - 2019
U6  - https://doi.org/10.1038/s41467-019-12081-0
SN  - 2041-1723
VL  - 10
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - JOUR
A1  - Quiclet, Charline
A1  - Dittberner, Nicole
A1  - Gaessler, Anneke
A1  - Stadion, Mandy
A1  - Gerst, Felicia
A1  - Helms, Anett
A1  - Baumeier, Christian
A1  - Schulz, Tim Julius
A1  - Schurmann, Annette
T1  - Pancreatic adipocytes mediate hypersecretion of insulin in diabetes-susceptible mice
JF  - Metabolism - Clinical and experimental
N2  - Objective: Ectopic fat accumulation in the pancreas in response to obesity and its implication on the onset of type 2 diabetes remain poorly understood. Intermittent fasting (IF) is known to improve glucose homeostasis and insulin resistance. However, the effects of IF on fat in the pancreas and beta-cell function remain largely unknown. Our aim was to evaluate the impact of IF on pancreatic fat accumulation and its effects on islet function. Methods: New Zealand Obese (NZO) mice were fed a high-fat diet ad libitum (NZO-AL) or fasted every other day (intermittent fasting, NZO-IF) and pancreatic fat accumulation, glucose homoeostasis, insulin sensitivity, and islet function were determined and compared to ad libitum-fed B6.V-Lep(ob/ob) (ob/ob) mice. To investigate the crosstalk of pancreatic adipocytes and islets, co-culture experiments were performed. Results: NZO-IF mice displayed better glucose homeostasis and lower fat accumulation in both the pancreas (-32%) and the liver (-35%) than NZO-AL mice. Ob/ob animals were insulin-resistant and had low fat in the pancreas but high fat in the liver. NZO-AL mice showed increased fat accumulation in both organs and exhibited an impaired islet function. Co-culture experiments demonstrated that pancreatic adipocytes induced a hypersecretion of insulin and released higher levels of free fatty adds than adipocytes of inguinal white adipose tissue. Conclusions: These results suggest that pancreatic fat participates in diabetes development, but can be prevented by IF. (C) 2019 Published by Elsevier Inc.
Y1  - 2019
U6  - https://doi.org/10.1016/j.metabol.2019.05.005
SN  - 0026-0495
SN  - 1532-8600
VL  - 97
SP  - 9
EP  - 17
PB  - Elsevier
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Jonas, Wenke
A1  - Schürmann, Annette
T1  - Genetic and epigenetic factors determining NAFLD risk
JF  - Molecular metabolism
N2  - Background: Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. Scope of review: We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. Major conclusion: With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.
KW  - NAFLD
KW  - genetic variants
KW  - epigenetics
KW  - risk score
Y1  - 2020
U6  - https://doi.org/10.1016/j.molmet.2020.101111
SN  - 2212-8778
VL  - 50
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Graja, Antonia
A1  - Garcia-Carrizo, Francisco
A1  - Jank, Anne-Marie
A1  - Gohlke, Sabrina
A1  - Ambrosi, Thomas H.
A1  - Jonas, Wenke
A1  - Ussar, Siegfried
A1  - Kern, Matthias
A1  - Schürmann, Annette
A1  - Aleksandrova, Krasimira
A1  - Bluher, Matthias
A1  - Schulz, Tim Julius
T1  - Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism
JF  - Aging Cell
N2  - Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis.
KW  - adipogenic progenitor cells
KW  - adipose tissue
KW  - aging
KW  - extracellular matrix
KW  - fatty acid metabolism
KW  - periostin
Y1  - 2018
U6  - https://doi.org/10.1111/acel.12810
SN  - 1474-9718
SN  - 1474-9726
VL  - 17
IS  - 5
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Vogel, Heike
A1  - Kamitz, Anne
A1  - Hallahan, Nicole
A1  - Lebek, Sandra
A1  - Schallschmidt, Tanja
A1  - Jonas, Wenke
A1  - Jähnert, Markus
A1  - Gottmann, Pascal
A1  - Zellner, Lisa
A1  - Kanzleiter, Timo
A1  - Damen, Mareike
A1  - Altenhofen, Delsi
A1  - Burkhardt, Ralph
A1  - Renner, Simone
A1  - Dahlhoff, Maik
A1  - Wolf, Eckhard
A1  - Müller, Timo Dirk
A1  - Blüher, Matthias
A1  - Joost, Hans-Georg
A1  - Chadt, Alexandra
A1  - Al-Hasani, Hadi
A1  - Schürmann, Annette
T1  - A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes
JF  - Human molecular genetics
N2  - To explore the genetic determinants of obesity and Type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone New Zealand Obese mouse strain with four different lean strains (B6, DBA, C3H, 129P2) that vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 quantitative trait loci (QTL) for obesity, 190 QTL for diabetes-related traits and 100 QTL for plasma metabolites in the out-cross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data. The efficiency of the complex procedure was demonstrated for one obesity QTL. The genomic interval of 35 Mb with 502 annotated candidate genes was narrowed down to six candidates. Accordingly, congenic mice retained the obesity phenotype owing to an interval that contains three of the six candidate genes. Among these the phospholipase PLA2G4A exhibited an elevated expression in adipose tissue of obese human subjects and is therefore a critical regulator of the obesity locus. Together, our broad and complex approach demonstrates that combined- and comparative-cross analysis exhibits improved mapping resolution and represents a valid tool for the identification of disease genes.
Y1  - 2018
U6  - https://doi.org/10.1093/hmg/ddy217
SN  - 0964-6906
SN  - 1460-2083
VL  - 27
IS  - 17
SP  - 3099
EP  - 3112
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Saussenthaler, Sophie
A1  - Ouni, Meriem
A1  - Baumeier, Christian
A1  - Schwerbel, Kristin
A1  - Gottmann, Pascal
A1  - Christmann, Sabrina
A1  - Laeger, Thomas
A1  - Schürmann, Annette
T1  - Epigenetic regulation of hepatic Dpp4 expression in response to dietary protein
JF  - The journal of nutritional biochemistry
N2  - Dipeptidyl peptidase 4 (DPP4) is known to be elevated in metabolic disturbances such as obesity, type 2 diabetes and fatty liver disease. Lowering DPP4 concentration by pharmacological inhibition improves glucose homeostasis and exhibits beneficial effects to reduce hepatic fat content. As factors regulating the endogenous expression of Dpp4 are unknown, the aim of this study was to examine whether the Dpp4 expression is epigenetically regulated in response to dietary components. Primary hepatocytes were treated with different macronutrients, and Dpp4 mRNA levels and DPP4 activity were evaluated. Moreover, dietary low-protein intervention was conducted in New Zealand obese (NZO) mice, and subsequently, effects on Dpp4 expression, methylation as well as plasma concentration and activity were determined. Our results indicate that Dpp4 mRNA expression is mediated by DNA methylation in several tissues. We therefore consider the Dpp4 southern shore as tissue differentially methylated region. Amino acids increased Dpp4 expression in primary hepatocytes, whereas glucose and fatty acids were without effect. Dietary protein restriction in NZO mice increased Dpp4 DNA methylation in liver leading to diminished Dpp4 expression and consequently to lowered plasma DPP4 activity. We conclude that protein restriction in the adolescent and adult states is a sufficient strategy to reduce DPP4 which in turn contributes to improve glucose homeostasis. (C) 2018 Published by Elsevier Inc.
KW  - DPP4
KW  - DNA methylation
KW  - Protein restriction
KW  - Type 2 diabetes
KW  - NZO
Y1  - 2019
U6  - https://doi.org/10.1016/j.jnutbio.2018.09.025
SN  - 0955-2863
SN  - 1873-4847
VL  - 63
SP  - 109
EP  - 116
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Wilhelmi, Ilka
A1  - Grunwald, Stephan
A1  - Gimber, Niclas
A1  - Popp, Oliver
A1  - Dittmar, Gunnar
A1  - Arumughan, Anup
A1  - Wanker, Erich E.
A1  - Laeger, Thomas
A1  - Schmoranzer, Jan
A1  - Daumke, Oliver
A1  - Schürmann, Annette
T1  - The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic 13-cells
JF  - Molecular metabolism
N2  - Objective: Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic 13-cells. <br /> Methods: A 13-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation. <br /> Results: The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from 13-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from 13-cell-specific Arfrp1 knockout mice. <br /> Conclusion: Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting. (c) 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
KW  - Insulin secretion
KW  - Endosomal sorting
KW  - SNARE proteins
KW  - trans-Golgi
KW  - network
Y1  - 2020
U6  - https://doi.org/10.1016/j.molmet.2020.101151
SN  - 2212-8778
VL  - 45
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Frede, Katja
A1  - Schanze, Nancy
A1  - Vogel, Heike
A1  - Schürmann, Annette
A1  - Spruß, Astrid
A1  - Bergheim, Ina
A1  - Püschel, Gerhard Paul
T1  - Stimulation of fat accumulation in hepatocytes by PGE(2)-dependent repression of hepatic lipolysis, beta-oxidation and VLDL-synthesis
JF  - Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology
N2  - Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE(2), which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE(2)-generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE(2) attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE(2) enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE(2)-dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial beta-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1 alpha, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1 alpha completely blunted the PGE(2)-dependent fat accumulation. PGE(2) enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE(2) synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH. Laboratory Investigation (2012) 92, 1597-1606; doi:10.1038/labinvest.2012.128; published online 10 September 2012
KW  - cyclooxygenase
KW  - hepatic steatosis
KW  - mPGES
KW  - NAFLD
KW  - NASH
KW  - type 2 diabetes (T2DM)
KW  - PGC1 alpha
Y1  - 2012
U6  - https://doi.org/10.1038/labinvest.2012.128
SN  - 0023-6837
VL  - 92
IS  - 11
SP  - 1597
EP  - 1606
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Hesse, Deike
A1  - Jaschke, Alexander
A1  - Kanzleiter, Timo
A1  - Witte, Nicole
A1  - Augustin, Robert
A1  - Hommel, Angela
A1  - Püschel, Gerhard Paul
A1  - Petzke, Klaus-Jürgen
A1  - Joost, Hans-Georg
A1  - Schupp, Michael
A1  - Schürmann, Annette
T1  - GTPase ARFRP1 is essential for normal hepatic glycogen storage and insulin-like growth factor 1 secretion
JF  - Molecular and cellular biology
N2  - The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage.
Y1  - 2012
U6  - https://doi.org/10.1128/MCB.00522-12
SN  - 0270-7306
VL  - 32
IS  - 21
SP  - 4363
EP  - 4374
PB  - American Society for Microbiology
CY  - Washington
ER  -