TY - GEN
A1 - Schwerbel, Kristin
A1 - Kamitz, Anne
A1 - Jaehnert, Markus
A1 - Gottmann, P.
A1 - Schumacher, Fabian
A1 - Kleuser, Burkhard
A1 - Haltenhof, T.
A1 - Heyd, F.
A1 - Roden, Michael
A1 - Chadt, Alexandra
A1 - Al-Hasani, Hadi
A1 - Jonas, W.
A1 - Vogel, Heike
A1 - Schürmann, Annette
T1 - Two immune-related GTPases prevent from hepatic fat accumulation by inducing autophagy
T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
Y1 - 2018
SN - 0012-186X
SN - 1432-0428
VL - 61
SP - S259
EP - S259
PB - Springer
CY - New York
ER -
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 - 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.
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.
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.
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 - Kehm, Richard
A1 - Jähnert, Markus
A1 - Deubel, Stefanie
A1 - Flore, Tanina
A1 - König, Jeannette
A1 - Jung, Tobias
A1 - Stadion, Mandy
A1 - Jonas, Wenke
A1 - Schürmann, Annette
A1 - Grune, Tilman
A1 - Höhn, Annika
T1 - Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: role of thioredoxin-interacting protein (TXNIP)
JF - Redox Biology
N2 - Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetesprone NZO mice.
KW - aging
KW - redox homeostasis
KW - metabolic stress
KW - beta-cells
KW - cell cycle
KW - thioredoxin-interacting protein
Y1 - 2020
U6 - https://doi.org/10.1016/j.redox.2020.101748
SN - 2213-2317
VL - 37
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Castaño Martínez, María Teresa
A1 - Schumacher, Fabian
A1 - Schumacher, Silke
A1 - Kochlik, Bastian
A1 - Weber, Daniela
A1 - Grune, Tilman
A1 - Biemann, Ronald
A1 - McCann, Adrian
A1 - Abraham, Klaus
A1 - Weikert, Cornelia
A1 - Kleuse, Burkhard
A1 - Schürmann, Annette
A1 - Laeger, Thomas
T1 - Methionine restriction prevents onset of type 2 diabetes in NZO mice
JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2 - Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet-induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits via increased circulating levels of FGF21 and merits further investigation.-Castano-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schurmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice.
KW - energy expenditure
KW - hyperglycemia
KW - obesity
KW - vegan
KW - vegetarian
Y1 - 2019
U6 - https://doi.org/10.1096/fj.201900150R
SN - 0892-6638
SN - 1530-6860
VL - 33
IS - 6
SP - 7092
EP - 7102
PB - Federation of American Societies for Experimental Biology
CY - Bethesda
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 - Wittenbecher, Clemens
A1 - Ouni, Meriem
A1 - Kuxhaus, Olga
A1 - Jähnert, Markus
A1 - Gottmann, Pascal
A1 - Teichmann, Andrea
A1 - Meidtner, Karina
A1 - Kriebel, Jennifer
A1 - Grallert, Harald
A1 - Pischon, Tobias
A1 - Boeing, Heiner
A1 - Schulze, Matthias Bernd
A1 - Schürmann, Annette
T1 - Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) and the Risk of Developing Type 2 Diabetes
JF - Diabetes : a journal of the American Diabetes Association
N2 - Recent studies suggest that insulin-like growth factor binding protein 2 (IGFBP-2) may protect against type 2 diabetes, but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk.
Y1 - 2019
U6 - https://doi.org/10.2337/db18-0620
SN - 0012-1797
SN - 1939-327X
VL - 68
IS - 1
SP - 188
EP - 197
PB - American Diabetes Association
CY - Alexandria
ER -
TY - JOUR
A1 - Henkel, Janin
A1 - Coleman, Charles Dominic
A1 - Schraplau, Anne
A1 - Jöhrens, Korinna
A1 - Weber, Daniela
A1 - Castro, Jose Pedro
A1 - Hugo, Martin
A1 - Schulz, Tim Julius
A1 - Krämer, Stephanie
A1 - Schürmann, Annette
A1 - Püschel, Gerhard Paul
T1 - Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol
JF - Molecular medicine
N2 - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
KW - Nonalcoholic Steatohepatitis (NASH)
KW - Typical Western Diet
KW - Nonalcoholic Fatty Liver Disease (NAFLD)
KW - Dietary Cholesterol
KW - Kupffer Cells
Y1 - 2017
U6 - https://doi.org/10.2119/molmed.2016.00203
SN - 1076-1551
SN - 1528-3658
VL - 23
SP - 70
EP - 82
PB - Feinstein Inst. for Medical Research
CY - Manhasset
ER -
TY - JOUR
A1 - Aga-Barfknecht, Heja
A1 - Hallahan, Nicole
A1 - Gottmann, Pascal
A1 - Jähnert, Markus
A1 - Osburg, Sophie
A1 - Schulze, Gunnar
A1 - Kamitz, Anne
A1 - Arends, Danny
A1 - Brockmann, Gudrun
A1 - Schallschmidt, Tanja
A1 - Lebek, Sandra
A1 - Chadt, Alexandra
A1 - Al-Hasani, Hadi
A1 - Joost, Hans-Georg
A1 - Schürmann, Annette
A1 - Vogel, Heike
T1 - Identification of novel potential type 2 diabetes genes mediating beta-cell loss and hyperglycemia using positional cloning
JF - Frontiers in genetics
N2 - Type 2 diabetes (T2D) is a complex metabolic disease regulated by an interaction of genetic predisposition and environmental factors. To understand the genetic contribution in the development of diabetes, mice varying in their disease susceptibility were crossed with the obese and diabetes-prone New Zealand obese (NZO) mouse. Subsequent whole-genome sequence scans revealed one major quantitative trait loci (QTL),Nidd/DBAon chromosome 4, linked to elevated blood glucose and reduced plasma insulin and low levels of pancreatic insulin. Phenotypical characterization of congenic mice carrying 13.6 Mbp of the critical fragment of DBA mice displayed severe hyperglycemia and impaired glucose clearance at week 10, decreased glucose response in week 13, and loss of beta-cells and pancreatic insulin in week 16. To identify the responsible gene variant(s), further congenic mice were generated and phenotyped, which resulted in a fragment of 3.3 Mbp that was sufficient to induce hyperglycemia. By combining transcriptome analysis and haplotype mapping, the number of putative responsible variant(s) was narrowed from initial 284 to 18 genes, including gene models and non-coding RNAs. Consideration of haplotype blocks reduced the number of candidate genes to four (Kti12,Osbpl9,Ttc39a, andCalr4) as potential T2D candidates as they display a differential expression in pancreatic islets and/or sequence variation. In conclusion, the integration of comparative analysis of multiple inbred populations such as haplotype mapping, transcriptomics, and sequence data substantially improved the mapping resolution of the diabetes QTLNidd/DBA. Future studies are necessary to understand the exact role of the different candidates in beta-cell function and their contribution in maintaining glycemic control.
KW - type 2 diabetes
KW - beta-cell loss
KW - insulin
KW - positional cloning
KW - transcriptomics
KW - haplotype
Y1 - 2020
U6 - https://doi.org/10.3389/fgene.2020.567191
SN - 1664-8021
VL - 11
PB - Frontiers Media
CY - Lausanne
ER -