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.
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 - 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 -
TY - GEN
A1 - Henkel, Janin
A1 - Coleman Mac Gregor of Inneregny, Charles Dominic
A1 - Schraplau, Anne
A1 - Jöhrens, Korinna
A1 - Weiss, Thomas Siegfried
A1 - Jonas, Wenke
A1 - Schürmann, Annette
A1 - Püschel, Gerhard Paul
T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 483
KW - suppress VLDL secretion
KW - mice lacking
KW - nonalcoholic steatohepatthis
KW - insulin-resistance
KW - rat hepatocytes
KW - kupffer cells
KW - E-2
KW - disease
KW - expression
KW - accumulation
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-420879
SN - 1866-8372
IS - 483
ER -
TY - JOUR
A1 - Henkel, Janin
A1 - Coleman Mac Gregor of Inneregny, Charles Dominic
A1 - Schraplau, Anne
A1 - Jöhrens, Korinna
A1 - Weiss, Thomas Siegfried
A1 - Jonas, Wenke
A1 - Schürmann, Annette
A1 - Püschel, Gerhard Paul
T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
JF - Scientific Reports
N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
KW - suppress VLDL secretion
KW - mice lacking
KW - nonalcoholic steatohepatthis
KW - insulin-resistance
KW - rat hepatocytes
KW - kupffer cells
KW - E-2
KW - disease
KW - expression
KW - accumulation
Y1 - 2018
U6 - https://doi.org/10.1038/s41598-018-34633-y
SN - 2045-2322
IS - 8
SP - 1
EP - 11
PB - Nature Research
CY - London
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 - Henkel, Janin
A1 - Coleman, Charles Dominic
A1 - Schraplau, Anne
A1 - Joehrens, Korinna
A1 - Weiss, Thomas Siegfried
A1 - Jonas, Wenke
A1 - Schürmann, Annette
A1 - Püschel, Gerhard Paul
T1 - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
JF - Scientific reports
N2 - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
Y1 - 2018
U6 - https://doi.org/10.1038/s41598-018-34633-y
SN - 2045-2322
VL - 8
PB - Nature Publ. Group
CY - London
ER -
TY - JOUR
A1 - Stadion, Mandy
A1 - Schürmann, Annette
T1 - Intermittent fasting
T1 - Intermittierendes Fasten
BT - What effects does it have in humans?
BT - Welche Effekte hat es beim Menschen?
JF - Psychotherapeut
N2 - A long-term positive energy balance leads to overweight and obesity. Adiposity is the main risk factor for cardiovascular diseases, type 2 diabetes and cancer and is often accompanied by depression. The increasing prevalence creates a major problem for the healthcare system. The conservative management of obesity strives for weight loss by reducing the daily caloric intake and increasing physical activity as well as an improvement in the quality of life supported by psychological interventions. For reducing body weight, intermittent fasting represents an alternative to continuous calorie restriction as it can be easily integrated into daily life. In this form of diet calorie intake is limited in time, i.e. on 2 days in the week or 6-10 h per day. Animal and human studies provide evidence that intermittent fasting over a longer time period is a suitable method to decrease body fat and to improve many metabolic parameters. Fasting alters metabolism and activates specific cellular pathways. These have not only cardioprotective effects but also neuroprotective and antidepressive effects. In this article the currently discussed mechanisms induced by intermittent fasting are highlighted and the essential observations from randomized controlled human trials are presented.
KW - Obesity
KW - Brain-derived neurotrophic factor
KW - Insulin sensitivity
KW - Metabolic flexibility
KW - Circadian rhythm
Y1 - 2020
U6 - https://doi.org/10.1007/s00278-020-00471-5
SN - 0935-6185
SN - 1432-2080
VL - 66
IS - 1
SP - 23
EP - 27
PB - Springer
CY - New York
ER -
TY - JOUR
A1 - Ouni, Meriem
A1 - Schürmann, Annette
T1 - Epigenetic contribution to obesity
JF - Mammalian genome
N2 - Obesity is a worldwide epidemic and contributes to global morbidity and mortality mediated via the development of nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), cardiovascular (CVD) and other diseases. It is a consequence of an elevated caloric intake, a sedentary lifestyle and a genetic as well as an epigenetic predisposition. This review summarizes changes in DNA methylation and microRNAs identified in blood cells and different tissues in obese human and rodent models. It includes information on epigenetic alterations which occur in response to fat-enriched diets, exercise and metabolic surgery and discusses the potential of interventions to reverse epigenetic modifications.
Y1 - 2020
U6 - https://doi.org/10.1007/s00335-020-09835-3
SN - 0938-8990
SN - 1432-1777
VL - 31
IS - 5-6
SP - 134
EP - 145
PB - Springer
CY - New York, NY ; Berlin ; Heidelberg [u.a.]
ER -
TY - JOUR
A1 - Stadion, Mandy
A1 - Schürmann, Annette
T1 - Intermittierendes Fasten
BT - was gibt es Neues aus der Wissenschaft?
BT - what’s new from science?
JF - Der Diabetologe
N2 - Obesity increases the risk of metabolic disorders and can lead to type 2 diabetes. Therefore, the treatment and prevention of obesity represent important medical challenges. Increased physical activity and a reduction in daily caloric intake of 25-30% are often recommended. Another possibility is intermittent fasting, by limiting dietary caloric content over certain times, i.e. one or more days a week or for more than 14 h a day. Animal and human studies provide evidence that intermittent fasting in obesity leads to a reduction in body fat mass as well as to improvements of metabolic parameters and insulin sensitivity. These positive effects are mediated not only by the decrease in body mass, but also by the activation of metabolic pathways and cellular processes that are specific for fasting conditions. In this article, we describe the current knowledge about the mechanisms induced by intermittent fasting and present results from randomized controlled human trials.
N2 - Übergewicht und Adipositas erhöhen die Risiken für Stoffwechselstörungen und können zu einem Typ-2-Diabetes führen. Deshalb stellen die Behandlung und Prävention von Fettleibigkeit eine große medizinische Herausforderung dar. Häufig werden eine erhöhte körperliche Aktivität und die Reduktion der täglichen Kalorienaufnahme um 25–30 % angeraten. Eine andere Möglichkeit bietet intermittierendes Fasten, also eine Kalorieneinschränkung über bestimmte Zeiten, d. h. an einem oder mehreren Tagen pro Woche oder über mehr als 14 h pro Tag. Tier- und Humanstudien lieferten Hinweise darauf, dass intermittierendes Fasten bei Adipositas zu einer Verringerung der Körperfettmasse sowie zu Verbesserungen der Stoffwechselparameter und der Insulinsensitivität führt. Diese positiven Effekte werden nicht nur allein durch die Abnahme der Körpermasse, sondern auch durch die Aktivierung von Stoffwechselwegen und zellulären Prozessen ausgelöst, die für Fastenbedingungen spezifisch sind. In diesem Artikel beschreiben wir die derzeit bekannten Mechanismen, die durch intermittierendes Fasten induziert werden, und stellen Ergebnisse aus randomisierten kontrollierten Studien am Menschen vor.
T2 - Intermittent fasting
KW - Glucose metabolism disorders
KW - Lipid metabolism
KW - Insulin sensitivity
KW - Energy metabolism
KW - Circadian rhythm
KW - Glukosestoffwechselstörungen
KW - Fettstoffwechsel
KW - Insulinsensitivität
KW - Energiestoffwechsel
KW - Zirkadianer Rhythmus
Y1 - 2020
U6 - https://doi.org/10.1007/s11428-020-00666-z
SN - 1860-9716
SN - 1860-9724
VL - 16
IS - 7
SP - 641
EP - 646
PB - Springer Medizin
CY - Berlin
ER -
TY - JOUR
A1 - Kanzleiter, Timo
A1 - Jaehnert, Markus
A1 - Schulze, Gunnar
A1 - Selbig, Joachim
A1 - Hallahan, Nicole
A1 - Schwenk, Robert Wolfgang
A1 - Schürmann, Annette
T1 - Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice
JF - American journal of physiology : Endocrinology and metabolism
N2 - The adaptive response of skeletal muscle to exercise training is tightly controlled and therefore requires transcriptional regulation. DNA methylation is an epigenetic mechanism known to modulate gene expression, but its contribution to exercise-induced adaptations in skeletal muscle is not well studied. Here, we describe a genome-wide analysis of DNA methylation in muscle of trained mice (n = 3). Compared with sedentary controls, 2,762 genes exhibited differentially methylated CpGs (P < 0.05, meth diff >5%, coverage > 10) in their putative promoter regions. Alignment with gene expression data (n = 6) revealed 200 genes with a negative correlation between methylation and expression changes in response to exercise training. The majority of these genes were related to muscle growth and differentiation, and a minor fraction involved in metabolic regulation. Among the candidates were genes that regulate the expression of myogenic regulatory factors (Plexin A2) as well as genes that participate in muscle hypertrophy (Igfbp4) and motor neuron innervation (Dok7). Interestingly, a transcription factor binding site enrichment study discovered significantly enriched occurrence of CpG methylation in the binding sites of the myogenic regulatory factors MyoD and myogenin. These findings suggest that DNA methylation is involved in the regulation of muscle adaptation to regular exercise training.
KW - DNA methylation
KW - regular exercise training
KW - muscle development
Y1 - 2015
U6 - https://doi.org/10.1152/ajpendo.00289.2014
SN - 0193-1849
SN - 1522-1555
VL - 308
IS - 10
SP - E912
EP - E920
PB - American Chemical Society
CY - Bethesda
ER -
TY - JOUR
A1 - Kluth, Oliver
A1 - Stadion, Mandy
A1 - Gottmann, Pascal
A1 - Aga-Barfknecht, Heja
A1 - Jähnert, Markus
A1 - Scherneck, Stephan
A1 - Vogel, Heike
A1 - Krus, Ulrika
A1 - Seelig, Anett
A1 - Ling, Charlotte
A1 - Gerdes, Jantje
A1 - Schürmann, Annette
T1 - Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans
JF - Cell reports
N2 - An insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreatic islets of diabetes-prone NZO mice as compared with diabetes-resistant B6-ob/ob mice. Among 327 differentially expressed mouse cilia genes, 81 human orthologs are also affected in islets of diabetic donors. Islets of nondiabetic mice and humans show a substantial overlap of upregulated cilia genes that are linked to cell-cycle progression. The shRNA-mediated suppression of KIF3A, essential for ciliogenesis, impairs division of MINE beta cells as well as in dispersed primary mouse and human islet cells, as shown by decreased BrdU incorporation. These findings demonstrate the substantial role of cilia-gene regulation on islet function and T2D risk.
Y1 - 2019
U6 - https://doi.org/10.1016/j.celrep.2019.02.056
SN - 2211-1247
VL - 26
IS - 11
SP - 3027
EP - 3036
PB - Cell Press
CY - Maryland Heights
ER -
TY - JOUR
A1 - Aga-Barfknecht, Heja
A1 - Soultoukis, George A.
A1 - Stadion, Mandy
A1 - Garcia-Carrizo, Francisco
A1 - Jähnert, Markus
A1 - Gottmann, Pascal
A1 - Vogel, Heike
A1 - Schulz, Tim Julius
A1 - Schürmann, Annette
T1 - Distinct adipogenic and fibrogenic differentiation capacities of mesenchymal stromal cells from pancreas and white adipose tissue
JF - International journal of molecular sciences
N2 - Pancreatic steatosis associates with beta-cell failure and may participate in the development of type-2-diabetes. Our previous studies have shown that diabetes-susceptible mice accumulate more adipocytes in the pancreas than diabetes-resistant mice. In addition, we have demonstrated that the co-culture of pancreatic islets and adipocytes affect insulin secretion. The aim of this current study was to elucidate if and to what extent pancreas-resident mesenchymal stromal cells (MSCs) with adipogenic progenitor potential differ from the corresponding stromal-type cells of the inguinal white adipose tissue (iWAT). miRNA (miRNome) and mRNA expression (transcriptome) analyses of MSCs isolated by flow cytometry of both tissues revealed 121 differentially expressed miRNAs and 1227 differentially expressed genes (DEGs). Target prediction analysis estimated 510 DEGs to be regulated by 58 differentially expressed miRNAs. Pathway analyses of DEGs and miRNA target genes showed unique transcriptional and miRNA signatures in pancreas (pMSCs) and iWAT MSCs (iwatMSCs), for instance fibrogenic and adipogenic differentiation, respectively. Accordingly, iwatMSCs revealed a higher adipogenic lineage commitment, whereas pMSCs showed an elevated fibrogenesis. As a low degree of adipogenesis was also observed in pMSCs of diabetes-susceptible mice, we conclude that the development of pancreatic steatosis has to be induced by other factors not related to cell-autonomous transcriptomic changes and miRNA-based signals.
KW - MSCs
KW - fatty pancreas
KW - WAT
KW - lineage commitment
KW - transcriptomics
KW - miRNAs
Y1 - 2022
U6 - https://doi.org/10.3390/ijms23042108
SN - 1422-0067
VL - 23
IS - 4
PB - Molecular Diversity Preservation International
CY - Basel
ER -
TY - GEN
A1 - Volckmar, Anna-Lena
A1 - Han, Chung-Ting
A1 - Pütter, Carolin
A1 - Haas, Stefan
A1 - Vogel, Carla I. G.
A1 - Knoll, Nadja
A1 - Struve, Christoph
A1 - Göbel, Maria
A1 - Haas, Katharina
A1 - Herrfurth, Nikolas
A1 - Jarick, Ivonne
A1 - Grallert, Harald
A1 - Schürmann, Annette
A1 - Al- Hasani, Hadi
A1 - Hebebrand, Johannes
A1 - Sauer, Sascha
A1 - Hinney, Anke
T1 - Analysis of genes involved in body weight regulation by targeted re-sequencing
T2 - PLoS ONE
N2 - Introduction
Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing.
Methods
We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) >= 99th percentile and 176 lean adults (BMI <= 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults.
Results and Conclusion
We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (p(TDT) = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 423
KW - melanocortin-4 receptor gene
KW - stimulated glucose-uptake
KW - life-style intervention
KW - onset extreme obesity
KW - genome-wide analysis
KW - mass index
KW - FTO gene
KW - fat mass
KW - overweight children
KW - diabetes-melllitus
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-410289
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 -
TY - JOUR
A1 - Jonas, Wenke
A1 - Kluth, Oliver
A1 - Helms, Anett
A1 - Voss, Sarah
A1 - Jahnert, Markus
A1 - Gottmann, Pascal
A1 - Speckmann, Thilo
A1 - Knebel, Birgit
A1 - Chadt, Alexandra
A1 - Al-Hasani, Hadi
A1 - Schürmann, Annette
A1 - Vogel, Heike
T1 - Identification of novel genes involved in hyperglycemia in mice
JF - International journal of molecular sciences
N2 - Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options.
Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls.
Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis.
Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MINE cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting beta-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function.
KW - beta-cell
KW - diabetes
KW - proliferation
KW - apoptosis
KW - QTL
Y1 - 2022
U6 - https://doi.org/10.3390/ijms23063205
SN - 1661-6596
SN - 1422-0067
VL - 23
IS - 6
PB - MDPI
CY - Basel
ER -
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 - Gohlke, Sabrina
A1 - Zagoriy, Vyacheslav
A1 - Inostroza, Alvaro Cuadros
A1 - Meret, Michael
A1 - Mancini, Carola
A1 - Japtok, Lukasz
A1 - Schumacher, Fabian
A1 - Kuhlow, Doreen
A1 - Graja, Antonia
A1 - Stephanowitz, Heike
A1 - Jähnert, Markus
A1 - Krause, Eberhard
A1 - Wernitz, Andreas
A1 - Petzke, Klaus-Juergen
A1 - Schürmann, Annette
A1 - Kleuser, Burkhard
A1 - Schulz, Tim Julius
T1 - Identification of functional lipid metabolism biomarkers of brown adipose tissue aging
JF - Molecular Metabolism
N2 - Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism.
Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined.
Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation.
Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.
KW - Brown adipose tissue
KW - Aging
KW - Ceramides
KW - Sphingolipids
KW - Dolichol lipids
Y1 - 2019
U6 - https://doi.org/10.1016/j.molmet.2019.03.011
SN - 2212-8778
VL - 24
SP - 1
EP - 17
PB - Elsevier
CY - Amsterdam
ER -
TY - JOUR
A1 - Laeger, Thomas
A1 - Castano-Martinez, Teresa
A1 - Werno, Martin W.
A1 - Japtok, Lukasz
A1 - Baumeier, Christian
A1 - Jonas, Wenke
A1 - Kleuser, Burkhard
A1 - Schürmann, Annette
T1 - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes
JF - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2 - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.
KW - Energy expenditure
KW - FGF21
KW - Hyperglycaemia
KW - Insulin resistance
KW - NZO
KW - Obesity
KW - Protein restriction
Y1 - 2018
U6 - https://doi.org/10.1007/s00125-018-4595-1
SN - 0012-186X
SN - 1432-0428
VL - 61
IS - 6
SP - 1459
EP - 1469
PB - Springer
CY - New York
ER -
TY - JOUR
A1 - McNulty, Margaret A.
A1 - Goupil, Brad A.
A1 - Albarado, Diana C.
A1 - Castaño-Martinez, Teresa
A1 - Ambrosi, Thomas H.
A1 - Puh, Spela
A1 - Schulz, Tim Julius
A1 - Schürmann, Annette
A1 - Morrison, Christopher D.
A1 - Laeger, Thomas
T1 - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
JF - Bone Reports
N2 - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.
Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.
Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.
Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
KW - dietary restriction
KW - protein restriction
KW - FGF21
KW - GCN2
KW - microcomputed tomography
Y1 - 2020
U6 - https://doi.org/10.1016/j.bonr.2019.100241
SN - 2352-1872
VL - 12
SP - 1
EP - 10
PB - Elsevier
CY - Amsterdam
ER -
TY - GEN
A1 - McNulty, Margaret A.
A1 - Goupil, Brad A.
A1 - Albarado, Diana C.
A1 - Castaño-Martinez, Teresa
A1 - Ambrosi, Thomas H.
A1 - Puh, Spela
A1 - Schulz, Tim Julius
A1 - Schürmann, Annette
A1 - Morrison, Christopher D.
A1 - Laeger, Thomas
T1 - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2 - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.
Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.
Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.
Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1406
KW - dietary restriction
KW - protein restriction
KW - FGF21
KW - GCN2
KW - microcomputed tomography
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516297
SN - 1866-8372
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 Max
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 - 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 - Delpero, Manuel
A1 - Arends, Danny
A1 - Sprechert, Maximilian
A1 - Krause, Florian
A1 - Kluth, Oliver
A1 - Schürmann, Annette
A1 - Brockmann, Gudrun A.
A1 - Hesse, Deike
T1 - Identification of four novel QTL linked to the metabolic syndrome in the Berlin Fat Mouse
JF - International journal of obesity / North American Association for the Study of Obesity
N2 - Background The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and the metabolic syndrome. This study aimed to identify genetic variants associated with impaired glucose metabolism using the obese lines BFMI861-S1 and BFMI861-S2, which are genetically closely related, but differ in several traits. BFMI861-S1 is insulin resistant and stores ectopic fat in the liver, whereas BFMI861-S2 is insulin sensitive. Methods In generation 10, 397 males of an advanced intercross line (AIL) BFMI861-S1 x BFMI861-S2 were challenged with a high-fat, high-carbohydrate diet and phenotyped over 25 weeks. QTL-analysis was performed after selective genotyping of 200 mice using the GigaMUGA Genotyping Array. Additional 197 males were genotyped for 7 top SNPs in QTL regions. For the prioritization of positional candidate genes whole genome sequencing and gene expression data of the parental lines were used. Results Overlapping QTL for gonadal adipose tissue weight and blood glucose concentration were detected on chromosome (Chr) 3 (95.8-100.1 Mb), and for gonadal adipose tissue weight, liver weight, and blood glucose concentration on Chr 17 (9.5-26.1 Mb). Causal modeling suggested for Chr 3-QTL direct effects on adipose tissue weight, but indirect effects on blood glucose concentration. Direct effects on adipose tissue weight, liver weight, and blood glucose concentration were suggested for Chr 17-QTL. Prioritized positional candidate genes for the identified QTL were Notch2 and Fmo5 (Chr 3) and Plg and Acat2 (Chr 17). Two additional QTL were detected for gonadal adipose tissue weight on Chr 15 (67.9-74.6 Mb) and for body weight on Chr 16 (3.9-21.4 Mb). Conclusions QTL mapping together with a detailed prioritization approach allowed us to identify candidate genes associated with traits of the metabolic syndrome. In addition, we provided evidence for direct and indirect genetic effects on blood glucose concentration in the insulin-resistant mouse line BFMI861-S1.
Y1 - 2022
U6 - https://doi.org/10.1038/s41366-021-00991-3
SN - 0307-0565
SN - 1476-5497
VL - 46
IS - 2
SP - 307
EP - 315
PB - Nature Publ. Group
CY - Avenel, NJ
ER -
TY - GEN
A1 - Wardelmann, Kristina
A1 - Rath, Michaela
A1 - Castro, José Pedro
A1 - Blümel, Sabine
A1 - Schell, Mareike
A1 - Hauffe, Robert
A1 - Schumacher, Fabian
A1 - Flore, Tanina
A1 - Ritter, Katrin
A1 - Wernitz, Andreas
A1 - Hosoi, Toru
A1 - Ozawa, Koichiro
A1 - Kleuser, Burkhard
A1 - Weiß, Jürgen
A1 - Schürmann, Annette
A1 - Kleinridders, André
T1 - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2 - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1165
KW - brain insulin signaling
KW - mitochondria
KW - oxidative stress
KW - fatty acid metabolism
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-522985
SN - 1866-8372
IS - 5
ER -
TY - GEN
A1 - Hauffe, Robert
A1 - Rath, Michaela
A1 - Schell, Mareike
A1 - Ritter, Katrin
A1 - Kappert, Kai
A1 - Deubel, Stefanie
A1 - Ott, Christiane
A1 - Jähnert, Markus
A1 - Jonas, Wenke
A1 - Schürmann, Annette
A1 - Kleinridders, André
T1 - HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue
T2 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2 - Objective
Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance.
Methods
Control and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis.
Results
Male Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance.
Conclusions
We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.
T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1235
KW - Mitochondria
KW - Stress response
KW - Obesity
KW - Glucose homeostasis
KW - Insulin resistance
KW - Adipose tissue
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-548002
SN - 1866-8372
SP - 1
EP - 14
PB - Universitätsverlag Potsdam
CY - Potsdam
ER -
TY - JOUR
A1 - Wardelmann, Kristina
A1 - Rath, Michaela
A1 - Castro, José Pedro
A1 - Blümel, Sabine
A1 - Schell, Mareike
A1 - Hauffe, Robert
A1 - Schumacher, Fabian
A1 - Flore, Tanina
A1 - Ritter, Katrin
A1 - Wernitz, Andreas
A1 - Hosoi, Toru
A1 - Ozawa, Koichiro
A1 - Kleuser, Burkhard
A1 - Weiß, Jürgen
A1 - Schürmann, Annette
A1 - Kleinridders, André
T1 - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
JF - Antioxidants
N2 - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
KW - brain insulin signaling
KW - mitochondria
KW - oxidative stress
KW - fatty acid metabolism
Y1 - 2021
U6 - https://doi.org/10.3390/antiox10050711
SN - 2076-3921
VL - 10
IS - 5
PB - MDPI
CY - Basel
ER -
TY - JOUR
A1 - Hauffe, Robert
A1 - Rath, Michaela
A1 - Schell, Mareike
A1 - Ritter, Katrin
A1 - Kappert, Kai
A1 - Deubel, Stefanie
A1 - Ott, Christiane
A1 - Jähnert, Markus
A1 - Jonas, Wenke
A1 - Schürmann, Annette
A1 - Kleinridders, André
T1 - HSP60 reduction protects against diet-induced obesity by modulating energy metabolism in adipose tissue
JF - Molecular Metabolism
N2 - Objective
Insulin regulates mitochondrial function, thereby propagating an efficient metabolism. Conversely, diabetes and insulin resistance are linked to mitochondrial dysfunction with a decreased expression of the mitochondrial chaperone HSP60. The aim of this investigation was to determine the effect of a reduced HSP60 expression on the development of obesity and insulin resistance.
Methods
Control and heterozygous whole-body HSP60 knockout (Hsp60+/−) mice were fed a high-fat diet (HFD, 60% calories from fat) for 16 weeks and subjected to extensive metabolic phenotyping. To understand the effect of HSP60 on white adipose tissue, microarray analysis of gonadal WAT was performed, ex vivo experiments were performed, and a lentiviral knockdown of HSP60 in 3T3-L1 cells was conducted to gain detailed insights into the effect of reduced HSP60 levels on adipocyte homeostasis.
Results
Male Hsp60+/− mice exhibited lower body weight with lower fat mass. These mice exhibited improved insulin sensitivity compared to control, as assessed by Matsuda Index and HOMA-IR. Accordingly, insulin levels were significantly reduced in Hsp60+/− mice in a glucose tolerance test. However, Hsp60+/− mice exhibited an altered adipose tissue metabolism with elevated insulin-independent glucose uptake, adipocyte hyperplasia in the presence of mitochondrial dysfunction, altered autophagy, and local insulin resistance.
Conclusions
We discovered that the reduction of HSP60 in mice predominantly affects adipose tissue homeostasis, leading to beneficial alterations in body weight, body composition, and adipocyte morphology, albeit exhibiting local insulin resistance.
KW - Mitochondria
KW - Stress response
KW - Obesity
KW - Glucose homeostasis
KW - Insulin resistance
KW - Adipose tissue
Y1 - 2021
U6 - https://doi.org/10.1016/j.molmet.2021.101276
SN - 2212-8778
VL - 53
SP - 1
EP - 14
PB - Elsevier
CY - Amsterdam, Niederlande
ER -
TY - JOUR
A1 - Wilhelmi, Ilka
A1 - Neumann, Alexander
A1 - Jähnert, Markus
A1 - Ouni, Meriem
A1 - Schürmann, Annette
T1 - Enriched alternative splicing in islets of diabetes-susceptible mice
JF - International journal of molecular sciences
N2 - Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.
KW - alternative splicing
KW - epigenetic
KW - MicroRNA
KW - RNAseq
KW - diabetes
KW - beta-cell
KW - failure
Y1 - 2021
U6 - https://doi.org/10.3390/ijms22168597
SN - 1422-0067
VL - 22
IS - 16
PB - Molecular Diversity Preservation International
CY - Basel
ER -
TY - JOUR
A1 - Jonas, Wenke
A1 - Schwerbel, Kristin
A1 - Zellner, Lisa
A1 - Jähnert, Markus
A1 - Gottmann, Pascal
A1 - Schürmann, Annette
T1 - Alterations of lipid profile in livers with impaired lipophagy
JF - International journal of molecular sciences
N2 - Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver.
Various mechanisms such as an increased uptake in fatty acids or de novo synthesis contribute to the development of steatosis and progression to more severe stages. Furthermore, it has been shown that impaired lipophagy, the degradation of lipids by autophagic processes, contributes to NAFLD.
Through an unbiased lipidome analysis of mouse livers in a genetic model of impaired lipophagy, we aimed to determine the resulting alterations in the lipidome. Observed changes overlap with those of the human disease.
Overall, the entire lipid content and in particular the triacylglycerol concentration increased under conditions of impaired lipophagy.
In addition, we detected a reduction in long-chain polyunsaturated fatty acids (PUFAs) and an increased ratio of n-6 PUFAs to n-3 PUFAs, which was due to the depletion of n-3 PUFAs.
Although the abundance of major phospholipid classes was reduced, the ratio of phosphatidylcholines to phosphatidylethanolamines was not affected. In conclusion, this study demonstrates that impaired lipophagy contributes to the pathology of NAFLD and is associated with an altered lipid profile.
However, the lipid pattern does not appear to be specific for lipophagic alterations, as it resembles mainly that described in relation to fatty liver disease.
KW - non-alcoholic fatty liver disease
KW - lipophagy
KW - lipidomics
KW - fatty acid profile
KW - long-chain polyunsaturated fatty acids
Y1 - 2022
U6 - https://doi.org/10.3390/ijms231911863
SN - 1422-0067
VL - 23
IS - 19
PB - MDPI
CY - Basel
ER -