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  - 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  - THES
A1  - Hesse, Deike
T1  - Die Rolle des trans-Goli-Proteins ARFRP1 für den Glucose- und Lipidmetabolismus in der Leber und im Fettgewebe der Maus
Y1  - 2010
CY  - Potsdam
ER  -