👤 Swen Hesse

A single nucleotide polymorphism in the brain derived neurotrophic factor (BDNF)-encoding gene leads to diminished BDNF signaling resulting from Val66Met and has been linked to obesity. Previous imaging studies regarding the impact of BDNF Val66Met on the central serotonin system, which is involved in behavior, cognition and control of satiety, have not focused on body weight or food-intake related behavior. We revisited a cohort of thirty non-depressed individuals with obesity and 15 normal-weight controls. 29 obese and 13 controls underwent [ Show less

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 liver weight, liver triglycerides, and body weight using the obese BFMI sub-line BFMI861-S1. BFMI861-S1 mice are insulin resistant and store ectopic fat in the liver. In generation 10, 58 males and 65 females of the advanced intercross line (AIL) BFMI861-S1xB6N were phenotyped under a standard diet over 20 weeks. QTL analysis was performed after genotyping with the MiniMUGA Genotyping Array. Whole-genome sequencing and gene expression data of the parental lines was used for the prioritization of positional candidate genes. Three QTLs associated with liver weight, body weight, and subcutaneous adipose tissue (scAT) weight were identified. A highly significant QTL on chromosome (Chr) 1 (157-168 Mb) showed an association with liver weight. A QTL for body weight at 20 weeks was found on Chr 3 (34.1-40 Mb) overlapping with a QTL for scAT weight. In a multiple QTL mapping approach, an additional QTL affecting body weight at 16 weeks was identified on Chr 6 (9.5-26.1 Mb). Considering sequence variants and expression differences, Sec16b and Astn1 were prioritized as top positional candidate genes for the liver weight QTL on Chr 1; Met and Ica1 for the body weight QTL on Chr 6. Interestingly, all top candidate genes have previously been linked with metabolic traits. This study shows once more the power of an advanced intercross line for fine mapping. QTL mapping combined with a detailed prioritization approach allowed us to identify additional and plausible candidate genes linked to metabolic traits in the BFMI861-S1xB6N AIL. By reidentifying known candidate genes in a different crossing population the causal link with specific traits is underlined and additional evidence is given for further investigations. Show less

The liver is a major organ in whole body lipid metabolism and malfunctioning can lead to various diseases including dyslipidemia, fatty liver disease, and type 2 diabetes. Triglycerides and cholesteryl esters are packed in the liver as very low density lipoproteins (VLDLs). Generation of these lipoproteins is initiated in the endoplasmic reticulum and further maturation likely occurs in the Golgi. ADP-ribosylation factor-related protein 1 (ARFRP1) is a small trans-Golgi-associated guanosine triphosphatase (GTPase) that regulates protein sorting and is required for chylomicron lipidation and assembly in the intestine. Here we show that the hepatocyte-specific deletion of Arfrp1 (Arfrp1(liv-/-)) results in impaired VLDL lipidation leading to reduced plasma triglyceride levels in the fasted state as well as after inhibition of lipoprotein lipase activity by Triton WR-1339. In addition, the concentration of ApoC3 that comprises 40% of protein mass of secreted VLDLs is markedly reduced in the plasma of Arfrp1(liv-/-) mice but accumulates in the liver accompanied by elevated triglycerides. Fractionation of Arfrp1(liv-/-) liver homogenates reveals more ApoB48 and a lower concentration of triglycerides in the Golgi compartments than in the corresponding fractions from control livers. In conclusion, ARFRP1 and the Golgi apparatus play an important role in lipoprotein maturation in the liver by influencing lipidation and assembly of proteins to the lipid particles. Show less

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. Show less