14 research outputs found
Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity
Estrogen-dependent gallbladder carcinogenesis in LXRβ−/− female mice
Gallbladder cancer is a highly aggressive disease with poor prognosis that is two to six times more frequent in women than men. The development of gallbladder cancer occurs over a long time (more than 15 y) and evolves from chronic inflammation to dysplasia/metaplasia, carcinoma in situ, and invasive carcinoma. In the present study we found that, in female mice in which the oxysterol receptor liver X receptor–β (LXRβ) has been inactivated, preneoplastic lesions of the gallbladder developed and evolved to cancer in old animals. LXRβ is a nuclear receptor involved in the control of lipid homeostasis, glucose metabolism, inflammation, proliferation, and CNS development. LXRβ−/− female gallbladders were severely inflamed, with regions of dysplasia and high cell density, hyperchromasia, metaplasia, and adenomas. No abnormalities were evident in male mice, nor in LXRα−/− or LXRα−/−β−/− animals of either sex. Interestingly, the elimination of estrogens with ovariectomy prevented development of preneoplastic lesions in LXRβ−/− mice. The etiopathological mechanism seems to involve TGF-β signaling, as the precancerous lesions were characterized by strong nuclear reactivity of phospho-SMAD-2 and SMAD-4 and loss of E-cadherin expression. Upon ovariectomy, E-cadherin was reexpressed on the cell membranes and immunoreactivity of pSMAD-2 in the nuclei was reduced. These findings suggest that LXRβ in a complex interplay with estrogens and TGF-β could play a crucial role in the malignant transformation of the gallbladder epithelium
The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams
Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.Swedish Medical Research Council
2014-2775
Jane and Dan Ohlsson Foundation
Wilhelm and Martina Lundgren's Science Fund
Hjalmar Svensson Foundation
Adlerbert Research Foundation
Novo Nordisk Foundation
NNF16OC0020744
Strategic Research Programme (SRP) in Diabetes at Karolinska Institutet
Swedish federal government under LUA/ALF
ALFGBG-429501
FONDECYT
11130250
National Commission for Scientific and Technological Research (CONICYT, Chile)
Stockholm County Council
Karolinska Institute
Concurrent Activation of Liver X Receptor and Peroxisome Proliferator-Activated Receptor Alpha Exacerbates Hepatic Steatosis in High Fat Diet-Induced Obese Mice
Regulation of Insulin Resistance and Adiponectin Signaling in Adipose Tissue by Liver X Receptor Activation Highlights a Cross-Talk with PPARγ
Transcriptional regulatory network analysis of the over-expressed genes in adipose tissue
Adipose tissue plays important roles in whole body energy homeostasis and is now known to be a very important and active endocrine organ. The transcriptional regulatory network of adipose tissue metabolism is complex and much yet to be known. To identify transcriptional profile in adipose tissue, expressed sequence tag (EST) analysis using Digital Differential Display (DDD) was employed. The results of EST analysis were re-evaluated by microarray data using COXPRESdb (an available expression data repository). To uncover transcriptional regulatory mechanisms which play key roles in the adipose tissue metabolism, transcriptional regulatory network analysis was applied, using the promoter analysis and interaction network toolset. Sixty-five transcripts were found to be more frequent in adipose tissue in comparison to the other tissues. COXPRESdb result showed that 62 % of the identified over-expressed genes in adipose tissue by DDD had expression level greater than 1 (in base 2 logarithm). Based on coincidence of regulatory sites, candidate TFs were identified including TFs that previously known to be involved in adipose tissue metabolism (SP1, KROX, STAT1, LRF, VDR, LXR, SRF and HIF1) and TFs, such as CKROX, ZF5, ETF, AP-2, AP-2alpha, PAX-5, SPZ1, RBPJ and CACD, that had not been recognized previously. This work yielded several TF candidates activating in adipose tissue metabolism. These findings open a new avenue for future research on promoter occupancy and TF perturbation. © 2013 The Genetics Society of Korea.Mohammad Reza Bakhtiarizadeh, Mohammad Moradi-Shahrbabak, Esmaeil Ebrahimi