cross species association examination of ucn3 and crhr2 as potential pharmacological targets for antiobesity drugs跨物种协会考试ucn3和crhr2典型药物的药理作用靶点药物.pdfVIP

Cross Species Association Examination of UCN3 and CRHR2 as Potential Pharmacological Targets for Antiobesity Drugs Zhihua Jiang*, Jennifer J. Michal, Galen A. Williams, Tyler F. Daniels, Tanja Kunej Department of Animal Sciences, Washington State University, Pullman, Washington, United States of America Background. Obesity now constitutes a leading global public health problem. Studies have shown that insulin resistance affiliated with obesity is associated with intramyocellular lipid (IMCL) accumulation. Therefore, identification of genes associated with the phenotype would provide a clear target for pharmaceutical intervention and care for the condition. We hypothesized that urocortin 3 (UCN3) and corticotropin-releasing hormone receptor 2 (CRHR2) are associated with IMCL and subcutaneous fat depth (SFD), because the corticotropin-releasing hormone family of peptides are capable of strong anorectic and thermogenic effects. Methodology/Principal Findings. We annotated both bovine UCN3 and CRHR2 genes and identified 12 genetic mutations in the former gene and 5 genetic markers in the promoter region of the latter gene. Genotyping of these 17 markers on Wagyu 6Limousin F2 progeny revealed significant associations between promoter polymorphisms and SFD (P = 0.020320.0685) and between missense mutations of exon 2 and IMCL (P = 0.0055 20.0369) in the bovine UCN3 gene. The SFD associated promoter SNPs caused a gain/loss of 12 potential transcription regulatory binding sites, while the IMCL associated coding SNPs affected the secondary structure of UCN3 mRNA. However, none of five polymorphisms in CRHR2 gene clearly co-segregated with either trait in the population (P.0.6000). Conclusions/Significance. Because UCN3 is located on human chromosome 10p15.1 where quantit