Cross Species Association Examination of UCN3 and CRHR2 as Potential Pharmacological Targets for Antiobesity Drugs

Department of Animal Sciences, Washington State University, Pullman, Washington, United States of America.
PLoS ONE (Impact Factor: 3.23). 12/2006; 1(1):e80. DOI: 10.1371/journal.pone.0000080
Source: PubMed


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.
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 times Limousin F(2) progeny revealed significant associations between promoter polymorphisms and SFD (P = 0.0203-0.0685) and between missense mutations of exon 2 and IMCL (P = 0.0055-0.0369) 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).
Because UCN3 is located on human chromosome 10p15.1 where quantitative trait loci for obesity have been reported, our cross species study provides further evidence that it could be proposed as a potential target for developing antiobesity drugs. None of the markers in CRHR2 was associated with obesity-type traits in cattle, which is consistent with findings in human. Therefore, CRHR2 does not lend itself to the development of antiobesity drugs.

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    • "Finally, CRHR2, CHRNE, SUSP1 and TCF12 seem to exclusively influence the amount of FA in muscle. Concerning CRHR2, although Jiang et al. (2006) did not find Table 3 Gene symbol and name, main biological functions, previously described trait associations and references of 16 candidate genes associated with different lipid traits. "
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    • "Finally, CRHR2, CHRNE, SUSP1 and TCF12 seem to exclusively influence the amount of FA in muscle. Concerning CRHR2, although Jiang et al. (2006) did not find Table 3 Gene symbol and name, main biological functions, previously described trait associations and references of 16 candidate genes associated with different lipid traits. "
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    • "Therefore, the same orthologous genes may have conserved functions in biological or biochemical pathways, and thus explain the same or similar variations of the concordant QTL among different species [9]. Comparative approach may reveal novel candidate genes and functional insights into obesity in human [10]. In a previous study, we collected over 2,000 reports on genes/markers affecting fat phenotypes in several species [5], assigned them to the human orthologous regions and subsequently used the markers for identification of genetic networks associated with various fat and fat-related phenotypes in a Wagyu x Limousin cattle population [11]. "
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