Cross species association examination of UCN3 and CRHR2 as potential pharmacological targets for antiobesity drugs.
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.


RESULTS
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).


CONCLUSIONS
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.
Jiang
Zhihua
Z
Department of Animal Sciences, Washington State University, Pullman, Washington, United States of America. jiangz@wsu.edu
Michal
Jennifer J
JJ
Williams
Galen A
GA
Daniels
Tyler F
TF
Kunej
Tanja
T
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001483:Base Sequence; D002417:Cattle; D003346:Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009690:Nucleic Acid Conformation; D009765:Obesity / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000187:drug effects* / Q000235:genetics*; D050151:Subcutaneous Fat / Q000033:anatomy & histology; D054832:Urocortins / Q000187:drug effects* / Q000235:genetics*
D019440:Anti-Obesity Agents; C101531:CRF receptor type 2; D017931:DNA Primers; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; C426704:UCN3 protein, human; D054832:Urocortins; D003346:Corticotropin-Releasing Hormone