Targeted disruption of the XXXX gene.

@entity21166 @entity28 @entity19 @entity21167 @entity11951 @entity11952 @entity1718 @entity21464
@entity21464 -Adrenergic receptors ( @entity21464 -ARs) are expressed predominantly in white and brown adipose tissue, and @entity21464 -selective agonists are potential anti- @entity28 drugs. However, the role of @entity21464 -ARs in normal physiology is unknown. To address this issue, homologous recombination was used to generate @entity19 that lack @entity21464 -ARs. This was accomplished by direct injection of a DNA-targeting construct into @entity19 zygotes. Twenty-three @entity19 were generated, of which two had targeted disruption of the @entity21166 gene. @entity19 that were homozygous for the disrupted allele had undetectable levels of intact @entity21166 mRNA, as assessed by RNase protection assay and Northern blotting, and lacked functional @entity21464 -ARs, as demonstrated by complete loss of @entity21464 -agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis. @entity21166 -deficient @entity19 had modestly increased fat stores (females more than males), indicating that @entity21464 -ARs play a role in regulating energy balance. Importantly, @entity11952 but not @entity21167 mRNA levels up-regulated in white and brown adipose tissue of @entity21166 -deficient @entity19 (brown more than white), strongly implying that @entity21464 -ARs mediate physiologically relevant signaling under normal conditions and that "cross-talk" exists between @entity21464 -ARs and @entity11951 gene expression. Finally, acute treatment of normal @entity19 with CL 316,243 increased serum levels of free @entity1718 (FFAs) (3.2-fold) and insulin (140-fold), increased energy expenditure (2-fold), and reduced food intake (by 45%). These effects were completely absent in @entity21166 -deficient @entity19 , proving that the actions of CL are mediated exclusively by @entity21464 -ARs. @entity21166 -deficient @entity19 should be useful as a means to a better understanding of the physiology and pharmacology of @entity21464 -ARs.
