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Targeted Disruption of the β3-Adrenergic Receptor Gene *

V. Susulic,R. Frederich,J. Lawitts,E. Tozzo,B. Kahn,M. Harper,J. Himms‐Hagen,J. Flier,B. Lowell

Published 1995 in Journal of Biological Chemistry

ABSTRACT

β3-Adrenergic receptors (β3-ARs) are expressed predominantly in white and brown adipose tissue, and β3-selective agonists are potential anti-obesity drugs. However, the role of β3-ARs in normal physiology is unknown. To address this issue, homologous recombination was used to generate mice that lack β3-ARs. This was accomplished by direct injection of a DNA-targeting construct into mouse zygotes. Twenty-three transgenic mice were generated, of which two had targeted disruption of the β3-AR gene. Mice that were homozygous for the disrupted allele had undetectable levels of intact β3-AR mRNA, as assessed by RNase protection assay and Northern blotting, and lacked functional β3-ARs, as demonstrated by complete loss of β3-agonist (CL 316,243)-induced stimulation of adenylate cyclase activity and lipolysis. β3-AR-deficient mice had modestly increased fat stores (females more than males), indicating that β3-ARs play a role in regulating energy balance. Importantly, β1 but not β2-AR mRNA levels up-regulated in white and brown adipose tissue of β3-AR-deficient mice (brown more than white), strongly implying that β3-ARs mediate physiologically relevant signaling under normal conditions and that “cross-talk” exists between β3-ARs and β1-AR gene expression. Finally, acute treatment of normal mice with CL 316,243 increased serum levels of free fatty acids (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 β3-AR-deficient mice, proving that the actions of CL are mediated exclusively by β3-ARs. β3-AR-deficient mice should be useful as a means to a better understanding of the physiology and pharmacology of β3-ARs.

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