BETA-3 ADRENERGIC-RECEPTOR AGONISTS CAUSE AN INCREASE IN GASTROINTESTINAL TRANSIT-TIME IN WILD-TYPE MICE, BUT NOT IN MICE LACKING THE BETA-3 ADRENERGIC-RECEPTOR

The effects of beta-3 adrenergic receptor (beta(3)-AR) agonists on gas trointestinal (GI) motility, as reported by stomach retention and inte stinal transit of radiolabelled charcoal, were compared in wildtype (W T) mice and in transgenic mice lacking beta(3)-AR (beta(3)-AR[KO]) or having beta(3)-AR in white and brown adipose tissue only (beta(3)-AR[W AT+BAT]). After s.c. administration of 3 mg/kg of the selective, roden t specific beta(3)-AR agonists BRL 35135, CL 316,243 or ICI 198,157, W T mice exhibited a significant decrease in the extent of movement of r adiotracer through the stomach and intestines, indicative of decreased GI motility. These compounds also caused an increase in plasma glycer ol levels in the WT mice, suggesting that increased lipolysis in adipo se tissue had been evoked. None of these compounds had an effect on GI motility or evoked lipolysis in the beta(3)-AR[KO] mice. Treatment of WT mice with SR 56811A, a beta(3)-AR agonist that exhibited a relativ ely lower affinity for rodent beta(3)-AR in vitro, did not affect GI m otility or plasma glycerol levels in WT or beta(3)[KO] mice when admin istered s.c. at 3 mg/kg. Clonidine, an alpha-2 adrenergic receptor ago nist, used as a positive control in these GI studies, caused a decreas e in GI motility in both WT and beta(3)-AR[KO] mice, These results are consistent with a postulated role for beta(3)-AR in regulation of GI motility in the mouse. However, treatment of beta(3)-AR[WAT+BAT] mice with 3 mg/kg BRL 35135 resulted in elevated plasma glycerol levels, as well as increased stomach retention and decreased intestinal transit of radiotracer, These results suggest that this beta(3)-AR agonist may exert its effects on the GI tract indirectly, through an unknown sign aling mechanism activated by agonism of beta(3)-AR in adipose tissue.