Abstract

The effects of beta-3 adrenergic receptor (β₃-AR) agonists on gastrointestinal (GI) motility, as reported by stomach retention and intestinal transit of radiolabelled charcoal, were compared in wild-type (WT) mice and in transgenic mice lacking β₃-AR (β₃-AR[KO]) or having β₃-AR in white and brown adipose tissue only (β₃-AR[WAT+BAT]). After s.c. administration of 3 mg/kg of the selective, rodent specific β₃-AR agonists BRL 35135, CL 316,243 or ICI 198,157, WT mice exhibited a significant decrease in the extent of movement of radiotracer through the stomach and intestines, indicative of decreased GI motility. These compounds also caused an increase in plasma glycerol levels in the WT mice, suggesting that increased lipolysis in adipose tissue had been evoked. None of these compounds had an effect on GI motility or evoked lipolysis in the β₃-AR[KO] mice. Treatment of WT mice with SR 56811A, a β₃-AR agonist that exhibited a relatively lower affinity for rodent β₃-AR in vitro, did not affect GI motility or plasma glycerol levels in WT or β₃[KO] mice when administered s.c. at 3 mg/kg. Clonidine, an alpha-2 adrenergic receptor agonist, used as a positive control in these GI studies, caused a decrease in GI motility in both WT and β₃-AR[KO] mice. These results are consistent with a postulated role for β₃-AR in regulation of GI motility in the mouse. However, treatment of β₃-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 β₃-AR agonist may exert its effects on the GI tract indirectly, through an unknown signaling mechanism activated by agonism of β₃-AR in adipose tissue.