SR141716 (Rimonabant) has been shown to significantly inhibit food intake and reduce body weight in rodents and humans by antagonising CB1 receptors. The gut hormones peptide YY336 (PYY336) and oxyntomodulin (OXM), released from L-cells in the small intestine inhibit food intake in both rodents and humans and this effect is thought to be mediated via the hypothalamus.
To determine the effects of co-administration of SR141716 with either PYY336 or OXM in mice on food intake.
Mice (n=10 per group) fasted for 16 hours were given two intraperitoneal (i.p.) injections as described below:
Study 1: vehicle-saline, SR141716 (0.3 mg/kg)-saline, vehicle-PYY336 (50 μg/kg) or SR141716-PYY336.
Study 2: vehicle-saline, SR141716 (0.3 mg/kg)-saline, vehicle-OXM (1400 nmol/kg) or SR141716-OXM. Food intake was measured following injections.
Co-administration of SR141716-PYY336 resulted in a greater reduction in food intake when compared to administration of SR141716 or PYY336 alone [Food intake 01 hr (g): vehicle-saline 0.97±0.04, SR141716-saline 0.87±0.05, vehicle-PYY336 0.75±0.07, SR141716-PYY336 0.52±0.06 (P<0.01 SR141716-PYY vs. SR141716-saline; P<0.01 SR141716-PYY vs. vehicle-PYY336)]. Co-administration of SR141716 and OXM resulted in greater reduction in food intake when compared to administration of SR141716 or OXM alone [Food intake 01 hr (g): vehicle-saline 0.95±0.04, SR141716-saline 0.71±0.08, vehicle-OXM 0.68±0.06, SR141716-OXM 0.38±0.11 (P<0.01 SR141716-OXM vs. SR141716-saline; P<0.01 SR141716-OXM vs. vehicle-OXM)].
Our data shows that SR141716 in combination with PYY336 or OXM reduces food intake additively in mice. In addition it is possible that combination therapy with SR141716 and PYY336 or OXM may provide an effective therapy for obesity.
06 - 07 Nov 2006
Society for Endocrinology