Does repeated administration of baclofen in free feeding rats reduce body weight by stimulating brown fat metabolism through activation of the sympathetic nervous system?

Abstract

The results of previous research have suggested that chronic administration of the GABAB receptor agonist baclofen can lead to weight loss in rodents by potentially activating brown adipose tissue (BAT) to increase metabolism rate. Studies in anaesthetised rats have shown that baclofen injected directly into the ventromedial nucleus of the hypothalamus (VMH) stimulates BAT to increase thermogenesis. This effect was attenuated by pretreatment with the beta-adrenoceptor antagonist propranolol, suggesting that baclofen microinjected into the VMH stimulate the sympathetic outflow to BAT, consequently increasing metabolic rate. The present study was designed to test this hypothesis by investigating whether pretreatment with propranolol would attenuate the weight loss induced by repeated daily administration of baclofen in free feeding rats. In the first experiment, male Wistar rats were injected intraperitoneal (ip) once daily for 24 days with either saline followed by saline, saline followed by baclofen (4 mg / kg), propranolol (10 or 20 mg / kg) followed by saline, or propranolol (10 mg / kg) followed by baclofen (4 mg / kg), with 5 minutes separating each injection. Body weight was measured each day 24 h after drug administration. Baclofen treatment resulted in significant reductions in daily body weight compared to the saline group. Propranolol alone had no significant effect on body weight. Importantly, pretreatment with propranolol did not attenuate the weight loss induced by baclofen. A similar experimental protocol as described above was used in a second experiment except that the rats were pretreated with a 20 mg / kg dose of propranolol and body weight was measured for 6 days. The high dose of propranolol significantly decreased body weight compared with control data and potentiated the baclofen-induced reduction in body weight. These results suggest that the effects of baclofen of body weight in free feeding rats may not be dependant on the the activation of BAT through stimulation of the sympathetic nervous system (SNS). Further research is therefore necessary to understand how baclofen influences metabolism and weight loss.