The role of the β3-adrenergic receptor in lipolysis, thermogenesis, and glucose metabolism has generated persuasive therapeutic possibilities in obesity and diabetes. However, the β3-adrenergic based drugs have not lived up to the forecasted therapeutic potential due to off-target effects, poor efficacy, and oral bioavailability. Hence, although the role of the β3-adrenergic receptor has been demonstrated, further research is required to establish a safer and more potent β3-adrenergic targeted drug. Our project aims to map and understand the connection between the β3-adrenergic receptor and the melanocortin system. This will provide a better understanding of the β3-adrenergic-melanocortin pathway and potentially establish a central-based therapeutic target for obesity and diabetes.
4-week-old C47Bl/6J male mice were placed on either chow or high-fat diet for 20 weeks. Mice were housed and ICV treated with a β3 adrenergic agonist CL316,243 (0.30nmol/g of body weight or 10nmol) or vehicle (aCSF). Before and after the treatment, daily body weight and food intake of mice were recorded. An experimental glucose tolerance test was also performed. Blood glucose concentration was sampled 60 mins prior to treatment (-60 mins) and every 15 minutes from 0 min to 120 min. Mice were injected with glucose IP (2ug/g/bw) after 0 min of blood sampling. BAT, WAT and hypothalamic sections were collected from mice and RT-PCR was performed for the β3 adrenergic receptor. Whole brains were perfused and collected to perform immunofluorescence staining to identify the c-fos activity of POMC neurons. Images were later analyzed using ImageJ.
CL316,243 ICV administration significantly lowers plasma glucose in both lean and DIO mice. Our result also demonstrates that central CL316,243 treatment significantly improves glucose tolerance in lean mice. Interestingly, central CL316,243 treatment in DIO mice showed improvement but was found to be not significant. The body weight and food intake for both CL316-treated lean and DIO mice indicated a significant drop 2 days after the treatment as compared to the vehicle-treated mice. C-fos expression in POMC neurons was increased in both peripheral and centrally β3 agonist-treated mice compared to vehicle-treated mice. However, the difference between the expressions was not significant.
Our study suggests that the β3-adrenergic receptors play a crucial role in mediating the melanocortin pathway centrally, possibly through the POMC neurons. We will continue to look into the β3-adrenergic-melanocortin mechanism as well as the role of β3-adrenergic receptors centrally and peripherally in regulating the different metabolic aspects.