Background

Although it is widely accepted that the brain is the key regulator of appetite and energy control, the precise mechanisms controlling central body weight regulation are still not fully understood. As a result, the list of clinically approved drugs currently available for pharmaceutical intervention of obesity is limited and relatively ineffective when compared to surgical procedures such as gastric bypass. In this study we used light sheet microscopy and whole brain imaging to generate an unbiased map of c-Fos activity in response to various drugs (lorcasarin, rimonabant, sibutramine, bromocriptine, semaglutide and setmelanotide), all of which are documented to reduce body weight in humans.

Methods

Mice (n=8) were treated acutely with lorcasarin (7mg/kg; ip), rimonabant (10mg/kg; ip), bromocriptine (10mg/kg; ip), sibutramine (10mg/kg; po), semaglutide (0.04mg/kg; sc), setmelanotide (4mg/kg; sc) and compared to respective ip, sc, or po dosed vehicle controls. Two hours post injection, the animals were terminated, brains removed and processed for whole brain c-Fos immunohistochemistry. Brains were scanned on a Lavision Ultramicroscope II and mapped into a common reference atlas. The total number of c-Fos positive cells was quantified and the individual brains from each group were aligned into an average brain providing a heatmap of overall c-Fos activity.

Results

Using 3D imaging of whole mouse brains we have mapped c-Fos activated areas in in response to compounds that lower body weight in humans. We find that different drugs induce distinct activation patterns although some areas are common for all drugs (e.g., NTS, PB and CEA). Furthermore, we demonstrate that the brain response to peptide treatment is more selective compared to that of small molecules.

Conclusions

We present a new technology to visualize drug induced c-Fos activation in an unbiased manner and at an unprecedented level of detail. The data provides new insight into central mechanisms regulating food intake and body weight.