It is well known that neuropeptides have a key role in regulating feeding behaviour. However, many aspects of the mechanisms behind neuropeptide control of satiety and hunger are unclear. A recent study in mice demonstrates that two neuropeptides, neuropeptide Y and αMSH, exert opposing effects on cAMP signalling in MC4R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVHMC4R neurons), which promote satiety when stimulated. The results show how a drop in the levels of neuropeptide Y and a rise in the levels of αMSH gradually promote satiety over the course of a meal.

The researchers followed up by performing in vivo imaging that showed how cAMP signalling in PVHMC4R neurons occurs in response to neuropeptide Y and αMSH. To do this, they virally expressed a fluorescent cAMP sensor in PVHMC4R neurons in transgenic mice, and then imaged the neurons via two-photon microscopy through a gradient index lens. Compared with fed transgenic mice, fasted transgenic mice showed a considerable decrease in the PVHMC4R neuron levels of cAMP. To mimic the rise in αMSH that occurs during feeding, the scientists performed optogenetic stimulation of POMC neurons, which release αMSH when activated, in transgenic mice. In response to this increase in αMSH, levels of cAMP rose considerably in PVHMC4R neurons. Conversely, when the researchers mimicked the neuropeptide signalling associated with hunger by optogenetically stimulating AgRP neurons, which release neuropeptide Y when activated, levels of cAMP dropped.