There are two key cell types in the brain that are central to the regulation of feeding behaviors, agouti-related peptide (AgRP)-expressing neurons and proopiomelancortin (POMC)-expressing neurons. Previous work has shown that the AgRP neurons promote feeding and weight gain, while the POMC cells have been linked with appetite suppression and weight loss. Now a new study published by Cell Press in the February 9 issue of the journal Neuron uncovers a neural pathway that links fasting with activation of AgRP neurons. The research provides valuable insight into the complex mechanisms that control food seeking behavior.
"Given their critical roles in feeding behaviors, there is great interest in understanding the factors that regulate the activity of AgRP and POMC neurons," says senior study author, Dr. Bradford B. Lowell, from Beth Israel Deaconess Medical Center and Harvard Medical School. "However, although both types of neurons receive abundant excitatory and inhibitory inputs, the influence of these upstream signals has not received much attention."
Dr. Lowell and colleagues analyzed the impact of excitatory inputs on AgRP and POMC neurons by manipulating NMDA receptors (NMDARs) in each cell type. These receptors receive inputs from the major excitatory neurotransmitter in the brain. Interestingly, only mice lacking NMDARs on their AgRP neurons, and not those lacking NMDARs on their POMC neurons, exhibited altered body weight and food intake. Thus, this type of excitatory information is only critical for the function of AgRP neurons.
Importantly, the researchers also discovered that fasting, which is known to activate AgRP neurons and promote both food seeking and energy conservation, was associated with an increase in excitatory inputs and an increase in the number of dendritic spines on the AgRP neurons. Dendritic spines are physical protrusions on the neuron that receive incoming signals. These fasting-induced changes in AgRP neurons were also dependent on the presence of NMDARs.
Taken together, the results suggest that excitatory information received by NMDARs plays a critical role in regulating the connectivity of AgRP neurons and governing the cellular and behavioral response to fasting. "The next step will be to identify the neurotransmitters and hormones that modulate the excitatory inputs to AgRP neurons, and the mechanisms by which this modulation occurs," concludes Dr. Lowell. "This is likely to provide a better understanding of how various factors control feeding behavior."