GIRK2 potassium channels expressed by the AgRP neurons decrease adiposity and body weight in mice

It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that optogenetic and/or chemogenetic manipulations of NPY/AgRP neuronal activity alter food intake and/or energy expenditure (EE). However, little is known about intrinsic molecules regulating NPY/AgRP neuronal excitability to affect long-term metabolic function. Here, we found that the G protein-gated inwardly rectifying K+ (GIRK) channels are key to stabilize NPY/AgRP neurons and that NPY/AgRP neuron-selective deletion of the GIRK2 subunit results in a persistently increased excitability of the NPY/AgRP neurons. Interestingly, increased body weight and adiposity observed in the NPY/AgRP neuron-selective GIRK2 knockout mice were due to decreased sympathetic activity and EE, while food intake remained unchanged. The conditional knockout mice also showed compromised adaptation to coldness. In summary, our study identified GIRK2 as a key determinant of NPY/AgRP neuronal excitability and driver of EE in physiological and stress conditions.

Automated summary

This study found that GIRK channels play a key role in stabilizing NPY/AgRP neurons, and selective deletion of the GIRK2 subunit leads to persistent increased excitability of NPY/AgRP neurons. The increased body weight and adiposity observed in the knockout mice were due to decreased sympathetic activity and energy expenditure, while food intake remained unchanged. This study has important implications for understanding the regulation of metabolic function under physiological and stress conditions.