GPR40 signaling in agouti-related peptide neurons mediates fat preference

Fat preference is mediated by fatty acid receptors in the oral, intestinal, and central nervous systems, but their central nervous system roles remain unclear. Here, we investigated how GPR40, a medium- and long-chain fatty acid receptor, regulates fat preference via agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus (ARC).

AgRP neuron-specific Gpr40 knockout mice were generated to investigate the role of GPR40 in dietary fat preference. Behavioral tests were conducted to assess dietary preferences, and metabolic analyses were performed after starvation. We also measured the activity of AgRP neurons and the expression levels of AgRP and neuropeptide Y (NPY) to explore the mechanisms.

Our results indicate that GPR40 is a novel signaling pathway that regulates fat preference in hypothalamic AgRP neurons, but not in pro-opiomelanocortin (POMC) neurons. AgRP-specific Gpr40 knockout mice displayed a reduced preference for fat. This alteration in dietary preference was not associated with behavioral anomalies such as anxiety, depression, or deficits in short-term memory. Additionally, Gpr40 deletion in ARC AgRP neurons resulted in a diminished metabolic state, increased AgRP neuronal activity, and elevated levels of AgRP and NPY peptides following starvation, leading to reduced fat intake and increased carbohydrate intake. Inhibition of AgRP neuronal activity in AgRP-specific Gpr40 knockout mice rescued the observed changes in fat preference.

GPR40 signaling in AgRP neurons plays a critical role in regulating fat preference by modulating neuronal activity and the expression of AgRP and NPY peptides.