Bridging Energy Need and Feeding Behavior: The Impact of eIF2 Phosphorylation in AgRP Neurons

Eukaryotic translation initiation factor 2 alpha (eIF2 alpha) is a key mediator of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). In mammals, eIF2 alpha is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2 alpha (p-eIF2 alpha) in agouti-related peptide (AgRP) neurons using a mouse model (AgRPeIF2 alpha A/A) with an AgRP neuron-specific substitution from Ser 51 to Ala in eIF2 alpha, which impairs eIF2 alpha phosphorylation in AgRP neurons. These AgRPeIF2 alpha A/A mice had decreases in starvation-induced AgRP neuronal activity and food intake and an increased responsiveness to leptin. Intriguingly, impairment of eIF2 alpha phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2 alpha phosphorylation regulates AgRP neuronal activity by affecting intracellular responses such as the UPR and autophagy during starvation, thereby participating in the homeostatic control of whole-body energy metabolism.Article Highlights This study examines the impact of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation, triggered by an energy deficit, on hypothalamic AgRP neurons and its subsequent influence on whole-body energy homeostasis. Impaired eIF2 alpha phosphorylation diminishes the unfolded protein response and autophagy, both of which are crucial for energy deficit-induced activation of AgRP neurons. This study highlights the significance of eIF2 alpha phosphorylation as a cellular marker indicating the availability of energy in AgRP neurons and as a molecular switch that regulates homeostatic feeding behavior.