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Bridging Energy Need and Feeding Behavior: The Impact of eIF2α Phosphorylation in AgRP Neurons

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posted on 2023-07-21, 17:56 authored by Kwang Kon Kim, Tae Hwan Lee, Byong Seo Park, Dasol Kang, Dong Hee Kim, Bora Jeong, Jin Woo Kim, Hye Rim Yang, Han Rae Kim, Sungho Jin, Sung Hoon Back, Jeong Woo Park, Jae Geun Kim, Byung Ju Lee

 Eukaryotic translation initiation factor 2α (eIF2α) is a key mediator of the endoplasmic reticulum (ER) stress–induced unfolded protein response (UPR). In mammals, eIF2α is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2α (p-eIF2α) in AgRP neurons using a mouse model (AgRPeIF2αA/A) with an AgRP neuron–specific substitution from Ser 51 to Ala in eIF2α, which impairs eIF2α phosphorylation in AgRP neurons. These AgRPeIF2αA/A mice showed decreases in starvation-induced AgRP neuronal activity and food intake and also revealed an increased responsiveness to leptin. Intriguingly, impairment of eIF2α phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2α 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.

Funding

This research was supported by the Priority Research Centers program (NRF-2014R1A6A1030318) and a National Research Foundation (NRF) grant (NRF-2020R1A2C1008080) from the Korean government. KKK was supported by the Basic Science Research Program through the NRF of Korea (NRF-2020R1A6A3A01098849). BSP was supported by an NRF grant (NRF-2021R1C1C2005067).

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