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

Kwang Kon Kim, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Tae Hwan Lee, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Byong Seo Park, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Dasol Kang, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Dong Hee Kim, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Bora Jeong, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Jin Woo Kim, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Hye Rim Yang, Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
Han Rae Kim, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Sungho Jin, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Sung Hoon Back, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Jeong Woo Park, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.
Jae Geun Kim, Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea.
Byung Ju Lee, Department of Biological Sciences, University of Ulsan, Ulsan, 44610, Republic of Korea.

Document Type

Journal Article

Publication Date

7-21-2023

Journal

Diabetes

DOI

10.2337/db23-0004

Abstract

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 wholebody energy metabolism.

Department

Pharmacology and Physiology

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