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. 2025 Jun 3;37(6):1400-1412.e8.
doi: 10.1016/j.cmet.2025.04.005. Epub 2025 May 6.

Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior

Sungho Jin  1 , Nal Ae Yoon  1 , Mian Wei  2 , Tilla Worgall  3 , Luisa Rubinelli  4 , Tamas L Horvath  5 , Wei Min  2 , Nadia Diano  6 , Annarita di Lorenzo  4 , Sabrina Diano  7
Affiliations

Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior

Sungho Jin et al. Cell Metab. .

Abstract

Lipid sensing in the hypothalamus contributes to the control of feeding and whole-body metabolism. However, the mechanism responsible for this nutrient-sensing process is ill-defined. Here, we show that Nogo-A, encoded by reticulon 4 (Rtn4) gene and associated with brain development and synaptic plasticity, regulates feeding and energy metabolism by controlling lipid metabolism in Agouti-related protein (AgRP) neurons. Nogo-A expression was upregulated in AgRP neurons of fasted mice and was associated with a significant downregulation of enzymes involved in sphingolipid de novo biosynthesis and the upregulation of key enzymes in intracellular lipid transport and fatty acid oxidation. Deletion of Rtn4 in AgRP neurons reduced body weight, ghrelin-induced AgRP activity and food intake, and fasting-induced AgRP activation, together with an increase in ceramide levels. Finally, high-fat-diet-induced obesity induced a significant downregulation of Rtn4 and increased ceramide levels in AgRP neurons, suggesting a role for Nogo in AgRP dysregulation in obesity. Taken together, our data reveal that Nogo-A drives AgRP neuronal activity and associated feeding behavior by controlling mitochondrial function and cellular lipid metabolism.

Keywords: AgRP; ceramides; endoplasmic reticulum; feeding behavior; hypothalamus; lipid metabolism; mitochondria.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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