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Cell Metab., Apr 30 2025, S1550-4131(25)00215-3 | https://doi.org/10.1016/j.cmet.2025.04.005
Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior
Sungho Jin 1 9, Nal Ae Yoon 1 9, Mian Wei 2, Tilla Worgall 3, Luisa Rubinelli 4, Tamas L. Horvath 5 6, Wei Min 2, Nadia Diano 7, Annarita di Lorenzo 4, Sabrina Diano 1 8 10 *
1Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY 10032, USA
2Department of Chemistry, Columbia University, New York, NY 10027, USA
3Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
4Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10075, USA
5Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA
6Department of Anatomy and Histology, University of Veterinary Medicine, Budapest 1078, Hungary
7Department Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
8Department of Cellular Physiology and Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
9These authors contributed equally
10Lead contact
2Department of Chemistry, Columbia University, New York, NY 10027, USA
3Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
4Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10075, USA
5Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA
6Department of Anatomy and Histology, University of Veterinary Medicine, Budapest 1078, Hungary
7Department Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
8Department of Cellular Physiology and Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA
9These authors contributed equally
10Lead contact
*Corresponding author: correspondence to Sabrina Diano
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.
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-05-12)
- 국외 연구진
- 생명과학 > 신경생물학
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