UCP2 mediates mitochondrial dynamics to induce AgRP neuronal activity
Objectives: The hypothalamic agouti-related protein (AgRP)- expressing neurons regulate feeding and whole-body energy homeostasis. A growing body of evidence indicates that changes in mitochondrial dynamics, such as fission and fusion, play a crucial role in regulating AgRP neuronal activity. Howeve...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782500122X |
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| Summary: | Objectives: The hypothalamic agouti-related protein (AgRP)- expressing neurons regulate feeding and whole-body energy homeostasis. A growing body of evidence indicates that changes in mitochondrial dynamics, such as fission and fusion, play a crucial role in regulating AgRP neuronal activity. However, the mechanisms underlying this process remain to be elucidated. Here, we showed a role of mitochondrial UCP2-mediated mitochondrial dynamics in AgRP neurons in regulating AgRP neuronal activity and fasting-induced feeding behavior. Methods: We analyzed mitochondrial morphology, expression of activated dynamin-related protein 1 (DRP1), and mRNA expression levels of uncoupling protein 2 (Ucp2) in AgRP neurons of mice that were either in fed or fasted states. We then generated a mouse model in which Ucp2 was selectively deleted from adult AgRP neurons to assess the role of this mitochondrial protein in feeding behavior and whole-body energy metabolism. Results: We show fasting-induced AgRP neuronal activation is associated with UCP2-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking UCP2 in AgRP neurons (Ucp2AgRPKO) show attenuated fasting- or ghrelin-induced AgRP neuronal activation and feeding behaviors and exhibited a significant decrease in body weight and fat mass accompanied by a significant increase in energy expenditure. Conclusions: Altogether, our data revealed that UCP2-mediated mitochondrial dynamics and fatty acids oxidation in the hypothalamic AgRP neurons is necessary for AgRP neuronal function and fasting-induced food intake. |
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| ISSN: | 2212-8778 |