Bombesin receptor subtype-3-expressing neurons regulate energy homeostasis through a novel neuronal pathway in the hypothalamus

Objectives: Bombesin receptor subtype-3 (BRS-3) has been suggested to play a potential role in energy homeostasis. However, the physiological mechanism of BRS-3 on energy homeostasis remains unknown. Thus, we investigated the BRS-3-mediated neuronal pathway involved in food intake and energy expenditure. Materials and Methods: Expression of BRS-3 in the rat brain was histologically examined. The BRS-3 neurons activated by refeeding-induced satiety or a BRS-3 agonist were identified by c-Fos immunostaining. We also analyzed expression changes in feeding-relating peptides in the brain of fasted rats administered with the BRS-3 agonist. Results: In the paraventricular hypothalamic nucleus (PVH), dorsomedial hypothalamic nucleus (DMH), and medial preoptic area (MPA), strong c-Fos induction was observed in the BRS-3 neurons especially in PVH after refeeding. However, the BRS-3 neurons in the PVH did not express feeding-regulating peptides, while the BRS-3 agonist administration induced c-Fos expression in the DMH and MPA, which were not refeeding-sensitive, as well as in the PVH. The BRS-3 agonist administration changed the Pomc and Cart mRNA level in several brain regions of fasted rats. Conclusion: These results suggest that BRS-3 neurons in the PVH are a novel functional subdivision in the PVH that regulates feeding behavior. As the MPA and DMH are reportedly involved in thermoregulation and energy metabolism, the BRS-3 neurons in the MPA/DMH might mediate the energy expenditure control. POMC and CART may contribute to BRS-3 neuron-mediated energy homeostasis regulation. In summary, BRS-3-expressing neurons could regulate energy homeostasis through a novel neuronal pathway.