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

Abstract

ObjectivesBombesin 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 MethodsExpression 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.ResultsIn 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.ConclusionThese 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.

Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

“…Bombesin-like receptor 3 (BRS3, BB3, bombesin receptor subtype-3) is an orphan G protein-coupled receptor that regulates energy metabolism and the cardiovascular system (Ohki-Hamazaki et al, 1997). BRS3 is expressed in some peripheral sites (Jensen et al, 2008), but its effects on food intake, metabolic rate, Tb, HR, and blood pressure are due to action in the brain (Guan et al, 2010;Xiao and Reitman, 2016 restricted brain distribution (Maruyama et al, 2018;Piñ ol et al, 2018;Zhang et al, 2013), with its metabolic effects attributed to glutamatergic neurons and in part to those expressing MC4R and SIM1 (Xiao et al, 2017(Xiao et al, , 2020. Activation of BRS3 neurons in the DMH (DMH BRS3 ) increased energy expenditure, Tb, HR, and blood pressure, while activation of paraventricular nucleus of the hypothalamus (PVH) BRS3 neurons reduced food intake (Piñ ol et al, 2018).…”

Development and Characterization of a Novel, High-Affinity, Specific, Radiolabeled Ligand for BRS-3 Receptors

“…Bantag-1 was described in Moreno et al (2013), Guan et al (2010), Feng et al (2011); #1 in Mantey et al (1997); #2 in Mantey et al (1997); #6 in Mantey et al (2004); #7 in Mantey et al (2004); #15 in Mantey et al (2001); #34 in Boyle et al (2005); #54 in Weber et al (2002Weber et al ( , 2003; and #68 in Weber et al (2002Weber et al ( , 2003 for a number of reasons. First, the BRS-3 receptor is receiving increased attention (Gonzalez et al, 2015b;Maruyama et al, 2017;Nio et al, 2017;Xiao et al, 2017;Pinol et al, 2018) because of its prominent role in causing diabetes, hypertension, and obesity by regulating body weight and energy maintenance, body temperature control, and control of metabolic homeostasis, particularly insulin/glucose control, as evidenced from studies of BRS-3 knockout mice (Ohki-Hamazaki et al, 1997;Ladenheim et al, 2008;Majumdar and Weber, 2012a;Lateef et al, 2014;Gonzalez et al, 2015b). Studies using primarily non-ligand receptor localization methods (immunohistochemistry, BRS-3 mRNA methods) (Fathi et al, 1993;Jennings et al, 2003;Sano et al, 2004;Porcher et al, 2005;Guan et al, 2010;Zhang et al, 2013;Maruyama et al, 2017;Xiao et al, 2017) provide evidence that BRS-3 is highly expressed in hypothalamic nuclei associated with metabolic maintenance, and that glutamatergic neurons in this area (Xiao et al, 2017) are particularly important.…”

“…First, the BRS-3 receptor is receiving increased attention (Gonzalez et al, 2015b;Maruyama et al, 2017;Nio et al, 2017;Xiao et al, 2017;Pinol et al, 2018) because of its prominent role in causing diabetes, hypertension, and obesity by regulating body weight and energy maintenance, body temperature control, and control of metabolic homeostasis, particularly insulin/glucose control, as evidenced from studies of BRS-3 knockout mice (Ohki-Hamazaki et al, 1997;Ladenheim et al, 2008;Majumdar and Weber, 2012a;Lateef et al, 2014;Gonzalez et al, 2015b). Studies using primarily non-ligand receptor localization methods (immunohistochemistry, BRS-3 mRNA methods) (Fathi et al, 1993;Jennings et al, 2003;Sano et al, 2004;Porcher et al, 2005;Guan et al, 2010;Zhang et al, 2013;Maruyama et al, 2017;Xiao et al, 2017) provide evidence that BRS-3 is highly expressed in hypothalamic nuclei associated with metabolic maintenance, and that glutamatergic neurons in this area (Xiao et al, 2017) are particularly important. Furthermore, recent studies (Das et al, 2009;Moreno et al, 2013Moreno et al, , 2018 demonstrate that BRS-3 is overexpressed in Fig.…”

“…The latter problem is due to the lack of a convenient specific BRS-3 ligand that can be used for receptor localization/characterization in different tissues as well as the lack of agreement on the reliability of BRS-3 antibodies, with one recent review (Xiao and Reitman, 2016) concluding that existing BRS-3 receptor antibodies are of uncertain specificity. This is a particular issue with the CNS, allowing the correlation of BRS-3 location with the results of recent studies attempting to define the exact CNS areas responsible for many of the changes in energy homeostasis, food intake, metabolic rate, body temperature control, and body weight (Gonzalez et al, 2015b;Xiao and Reitman, 2016;Maruyama et al, 2017;Xiao et al, 2017;Pinol et al, 2018).…”

Preoptic BRS3 neurons increase body temperature and heart rate via multiple pathways

“…BRS3 is expressed in some peripheral sites (Jensen et al, 2008), but its effects on food intake, metabolic rate, Tb, HR, and blood pressure are due to action in the brain (Guan et al, 2010; Xiao and Reitman, 2016). BRS3 has a restricted brain distribution (Maruyama et al, 2018; Pinol et al, 2018; Zhang et al, 2013), with its metabolic effects attributed to glutamatergic neurons and in part to those expressing MC4R and SIM1 (Xiao et al, 2020; Xiao et al, 2017). Activation of BRS3 neurons in the DMH (DMH BRS3 ) increased energy expenditure, Tb, HR, and blood pressure, while activation of paraventricular nucleus of the hypothalamus (PVH) BRS3 neurons reduced food intake (Pinol et al, 2018).…”