Bombesin-like receptor 3 ( Brs3 ) expression in glutamatergic, but not GABAergic, neurons is required for regulation of energy metabolism

Abstract

ObjectiveBombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor. Brs3 null mice have reduced resting metabolic rate and body temperature, increased food intake, and obesity. Here we study the role of Brs3 in different neuron types.MethodsMice able to undergo Cre recombinase-dependent inactivation or re-expression of Brs3 were generated, respectively Brs3fl/y and Brs3loxTB/y. We then studied four groups of mice with Brs3 selectively inactivated or re-expressed in cells expressing Vglut2-Cre or Vgat-Cre.ResultsDeletion of Brs3 in glutamatergic neurons expressing Vglut2 reproduced the global null phenotype for regulation of food intake, metabolic rate, body temperature, adiposity, and insulin resistance. These mice also no longer responded to a BRS-3 agonist, MK-5046. In contrast, deletion of Brs3 in GABAergic neurons produced no detectable phenotype. Conversely, the wild type phenotype was restored by selective re-expression of Brs3 in glutamatergic neurons, with no normalization achieved by re-expressing Brs3 in GABAergic neurons.ConclusionsBrs3 expression in glutamatergic neurons is both necessary and sufficient for full Brs3 function in energy metabolism. In these experiments, no function was identified for Brs3 in GABAergic neurons. The data suggest that the anti-obesity pharmacologic actions of BRS-3 agonists occur via agonism of receptors on glutamatergic neurons.

Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake

“…5a-c ). Thus, selective activation of the DMH Brs3 →RPa pathway is sufficient to increase Tb, most likely through glutamatergic projections 1,16,28,29,32 . Indeed, DMH Brs3 →RPa neurons rarely expressed Gad2 (2.6 ± 0.5%), a marker for GABAergic neurons ( Fig.…”

“…Concordantly, BRS3 agonists increase resting Tb, energy expenditure, heart rate, blood pressure, activate brown adipose tissue (BAT) and decrease food intake 4,12–15 . The global BRS3 null phenotype is replicated by selective loss of Brs3 in neurons expressing vesicular glutamate transporter 2 (Vglut2) 16 . Both the location of the responsible Brs3 neuron populations and the specific circuits directing this physiology remain to be elucidated.…”

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).…”