Progress in FY2016 includes the following: In order to study the specific cells, sites, tissues, and transmitters by which BRS-3 acts, we have generated floxed Brs3 mouse. The floxed mice allow determination of necessity of Brs3 in the particular cells. We are in the process of using this mouse by breeding with germline cre-expressing mice. These allow knockout of Brs3 in cells defined by their cre driver expression pattern. Similarly, we have generated loxTB-Brs3 mice. The loxTB-Brs3 mice allow determination of sufficiency of Brs3 in the particular cells. We are in the process of breeding this mouse with germline cre-expressing mice. These allow knockout of Brs3 in cells defined by their cre driver expression pattern. Finally we have generated Brs3-T2A-CreERT2 mice, in which cre is expressed as a fusion mRNA with the endogenous Brs3 mRNA. These mice express cre in a tamoxifen-dependent manner and in the reported distribution pattern of Brs3. This mouse is being used to selectively activate Brs3 neurons using chemogenetics and optogenetics. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate in mice (2). In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a central sympatholytic. Taken together, the data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism. To date, no high affinity endogenous ligand has been identified. In an effort to detect a circulating endogenous BRS-3 ligand, we successfully generated parabiotic pairs of mice between Brs3-/y and wild type (WT) mice or between WT controls (2). The Brs3-/y-WT and WT-WT pairs lost similar weight immediately after surgery and after 9 weeks on a high fat diet, the Brs3-/y-WT pairs weighed more than the WT-WT pairs. Within the Brs3-/y-WT pairs, the Brs3-/y mice had greater adiposity than the WT mice, but comparable lean and liver weights. Compared to WT mice in WT-WT pairs, Brs3-/y and WT mice in Brs3-/y-WT pairs each had greater lean mass, and the Brs3-/y mice also had greater adiposity. These results contrast to those reported for parabiotic pairs of leptin receptor null (db/db) and WT mice, where high leptin levels in the db/db mice cause the WT parabiotic partners to lose weight. Our data demonstrate that a circulating endogenous BRS-3 ligand, if present, is not sufficient to reduce adiposity in parabiotic partners of Brs3-/y mice. We also published a short review on Brs3 (3).

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Xiao, Cuiying; Piñol, Ramón A; Carlin, Jesse Lea et al. (2018) Corrigendum to ""Bombesin-like receptor 3 (Brs3) expression in glutamatergic, but not GABAergic, neurons is required for regulation of energy metabolism"" [Mol Metabol 6 (2017) 1540-1550]. Mol Metab 9:220
Piñol, Ramón A; Zahler, Sebastian H; Li, Chia et al. (2018) Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake. Nat Neurosci 21:1530-1540
Xiao, Cuiying; Reitman, Marc L (2016) Bombesin-Like Receptor 3: Physiology of a Functional Orphan. Trends Endocrinol Metab 27:603-605
Lateef, Dalya M; Xiao, Cuiying; Brychta, Robert J et al. (2016) Bombesin-like receptor 3 regulates blood pressure and heart rate via a central sympathetic mechanism. Am J Physiol Heart Circ Physiol 310:H891-8
Lateef, Dalya M; Xiao, Cuiying; Reitman, Marc L (2015) Search for an Endogenous Bombesin-Like Receptor 3 (BRS-3) Ligand Using Parabiotic Mice. PLoS One 10:e0142637
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Chobanian, Harry R; Guo, Yan; Liu, Ping et al. (2012) The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization. Bioorg Med Chem 20:2845-9

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