Progress in FY2017 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 (Vgat-Cre, Vglut2-Cre). 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 (Vgat-Cre, Vglut2-Cre). These allow re-expression of Brs3 in cells defined by their Cre driver expression pattern. Preliminary data using these mice reveal that deletion 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 clear 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. We conclude that Brs3 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. 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.

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7
Fiscal Year
2017
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U.S. National Inst Diabetes/Digst/Kidney
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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
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
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; Reitman, Marc L (2015) Search for an Endogenous Bombesin-Like Receptor 3 (BRS-3) Ligand Using Parabiotic Mice. PLoS One 10:e0142637
Lateef, Dalya M; Abreu-Vieira, Gustavo; Xiao, Cuiying et al. (2014) Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3. Am J Physiol Endocrinol Metab 306:E681-7
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Reitman, Marc L (2013) FGF21 mimetic shows therapeutic promise. Cell Metab 18:307-9
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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