As part of our studies to elucidate the mechanism of action of BRS-3 agonists, we have preliminary data that BRS-3 agonists increase metabolic rate via stimulating brown adipose tissue. These studies are being confirmed and expanded upon. In order to study the specific cells, sites, tissues, and transmitters by which BRS-3 acts, we are generating the following tools: 1) a conditional knockout floxed Brs3 mouse, 2) a knockin mouse with Cre recombinase driven by Brs3, and 3) a BAC transgenic mouse with Brs3 driving GFP expression. The long-term investment required to generate and validate these tools is expected to yield great rewards in future years. We are collaborating with Merck, using selective BRS-3 compounds (particularly the agonists MK-5046 and MK-7255). Additionally, work on BRS-3 that I was involved with at Merck Research Laboratories prior to my arrival at NIDDK continues to be guided through to publication.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$696,591
Indirect Cost
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Xiao, Cuiying; Reitman, Marc L (2016) Bombesin-Like Receptor 3: Physiology of a Functional Orphan. Trends Endocrinol Metab 27:603-5
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
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
Hatoum, Ida J; Greenawalt, Danielle M; Cotsapas, Chris et al. (2013) Weight loss after gastric bypass is associated with a variant at 15q26.1. Am J Hum Genet 92:827-34
Moreno, Paola; Mantey, Samuel A; Nuche-Berenguer, Bernardo et al. (2013) Comparative pharmacology of bombesin receptor subtype-3, nonpeptide agonist MK-5046, a universal peptide agonist, and peptide antagonist Bantag-1 for human bombesin receptors. J Pharmacol Exp Ther 347:100-16
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
Reitman, Marc L; Dishy, Victor; Moreau, Allison et al. (2012) Pharmacokinetics and pharmacodynamics of MK-5046, a bombesin receptor subtype-3 (BRS-3) agonist, in healthy patients. J Clin Pharmacol 52:1306-16
Guan, Xiao-Ming; Metzger, Joseph M; Yang, Liming et al. (2011) Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist. J Pharmacol Exp Ther 336:356-64

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