Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIADK075057-02
Application #
8553647
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$696,591
Indirect Cost

  Institution

Name
National Institute of Diabetes and Digestive and Kidney Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

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
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

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