Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3(-/Y) (BRS-3 null) mice but was maintained in Npy(-/-)Agrp(-/-), Mc4r(-/-), Cnr1(-/-), and Lepr(db/db) mice. In addition, Brs3(-/Y) mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.
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PMID:Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity. 2009 42

The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2), produced in lateral hypothalamic neurons, are critical regulators of feeding behavior, the reward system, and sleep/wake states. Orexin-producing neurons (orexin neurons) are regulated by various factors involved in regulation of energy homeostasis and sleep/wakefulness states. Bombesin receptor subtype 3 (BRS3) is an orphan receptor that might be implicated in energy homeostasis and is highly expressed in the hypothalamus. However, the neural pathway by which BRS3 regulates energy homeostasis is largely unknown. We examined whether BRS3 is involved in the regulation of orexin neurons. Using a calcium imaging method, we found that a selective BRS3 agonist [Ac-Phe-Trp-Ala-His-(tauBzl)-Nip-Gly-Arg-NH2] increased the intracellular calcium concentration of orexin neurons. However, intracellular recordings from slice preparations revealed that the BRS3 agonist hyperpolarized orexin neurons. The BRS3 agonist depolarized orexin neuron in the presence of tetrodotoxin. Moreover, in the presence of GABA receptor blockers, picrotoxin and CGP55845, the BRS3 agonist induced depolarization and increased firing frequency. Additionally, double-label in situ hybridization study revealed that Brs3 mRNA was expressed in almost all orexin neurons and many cells around these neurons. These findings suggest that the BRS3 agonist indirectly inhibited orexin neurons through GABAergic input and directly activated orexin neurons. Inhibition of activity of orexin neurons through BRS3 might be an important pathway for regulation of feeding and sleep/wake states. This pathway might serve as a novel target for the treatment of obesity.
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PMID:Activation of bombesin receptor subtype-3 influences activity of orexin neurons by both direct and indirect pathways. 2046 15

Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.
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PMID:The design and synthesis of potent, selective benzodiazepine sulfonamide bombesin receptor subtype 3 (BRS-3) agonists with an increased barrier of atropisomerization. 2249 42

Bombesin receptor subtype 3 (BRS-3) is an orphan G protein-coupled receptor. Based on the obese phenotype of male BRS-3-deficient mice, BRS-3 has been considered an attractive target for obesity treatment. Here, we developed a selective BRS-3 agonist (compound-A) and evaluated its antiobesity effects. Compound-A showed anorectic effects and enhanced energy expenditure in diet-induced-obese (DIO)-F344 rats. Moreover, repeated oral administration of compound-A for 7 days resulted in a significant body weight reduction in DIO-F344 rats. We also evaluated compound-A for cardiovascular side effects using telemeterized Sprague-Dawley (SD) rats. Oral administration of compound-A resulted in transient blood pressure increases in SD rats. To investigate the underlying mechanisms of BRS-3 agonist effects, we focused on the suprachiasmatic nucleus (SCN), the main control center of circadian rhythms in the hypothalamus, also regulating sympathetic nervous system. Compound-A significantly increased the messenger RNA expression of Brs-3, c-fos, and circadian rhythm genes in SCN of DIO-F344 rats. Because SCN also controls the hypothalamic-pituitary-adrenal (HPA) axis, we evaluated the relationship between BRS-3 and the HPA axis. Oral administration of compound-A caused a significant increase of plasma corticosterone levels in DIO-F344 rats. On this basis, energy expenditure enhancement by compound-A may be due to a circadian rhythm change in central and peripheral tissues, enhancement of peripheral lipid metabolism, and stimulation of the sympathetic nervous system. Furthermore, the blood pressure increase by compound-A could be associated with sympathetic nervous system stimulation via SCN and elevation of plasma corticosterone levels through activation of the HPA axis.
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PMID:A Selective Bombesin Receptor Subtype 3 Agonist Promotes Weight Loss in Male Diet-Induced-Obese Rats With Circadian Rhythm Change. 2832 17