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ß₃-Adrenergic Receptor-Mediated Lipolysis and Oxygen Consumption in Brown Adipocytes from Cynomolgus Monkeys

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000

Address all correspondence and requests for reprints to: Cynthia M. Arbeeny, Ph.D., Sepracor Pharmaceuticals, 111 Locke Drive, Marlborough, Massachusetts 01752. E-mail: carbeeny{at}sepracor.com

Primary adipocytes were isolated from axillary brown adipose tissue from adult cynomolgus monkeys. That this tissue contained brown adipocytes was verified by morphological examination and by demonstrating the presence of uncoupling protein messenger ribonucleic acid in the isolated adipocytes. The contributions of ß₁-, ß₂-, and ß₃-adrenergic receptors (AR) to lipolysis and oxygen consumption of isolated brown adipocytes were determined after agonist stimulation. Dose responses were determined using isoproterenol (a nonselective ß-AR agonist), denopamine (ß₁-AR agonist), procaterol (ß₂-AR agonist), and CGP12177A (ß₁- and ß₂-AR antagonist, ß₃-AR agonist). Isoproterenol, denopamine, and procaterol stimulated lipolysis with EC₅₀ values of 4, 500, and 83 nmol/L, respectively. Intrinsic activities (relative to isoproterenol maxima) were 100%, 74%, and 59%, respectively. The presence of ß₃-ARs coupled to lipolysis was demonstrated by the activity of CGP12177A (EC₅₀ = 1.6 µmol/L; intrinsic activity = 62%). Isoproterenol stimulated oxygen consumption of brown adipocytes by 75–100% above the basal rate, with an EC₅₀ of 1 µmol/L. Denopamine, procaterol, and CGP12177A stimulated oxygen consumption at a concentration of 100 µmol/L. These results demonstrate that all three ß-adrenergic receptor subtypes are coupled to lipolysis and oxygen consumption in brown adipocytes from cynomolgus monkeys.