BETA-3-ADRENERGIC RECEPTORS ON WHITE AND BROWN ADIPOCYTES MEDIATE BETA-3-SELECTIVE AGONIST-INDUCED EFFECTS ON ENERGY-EXPENDITURE, INSULIN-SECRETION, AND FOOD-INTAKE - A STUDY USING TRANSGENIC AND GENE KNOCKOUTMICE

beta 3-Adrenergic receptors (beta,7-ARs) are expressed predominantly o n white and brown adipocytes, and acute treatment of mice with CL 316, 243, a potent and highly selective beta 3-AR agonist, produces a a-fol d increase in energy expenditure, a 50-100-fold increase in insulin le vels, and a 40-50% reduction in food intake, Recently, we generated ge ne knockout mice lacking functional beta 3-ARs and demonstrated that e ach of these responses were mediated exclusively by beta 3-ARs. Howeve r, the tissue site responsible for producing these actions is unknown. In the present study, genetically engineered mice were created in whi ch beta 3-ARs are expressed exclusively ill white and brown adipocytes (WAT+BAT-mice), or in brown adipocytes only (BAT-mice). This was acco mplished by injecting tissue-specific beta 3-AR transgenic constructs into mouse zygotes homozygous for the beta 3-AR knockout allele. Contr ol, knockout, WAT+BAT, and BAT-mice were then treated acutely with CL, and the effects on various parameters were assessed, As previously ob served, all effects of CL were completely absent in gene knockout mice lacking beta 3-ARs. The effects on O-2 consumption, insulin secretion , and food intake were completely rescued with transgenic re-expressio n of beta 3-ARs in white and brown adipocytes (WAT+BAT-mice), demonstr ating that each of these responses is mediated exclusively by beta 3-A rs in white and/or brown adipocytes, and that beta 3-ARs in other tiss ue sites were not required. Importantly, transgenic re-expression of b eta 3-Ars in brown adipocytes only (BAT-mice) failed to rescue, in any way, CL-mediated effects on insulin levels and food intake and only m inimally restored effects on oxygen consumption, indicating that any e ffect on insulin secretion and food intake, and a full stimulation of oxygen consumption required the presence of beta 3-ARs in white adipoc ytes. The mechanisms by which beta 3-AR. agonist stimulation of white adipocytes produces these responses are unknown but may involve novel mediators not previously known to effect: these processes.