Clenbuterol-induced desensitization in murine adipocytes: relationship to in vivo effectiveness

In vitro lipolytic response of isolated murine fat cells to epinephrine (EPI) or clenbuterol (CB) was used to evaluate the potential for the beta 2-adrenergic agonist, CB, to induce cellular resistance to further beta-adrenergic stimulation. Feeding CB (20 mg/kg diet) to mice for 1, 3 or 6 wk decreased adipocyte sensitivity to EPI or CB by 35-45%, with no differences in magnitude of this desensitization across time. Basal and maximal rates of lipolysis were similar for control- and clenbuterol-fed mice. In agreement with the feeding studies, a 2 hr preincubation of control-fat tissue with either 10 microM EPI or 100 microM CB, followed by adipocyte isolation and restimulation with EPI, reduced adipocyte sensitivity by 50%. In addition, maximal rates of lipolysis were decreased 24% and 34% for EPI and CB treated tissue, respectively. The similar adaptive responses of the adipocytes to CB exposure in vivo or in vitro suggest that CB interacts directly with fat cells in vivo and can induce tolerance. Mice fed CB for 12 wk had 33% smaller epididymal fat pads compared to controls, but pad weight differences were only 10% if feeding of CB was discontinued 1 wk before the 12 wk analysis. The reversal in fat pad gain with a 1 wk removal of CB from the diet indicates at least partial effectiveness of CB through 12 wk. The modest beta-adrenergic desensitization established by wk 1 was similar on wk 6 suggesting that CB-induced adipocyte resistance is of little consequence to the fat-reducing properties of CB administration.