Sibutramine-dependent brown fat activation in rats: an immunohistochemical study

To evaluate morphological aspects and immunohistochemical markers of brown adipose tissue (BAT) activation following chronic treatment with sibutramine, a novel anti-obesity drug which increases thermogenesis and energy expenditure in mammals, and to establish whether chronic sibutramine treatment induces recruitment of BAT in white adipose tissue (WAT) depots.

Adult rats were administered 7 mg/kg/day oral sibutramine for 4 weeks. Body weight was monitored daily. At the end of the 4 weeks rats were perfused with buffered paraformaldehyde solution; interscapular BAT and retroperitoneal and epididymal WAT were carefully dissected for weight and volume measurements and processed for light microscopic studies and immunohistochemistry on paraffin-embedded sections. Where possible, semiquantitative morphometric analyses were performed.

Chronic sibutramine treatment determined a significant (about 8%) reduction in body weight. Compared with controls, sibutramine-treated rats showed: (1) interscapular brown adipocytes staining more intensely for uncoupling protein 1 (UCP1), the thermogenic mitochondrial protein; (2) a significantly larger number (about 45%) of brown adipocyte nuclei positive for peroxisome proliferator-activated receptor gamma, the transcription factor driving UCP1 expression; (3) surprisingly, a significant reduction (about 30%) in BAT parenchymal noradrenergic nerve staining; and (4) a significant weight and volume reduction of WAT depots, but no significant signs of transdifferentiation of white into brown adipocytes.

This study confirms the ability of sibutramine to induce weight loss by selective and sustained activation of BAT in rodents without recruitment of brown fat in WAT depots. The parallel findings of a high level of brown adipocyte activation and low parenchymal noradrenergic innervation are discussed and a possible direct effect of sibutramine and/or its active metabolites on peripheral BAT sympathetic nerve terminals is hypothesized.