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

Abstract

OBJECTIVES: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. DESIGN: 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. RESULTS: 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 g, 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. CONCLUSION: 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.

Orexin Restores Aging-Related Brown Adipose Tissue Dysfunction in Male Mice

“…Therefore, there is a burning need to design strategies that activates brown fat selectively and also induces maturation in peradipocytes of obese aging subjects. It is important to realize that most brown fat-related studies have exploited young animals in demonstrating weight loss by thermogenic activation (36). In our opinion, aged mice with their relatively dysfunctional brown fat provide an alternate preclinical model suitable for testing thermogenic potential of candidate drugs.…”

Locomotor and peripheral effects of sibutramine modulated by 5-HT2 receptors

“…The quantity of food and the mass of the rats were controlled to verify the anti-obesity and orexigenic effects of sibutramine and cyproheptadine, respectively. Drugs were administered in accordance with the following experimental groups: (i) control, rats that received 50 mL of water per day; (ii) sibutramine, rats that received 14 mgÁ(kg body mass) -1 Áday -1 of sibutramine dissolved in 50 mL of water (Giordano et al 2002); (iii) cyproheptadine, rats that received 0.52 mgÁ(kg body mass) -1 Áday -1 of cyproheptadine dissolved in 50 mL of water (Konstandi et al 1996); and (iv) sibutramine-cyproheptadine, rats that received 14 mgÁ(kg body mass) -1 Áday -1 of sibutramine and 0.52 mgÁ(kg body mass) -1 Áday -1 of cyproheptadine dissolved in 50 mL of water. The fluid intake was also measured daily for each of the experimental groups and the average consumption was 33.5 ± 1.4 mL/day with no significant differences between the treatment groups.…”

Brown adipose tissue: what have we learned since its recent identification in human adults

“…Past studies with sibutramine and more recent ones with intracerebral injection of GLP-1, in animals, suggest that both drugs could activate BAT (94)(95)(96). Although this does not change clinical prescription, the presence or absence of BAT could be a possible explanation for the sometimes incomprehensible interindividual variability in weight loss with both sibutramine and GLP-1 agonists (97,98).…”