Giordano A, Centemeri C, Zingaretti M C, Cinti S
Institute of Normal Human Morphology-Anatomy, Faculty of Medicine, University of Ancona, Ancona, Italy.
Int J Obes Relat Metab Disord. 2002 Mar;26(3):354-60. doi: 10.1038/sj.ijo.0801926.
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.
评估西布曲明长期治疗后棕色脂肪组织（BAT）激活的形态学特征和免疫组化标志物。西布曲明是一种新型抗肥胖药物，可增加哺乳动物的产热和能量消耗，并确定长期西布曲明治疗是否会诱导白色脂肪组织（WAT）库中BAT的募集。
成年大鼠口服7mg/kg/天的西布曲明，持续4周。每天监测体重。在4周结束时，用缓冲多聚甲醛溶液灌注大鼠；仔细解剖肩胛间BAT以及腹膜后和附睾WAT，进行重量和体积测量，并对石蜡包埋切片进行光学显微镜研究和免疫组化分析。在可能的情况下，进行半定量形态计量分析。
长期西布曲明治疗使体重显著降低（约8%）。与对照组相比，西布曲明治疗的大鼠表现为：（1）肩胛间棕色脂肪细胞中解偶联蛋白1（UCP1）染色更强，UCP1是产热线粒体蛋白；（2）过氧化物酶体增殖物激活受体γ阳性的棕色脂肪细胞核数量显著增加（约45%），过氧化物酶体增殖物激活受体γ是驱动UCP1表达的转录因子；（3）令人惊讶的是，BAT实质去甲肾上腺素能神经染色显著减少（约30%）；（4）WAT库的重量和体积显著减少，但没有白色脂肪细胞向棕色脂肪细胞转分化的明显迹象。
本研究证实西布曲明能够通过选择性和持续激活啮齿动物的BAT来诱导体重减轻，而不会在WAT库中募集棕色脂肪。讨论了棕色脂肪细胞高度激活和实质去甲肾上腺素能神经支配水平低的平行发现，并假设西布曲明和/或其活性代谢物对外周BAT交感神经末梢可能有直接作用。
