Digby J E, Montague C T, Sewter C P, Sanders L, Wilkison W O, O'Rahilly S, Prins J B
Department of Medicine, University of Cambridge, UK.
Diabetes. 1998 Jan;47(1):138-41. doi: 10.2337/diab.47.1.138.
Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.
噻唑烷二酮类药物（TZDs）是一类新型的胰岛素增敏剂，用于治疗非胰岛素依赖型糖尿病，是核激素受体过氧化物酶体增殖物激活受体γ（PPARγ）的强效激动剂。噻唑烷二酮类药物BRL 49653已被证明可促进HIB-1B棕色前脂肪细胞系的分化，并增加大鼠肩胛间棕色脂肪组织（BAT）的质量。鉴于棕色脂肪在啮齿动物能量代谢控制中的重要性，这可能代表了这类化合物的重要治疗作用。然而，迄今为止，尚未有研究报道TZDs对人类棕色脂肪的影响。在本研究中，我们测量了从不同成人脂肪组织库分离的脂肪细胞和传代培养的前脂肪细胞中解偶联蛋白1（UCP-1）mRNA的水平，UCP-1 mRNA是BAT的特异性标志物。与先前对成人全脂肪组织的研究一致，在所研究的所有脂肪库分离的人脂肪细胞中均可检测到UCP-1 mRNA，其含量顺序为肾周、网膜和皮下。与用载体处理的细胞相比，用BRL 49653处理从所有脂肪库分离的传代培养的人前脂肪细胞，可使UCP-1 mRNA水平升高。当暴露于BRL 49653 5天时，来自人类肾周脂肪库的前脂肪细胞积累了脂质，并且通过共聚焦显微镜观察，一部分细胞显示出UCP-1蛋白的清晰线粒体染色。因此，在所有研究的人类脂肪库中均可检测到棕色脂肪谱系的细胞，并且培养的人前脂肪细胞，特别是来自肾周脂肪库的前脂肪细胞，对噻唑烷二酮类药物的反应显示UCP-1表达显著增加。鉴于棕色脂肪细胞在增加能量消耗中的作用，噻唑烷二酮类药物促进棕色脂肪生成可能有助于这些药物对人类胰岛素抵抗的有益作用。
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