Adams M, Montague C T, Prins J B, Holder J C, Smith S A, Sanders L, Digby J E, Sewter C P, Lazar M A, Chatterjee V K, O'Rahilly S
Department of Medicine, Addenbrookes Hospital, University of Cambridge, Cambridge CB2 2QQ, United Kingdom.
J Clin Invest. 1997 Dec 15;100(12):3149-53. doi: 10.1172/JCI119870.
Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity.
过氧化物酶体增殖物激活受体（PPAR）γ是一种在脂肪细胞中高度表达的核受体，其激活可诱导小鼠前脂肪细胞系的分化。最近，噻唑烷二酮类（TZDs）作为一类新型的胰岛素增敏化合物，在治疗非胰岛素依赖型糖尿病（NIDDM）方面有效，已被证明能以高亲和力与PPARγ结合。我们研究了这些化合物对源自皮下（SC）和网膜（Om）脂肪的人前脂肪细胞分化的影响。通过脂质积累、3-磷酸甘油脱氢酶活性和mRNA水平评估，从SC或Om脂肪库分离的传代培养前脂肪细胞在限定的无血清培养基中未分化。添加TZDs（BRL49653或曲格列酮）或15-脱氧Δ12,14前列腺素J2（一种天然的PPARγ配体），通过所有这三个标准评估，显著增强了来自SC部位的前脂肪细胞的分化。这些试剂诱导分化的效力顺序与其通过人PPARγ激活转录的能力相匹配。相比之下，同一受试者Om部位的前脂肪细胞对TZDs不敏感，尽管两个脂肪库中PPARγ的表达水平相似。这种脂肪库特异性TZDs反应的机制尚不清楚。然而，鉴于Om肥胖与NIDDM之间的关联，人前脂肪细胞对TZDs的部位特异性反应性可能与这些化合物对体内胰岛素敏感性的有益作用有关。
