Activators of peroxisome proliferator-activated receptor γ have depot-specific effects on human preadipocyte differentiation
Activators of peroxisome proliferator-activated receptor γ have depot-specific effects on human preadipocyte differentiation
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DOI：
10.1172/jci119870
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发表时间：
1997-12-15
影响因子：
15.9
通讯作者：
O'Rahilly, S
中科院分区：
文献类型：
--
作者：
Adams, M;Montague, CT;O'Rahilly, S
过氧化物酶体增殖激活受体(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（TZDs）是一类新的胰岛素增敏化合物，可有效治疗非胰岛素依赖型糖尿病（NIDDM），已被证明与PPAR γ高亲和力结合。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、甘油3-磷酸脱氢酶活性和mRNA水平评估，从SC或Om仓库分离的传代前脂肪细胞在确定的无血清培养基中没有分化。添加TZDs （BRL49653或曲格列酮）或15-脱氧δ(12,14)前列腺素J(2)（一种天然PPAR γ配体）可显著增强SC部位的前脂肪细胞分化。这些药物在诱导分化方面的效力等级与其通过人PPAR γ激活转录的能力相匹配。相比之下，来自同一个体的Om位点的前脂肪细胞对TZDs不耐受，尽管PPAR γ在两个位点的表达水平相似。这种储存库特有的TZD反应机制尚不清楚。然而，鉴于肥胖与NIDDM之间的关联，人类脂肪前细胞对TZDs的位点特异性反应可能参与了这些化合物对体内胰岛素敏感性的有益作用。
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 PPAR gamma 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-deoxy Delta(12,14)prostaglandin J(2) (a natural PPAR gamma 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 PPAR gamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPAR gamma 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.