Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes
Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes
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DOI：
10.1073/pnas.93.12.5793
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发表时间：
1996-06-11
影响因子：
11.1
通讯作者：
Lazar, MA
中科院分区：
文献类型：
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作者：
Kallen, CB;Lazar, MA
瘦素（ob）蛋白的缺乏会导致小鼠肥胖。瘦素基因产物对食欲和代谢率的正常调节很重要，仅由脂肪细胞产生。瘦素mRNA在3T3-L1细胞的脂肪转化过程中被诱导，这对于研究受控条件下脂肪细胞的分化和功能是有用的。我们研究了抗糖尿病噻唑烷二酮化合物对瘦素的调节，这些化合物是脂肪细胞特异性核受体过氧化物酶体增殖激活受体γ (PPAR γ)的配体，该配体调节其他脂肪细胞特异性基因的转录。值得注意的是，瘦素基因表达在噻唑烷二酮治疗后的几个小时内被显著抑制。噻唑烷二酮BRL49653抑制瘦素表达的ED（50）在5 ~ 50 nM之间，与其与PPAR γ结合的K-d相似。相对较弱的非噻唑烷二酮类PPAR激活剂WY 14643也能抑制瘦素的表达，但其抑制作用约为BRL49653的1000倍。这些结果表明，抗糖尿病的噻唑烷二酮下调瘦素基因表达的能力与其结合和激活PPAR γ的能力相关。
Lack of leptin (ob) protein causes obesity in mice. The leptin gene product is important for normal regulation of appetite and metabolic rate and is produced exclusively by adipocytes. Leptin mRNA was induced during the adipose conversion of 3T3-L1 cells, which are useful for studying adipocyte differentiation and function under controlled conditions, We studied leptin regulation by antidiabetic thiazolidinedione compounds, which are ligands for the adipocyte-specific nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) that regulates the transcription of other adipocyte-specific genes. Remarkably, leptin gene expression was dramatically repressed within a few hours after thiazolidinedione treatment. The ED(50) for inhibition of leptin expression by the thiazolidinedione BRL49653, was between 5 and 50 nM, similar to its K-d for binding to PPAR gamma. The relatively weak, nonthiazolidinedione PPAR activator WY 14,643 also inhibited leptin expression, but was approximate to 1000 times less potent than BRL49653. These results indicate that antidiabetic thiazolidinediones down-regulate leptin gene expression with potencies that correlate with their abilities to bind and activate PPAR gamma.