The multi-level action of fatty acids on adiponectin production by fat cells.
The multi-level action of fatty acids on adiponectin production by fat cells.
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DOI：
10.1371/journal.pone.0028146
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kandror KV
中科院分区：
文献类型：
--
作者：
Karki S;Chakrabarti P;Huang G;Wang H;Farmer SR;Kandror KV
目前糖尿病的流行主要是由广泛的肥胖引起的。肥胖和胰岛素抵抗之间最确定的联系是循环游离脂肪酸水平升高和/或失调，导致和加重胰岛素抵抗、2型糖尿病、心血管疾病和其他危险的代谢状况。在这里，我们研究了一种主要的膳食饱和脂肪酸，棕榈酸，对培养的脂肪细胞产生的胰岛素增敏脂肪因子脂联素的影响。我们已经发现棕榈酸酯快速抑制脂联素基因的转录和脂联素从脂肪细胞的释放。脂联素基因的表达主要受PPARγ和C/EBPα的调控。使用来自C/EBPα缺失小鼠的小鼠胚胎成纤维细胞，我们已经确定后一种转录因子可能不仅介导棕榈酸酯对脂联素转录的抑制作用，还使PPARγ成为棕榈酸酯的可能靶点。与该模型一致，棕榈酸增加了PPARγ在Ser 273上的磷酸化，并且将未磷酸化的突变体Ser 273 Ala替换为PPARγ阻断了棕榈酸对脂联素转录的影响。棕榈酸对脂联素基因表达的抑制作用需要其通过酰基辅酶A合成酶1介导的途径在细胞内代谢。此外，我们发现，棕榈酸酯刺激降解细胞内脂联素的溶酶体，和溶酶体抑制剂，氯喹，抑制棕榈酸酯对脂联素从脂肪细胞释放的影响。我们目前的证据表明，细胞内的分选受体，分拣蛋白，脂联素的溶酶体靶向发挥了重要作用。因此，棕榈酸不仅在转录水平上降低脂联素的表达，而且还可能刺激新合成的脂联素的溶酶体降解。
Current epidemics of diabetes mellitus is largely caused by wide spread obesity. The best-established connection between obesity and insulin resistance is the elevated and/or dysregulated levels of circulating free fatty acids that cause and aggravate insulin resistance, type 2 diabetes, cardiovascular disease and other hazardous metabolic conditions. Here, we investigated the effect of a major dietary saturated fatty acid, palmitate, on the insulin-sensitizing adipokine adiponectin produced by cultured adipocytes. We have found that palmitate rapidly inhibits transcription of the adiponectin gene and the release of adiponectin from adipocytes. Adiponectin gene expression is controlled primarily by PPARγ and C/EBPα. Using mouse embryonic fibroblasts from C/EBPα-null mice, we have determined that the latter transcription factor may not solely mediate the inhibitory effect of palmitate on adiponectin transcription leaving PPARγ as a likely target of palmitate. In agreement with this model, palmitate increases phosphorylation of PPARγ on Ser273, and substitution of PPARγ for the unphosphorylated mutant Ser273Ala blocks the effect of palmitate on adiponectin transcription. The inhibitory effect of palmitate on adiponectin gene expression requires its intracellular metabolism via the acyl-CoA synthetase 1-mediated pathway. In addition, we found that palmitate stimulates degradation of intracellular adiponectin by lysosomes, and the lysosomal inhibitor, chloroquine, suppressed the effect of palmitate on adiponectin release from adipocytes. We present evidence suggesting that the intracellular sorting receptor, sortilin, plays an important role in targeting of adiponectin to lysosomes. Thus, palmitate not only decreases adiponectin expression at the level of transcription but may also stimulate lysosomal degradation of newly synthesized adiponectin.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.1
作者：
GORDON, ES
通讯作者：
GORDON, ES
影响因子：
6.9
作者：
Bradley, Richard L.;Fisher, FFolliott M.;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria
影响因子：
4.2
作者：
Ajuwon, KM;Spurlock, ME
通讯作者：
Spurlock, ME
影响因子：
--
作者：
APPEL, B;FRIED, SK
通讯作者：
FRIED, SK