Oral treatment with γ-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice.
Oral treatment with γ-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice.
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DOI：
10.1371/journal.pone.0025338
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kaufman DL
中科院分区：
文献类型：
--
作者：
Tian J;Dang HN;Yong J;Chui WS;Dizon MP;Yaw CK;Kaufman DL
脂肪细胞和β细胞功能障碍以及巨噬细胞相关的慢性炎症对于肥胖相关的胰岛素抵抗和2型糖尿病（T2 DM）的发展至关重要，这可以由T3负性调节。我们以前的研究和其他人的研究表明，γ-氨基丁酸（GABA）受体的激活抑制小鼠的炎症。然而，GABA是否能调节高脂饮食（HFD）诱导的肥胖、葡萄糖耐受不良和胰岛素抵抗还没有研究。在这里，我们表明，尽管口服GABA不会影响水和食物的消耗，但它会抑制HFD诱导的C57 BL/6小鼠体重增加。此外，口服GABA可显著降低HFD喂养小鼠的空腹血糖浓度，并改善葡萄糖耐量和胰岛素敏感性。更重要的是，在肥胖和T2 DM发作后，口服GABA治疗可抑制HFD诱导的持续体重增加，降低空腹血糖浓度，并改善小鼠的葡萄糖耐量和胰岛素敏感性。此外，GABA经口给药降低了HFD喂养小鼠的附睾脂肪质量、脂肪细胞大小和脂肪组织中巨噬细胞浸润的频率。值得注意的是，口服GABA治疗显著增加了小鼠中CD 4 + Foxp 3 + T细胞的频率。总的来说，我们的数据表明，外周GABA受体的激活抑制HFD诱导的葡萄糖耐受不良，胰岛素抵抗和肥胖，通过抑制肥胖相关的炎症和上调Treg反应在体内。鉴于GABA对人类消费是安全的，GABA受体激活剂可能对预防肥胖和干预临床T2 DM有价值。
Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4+Foxp3+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.
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