Park Jae Eun, Han Ji Sook
Department of Food Science and Nutrition, Pusan National University, 2, Busandaehak-ro 63beon-gil, Geumgeong-gu, Busan 46241, Republic of South Korea.
Toxicol Res (Camb). 2022 Aug 26;11(5):774-783. doi: 10.1093/toxres/tfac055. eCollection 2022 Oct.
Increased free fatty acid levels in the blood are common in obesity and cause insulin resistance associated with type 2 diabetes in the muscles. Previous studies have confirmed the antidiabetic and anti-obesity potential of ()-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone). However, it is unknown how HM-chromanone alleviates obesity-related insulin resistance in L6 skeletal muscle cells. Palmitate induced insulin resistance and reduced glucose uptake, whereas HM-chromanone significantly increased glucose uptake. In palmitate-treated L6 skeletal muscle cells, HM-chromanone stimulated liver kinase B1 (LKB1) and 5'-adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. The AMPK inhibitor compound C, and the LKB1 inhibitor radicicol blocked the effects of HM-chromanone. Furthermore, HM-chromanone significantly inhibited mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase 1 (S6K1) activation, but there was no change in protein kinase C θ (PKC θ) expression. When pAMPK was inhibited with compound C, the effect of HM-chromanone on the inhibition of mTOR and S6K1 was significantly diminished. This indicates that HM-chromanone inhibits mTOR and S6K1 activation through pAMPK activation. Inhibition of mTOR and S6K1 by HM-chromanone significantly reduced IRS-1 and IRS-1 phosphorylation, leading to insulin resistance. This resulted in an increase in PM-GLUT4 (glucose transporter 4) expression, thereby stimulating glucose uptake in insulin-resistant muscle cells. HM-chromanone can improve palmitate-induced insulin resistance by inhibiting mTOR and S6K1 through activation of the AMPK pathway in L6 skeletal muscle cells. These results show the therapeutic potential of HM-chromanone for improving insulin resistance in type 2 diabetes.
血液中游离脂肪酸水平升高在肥胖症中很常见，并会导致与2型糖尿病相关的肌肉胰岛素抵抗。先前的研究已经证实了()-5-羟基-7-甲氧基-3-(2-羟基苄基)-4-色满酮（HM-色满酮）的抗糖尿病和抗肥胖潜力。然而，尚不清楚HM-色满酮如何减轻L6骨骼肌细胞中与肥胖相关的胰岛素抵抗。棕榈酸酯诱导胰岛素抵抗并降低葡萄糖摄取，而HM-色满酮显著增加葡萄糖摄取。在棕榈酸酯处理的L6骨骼肌细胞中，HM-色满酮刺激肝激酶B1（LKB1）和5'-腺苷单磷酸激活蛋白激酶（AMPK）磷酸化。AMPK抑制剂化合物C和LKB1抑制剂萝卜硫素阻断了HM-色满酮的作用。此外，HM-色满酮显著抑制雷帕霉素靶蛋白（mTOR）和核糖体蛋白S6激酶1（S6K1）的激活，但蛋白激酶Cθ（PKCθ）表达没有变化。当用化合物C抑制pAMPK时，HM-色满酮对mTOR和S6K1的抑制作用显著减弱。这表明HM-色满酮通过激活pAMPK抑制mTOR和S6K1的激活。HM-色满酮对mTOR和S6K1的抑制显著降低了IRS-1和IRS-1的磷酸化，导致胰岛素抵抗。这导致质膜-葡萄糖转运蛋白4（PM-GLUT4）表达增加，从而刺激胰岛素抵抗的肌肉细胞摄取葡萄糖。HM-色满酮可通过激活L6骨骼肌细胞中的AMPK途径抑制mTOR和S6K1，从而改善棕榈酸酯诱导的胰岛素抵抗。这些结果显示了HM-色满酮在改善2型糖尿病胰岛素抵抗方面的治疗潜力。
