UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
Diabetes. 2016 Apr;65(4):913-26. doi: 10.2337/db15-1029. Epub 2016 Jan 6.
Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.
脂联素是一种胰岛素增敏激素，抵抗素已知可促进胰岛素抵抗，它构成了肥胖症和 2 型糖尿病之间的潜在联系。此外，成纤维细胞生长因子 (FGF)21 的作用类似于脂联素，可调节葡萄糖和脂质代谢以及胰岛素敏感性。然而，在胰岛素抵抗发生过程中脂联素、FGF21 和抵抗素信号通路之间的相互作用尚不清楚。在这里，我们研究了中枢抵抗素是否通过损害脂联素和 FGF21 信号来促进胰岛素抵抗。我们发现，慢性侧脑室注射抵抗素会下调下丘脑和肝脏中的 APPL1，这是脂联素信号的关键蛋白，与 Akt-APPL1 相互作用减少和 Akt 与其内源性抑制剂 tribbles 同源物 3 结合增加有关。抵抗素处理还降低了血浆脂联素水平，并减少了下丘脑和外周组织中脂联素受体的表达。此外，我们报告称，侧脑室注射抵抗素会增加血浆 FGF21 水平，并下调下丘脑和外周组织中 FGF21 受体成分，从而导致 FGF21 抵抗。有趣的是，我们还表明，TLR4 敲除小鼠和表达 TLR4 siRNA 的神经元细胞中的抵抗素作用被消除。我们的研究揭示了一种由中枢抵抗素-TLR4 途径介导的胰岛素抵抗发病的新机制，该途径损害脂联素信号并促进 FGF21 抵抗。
