Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Diabetologia. 2012 Jan;55(1):215-25. doi: 10.1007/s00125-011-2332-0. Epub 2011 Oct 14.
AIMS/HYPOTHESIS: It has been suggested that amylin amplifies leptin's effects and affects energy homeostasis synergistically with leptin in animals and humans. However, no previous study has reported on amylin and leptin signalling in hypothalamic, muscle and liver cells.
Leptin and amylin signalling studies were performed in vitro in mouse GT1-7 hypothalamic, C₂C₁₂ muscle and AML12 liver cell lines.
Treatment of mouse GT1-7 and C₂C₁₂ cells with leptin or amylin increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in a dose- and time-dependent manner. In mouse AML12 cells, leptin and amylin produced a biphasic response of STAT3 activity. Importantly, all leptin and amylin signalling pathways were saturable at leptin and amylin concentrations of ∼100 and ∼50 to 100 ng/ml, respectively. Leptin and amylin in combination activated STAT3, AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK) 1/2 and Akt signalling pathways in an additive manner, effects that were abolished under endoplasmic reticulum (ER) stress. Leptin, but not amylin, increased IRS-1 phosphorylation in GT1-7 hypothalamic, but not in C₂C₁₂ muscle and AML12 liver cell lines.
CONCLUSIONS/INTERPRETATION: Our data suggest that leptin and amylin have overlapping and additive, but not synergistic, effects in the activation of intracellular signalling pathways. ER stress may induce leptin and amylin resistance in hypothalamic, muscle and liver cell lines. These novel insights into the mode of action of leptin and amylin suggest that these hormones may play an additive role in regulating energy homeostasis in humans.
目的/假设：有人认为，在动物和人类中，胰淀素与瘦素协同作用，放大瘦素的效应并影响能量稳态。然而，以前没有研究报道过胰淀素和瘦素在下丘脑、肌肉和肝脏细胞中的信号转导。
在体外使用小鼠 GT1-7 下丘脑、C₂C₁₂ 肌肉和 AML12 肝脏细胞系进行了瘦素和胰淀素信号转导研究。
瘦素或胰淀素处理 GT1-7 和 C₂C₁₂ 细胞可剂量和时间依赖性地增加信号转导和转录激活因子 3（STAT3）磷酸化。在 AML12 细胞中，瘦素和胰淀素产生 STAT3 活性的双相反应。重要的是，所有瘦素和胰淀素信号通路在瘦素和胰淀素浓度分别约为 100ng/ml 和 50-100ng/ml 时均达到饱和。瘦素和胰淀素联合以附加方式激活 STAT3、AMP 激活的蛋白激酶（AMPK）、细胞外信号调节激酶（ERK）1/2 和 Akt 信号通路，该作用在内质网（ER）应激下被消除。瘦素而非胰淀素增加了 GT1-7 下丘脑而不是 C₂C₁₂ 肌肉和 AML12 肝脏细胞系中 IRS-1 的磷酸化。
结论/解释：我们的数据表明，瘦素和胰淀素在激活细胞内信号通路方面具有重叠和相加但非协同作用。内质网应激可能会诱导下丘脑、肌肉和肝脏细胞系中瘦素和胰淀素的抵抗。这些关于瘦素和胰淀素作用方式的新见解表明，这些激素可能在调节人类能量稳态方面发挥附加作用。
