Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
INRA, Unité de Nutrition Humaine, Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
Cell Metab. 2019 Mar 5;29(3):707-718.e8. doi: 10.1016/j.cmet.2018.12.016. Epub 2019 Jan 10.
GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.
生长分化因子 15（GDF15）是一种已确立的细胞应激生物标志物。事实上，它通过特定的后脑受体 GFRAL 发出信号，而缺乏 GDF15 的小鼠表现出饮食诱导的肥胖，这表明 GDF15 可能在能量平衡中发挥生理作用。我们在人类、小鼠和细胞中进行了实验，以确定营养干扰是否以及如何改变 GDF15 的表达。与经典的肠源性饱腹感激素和瘦素不同，循环 GDF15 水平在小鼠或人类适度的热量过剩或不足时仅发生非常微小的变化。然而，在小鼠持续高脂肪喂养或饮食氨基酸失衡后，GDF15 水平会升高。我们证明 GDF15 的表达受到综合应激反应的调节，并在这些情况下在小鼠的选定组织中被诱导。最后，我们发现给小鼠施用 GDF15 可引发条件性味觉厌恶，表明 GDF15 可能会对营养应激产生厌恶反应。
