St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney and University of New South Wales, Sydney, NSW 2010, Australia.
St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney and University of New South Wales, Sydney, NSW 2010, Australia.
Cell Metab. 2023 Aug 8;35(8):1341-1355.e3. doi: 10.1016/j.cmet.2023.06.009. Epub 2023 Jul 10.
GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is expressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potentiation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hindbrain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL- and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15's metabolic actions.
GDF15 通过后脑区的迷走神经背核（AP）和孤束核（NTS）神经元调节其厌食作用，其受体，胶质细胞衍生的神经营养因子受体 α 样（GFRAL），在这些神经元中表达。GDF15 的作用可能与肥胖时升高的其他食欲调节剂相互作用，如瘦素。在这里，我们报告在高脂肪饮食诱导肥胖（HFD）的小鼠中，GDF15 和瘦素的联合输注比单独使用任何一种治疗方法引起的体重和肥胖减轻更为显著，表明 GDF15 和瘦素之间存在增效作用。此外，肥胖、瘦素缺乏的 ob/ob 小鼠对 GDF15 的反应性降低，正常小鼠用竞争性瘦素拮抗剂治疗也是如此。GDF15 和瘦素在 HFD 小鼠中诱导更多的后脑神经元激活，比单独使用任何一种治疗方法诱导的激活都多。我们报告了 GFRAL 和 LepR 表达神经元之间的广泛连接，并发现 NTS 中的 LepR 敲低可减少 GDF15 介导的 AP 神经元激活。总的来说，这些发现表明，后脑的瘦素信号通路增加了 GDF15 的代谢作用。
