Non - homeostatic body weight regulation through a brainstem-restricted receptor for GDF15
Non - homeostatic body weight regulation through a brainstem-restricted receptor for GDF15
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DOI：
10.1038/nature24042
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发表时间：
2017-10-12
期刊：
影响因子：
64.8
通讯作者：
Allan, Bernard B. .
中科院分区：
文献类型：
--
作者：
Hsu, Jer-Yuan;Crawley, Suzanne;Allan, Bernard B. .
在稳态条件下，动物使用明确的下丘脑神经回路，通过整合来自外周的代谢和激素信号来平衡食物消耗和能量消耗，帮助维持稳定的体重（1，2）。然而，在压力或疾病条件下，动物使用替代神经元通路来适应能量需求改变的代谢挑战（3）。最近的研究已经确定了下丘脑外的大脑区域在这些“非稳态”条件下被激活（4-6），但激活这些回路的外周信号和大脑定位受体的分子性质仍然难以捉摸。在这里，我们确定胶质细胞源性神经营养因子（GDNF）受体α样（GFRAL）作为脑干限制性受体的生长和分化因子15（GDF 15）。GDF 15调节食物摄入量，能量消耗和体重以响应代谢和毒素诱导的应激;我们表明Gfral敲除小鼠在应激条件下是贪食的，并且对化疗诱导的厌食症和体重减轻具有抗性。GDF 15激活仅位于小鼠脑干最后区和孤束核中的GFRAL表达神经元。然后，它触发了位于臂旁核和中央杏仁核内的神经元的激活，这些神经元构成了“应急回路”的一部分，该回路塑造了对压力条件的进食反应（7）。GDF 15水平响应于组织应激和损伤而增加，并且升高的水平与许多慢性人类疾病中的体重减轻相关（8，9）。通过分离GFRAL作为GDF 15诱导的厌食症和体重减轻的受体，我们确定了通过与组织损伤和应激相关的外周信号对神经回路进行非稳态调节的机制基础。这些发现为开发用于治疗能量需求改变的疾病的治疗剂提供了机会。
Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure(1,2). In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand(3). Recent studies have identified brain areas outside the hypothalamus that are activated under these 'non-homeostatic' conditions(4-6), but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the 'emergency circuit' that shapes feeding responses to stressful conditions(7). GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases(8,9). By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.