Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1^R346T) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.

磷脂水平受外周代谢的影响。在中枢神经系统内，突触磷脂调节谷氨酸能传递和皮质兴奋性。外周代谢的变化是否会影响脑脂质水平和皮质兴奋性仍然未知。在这里，我们发现血液和脑脊液中溶血磷脂酸 (LPA) 的水平在禁食过夜后升高并导致更高的皮质兴奋性。LPA 相关的皮层兴奋性增加禁食引起的摄食过多，并在抑制 LPA 合成后降低。表达人类突变的小鼠 ( Prg-1 ^R346T) 导致更高的突触脂质介导的皮质兴奋性显示增加的禁食引起的摄食过度。因此，具有这种突变的人类受试者具有更高的体重指数和 2 型糖尿病的患病率。我们进一步表明，禁食后 LPA 的作用受下丘脑刺豚鼠相关肽 (AgRP) 神经元的控制。耗尽成年小鼠中表达 AgRP 的细胞可降低禁食诱导的循环 LPA 升高以及皮质兴奋性，同时抑制食欲过盛。这些发现揭示了下丘脑 AgRP 神经元控制下的循环 LPA 对皮层兴奋性的直接影响，揭示了另一种非神经元途径，下丘脑可以通过该途径对皮层产生强烈影响，从而影响食物摄入。