Hypothalamic lipid signaling in metabolism regulation

代谢调节中的下丘脑脂质信号传导

• 批准号: 10745160
• 负责人: Sabrina Diano
• 金额: $ 69.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745160
• 关键词: Acute; Affect; Anabolism; Appetite Stimulants; Behavior; Catabolic Process; Catabolism; Ceramides; Chimeric Proteins; Chronic; Data; Development; Disinhibition; Down-Regulation; Eating; Elements; Endoplasmic Reticulum; Energy Metabolism; Enzymes; Etiology; Fasting; Fatty Acids; Feeding behaviors; Food deprivation (experimental); Generations; Genes; High Fat Diet; Hypothalamic structure; Link; Lipids; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Neurons; Obese Mice; Pathway interactions; Phenotype; Physiological Processes; Play; Production; Protein Family; Proteins; RTN4 gene; Regulation; Role; Signal Transduction; Site; Sphingolipids; Sphingosine-1-Phosphate Receptor; Structure of nucleus infundibularis hypothalami; Testing; Up-Regulation; diet-induced obesity; fatty acid metabolism; feeding; in vivo calcium imaging; insight; lipid metabolism; long chain fatty acid; member; motivated behavior; novel; oxidation; parabrachial nucleus; sphingosine 1-phosphate

Our recent studies have demonstrated that mitochondrial fission is tightly connected to lipid metabolism and more specifically, that mitochondrial fission is an inherent element in oxidation of long chain fatty acids by the orexigenic AgRP neurons (Jin et al., 2021). Intriguingly, while mitochondrial fission is associated with lipid catabolic processes, mitochondrial fusion is associated with lipid anabolism. More specifically, mitofusin 2, critical mitochondrial fusion protein, plays a critical role in the formation of the endoplasmic reticulum (ER)-mitochondria contact sites, relevant sites of lipid metabolism where intact fatty acids are used as precursors for the generation, for example, of sphingolipids. Besides mitofusin 2, other proteins have been shown to regulate the ER- mitochondria interaction. Among those, the Neurite OutGrowth inhibitor (Nogo), a member of the reticulon family of proteins (Reticulon 4 gene; Rtn4) located on the ER, plays also a critical role in regulating sphingolipids production (Cantalupo et al., 2015). Among sphingolipids, Sphingosine-1-phosphate (S1P) has been shown to play a crucial role in a large number of physiological processes including most recently feeding behavior via its action in the hypothalamus. However, the specific site of synthesis of S1P and its target within the hypothalamus have not been identified. Our preliminary data have shown that AgRP neurons are enriched of enzymes involved in the S1P de novo biosynthesis and their mRNA levels are regulated by the metabolic state, with fasting upregulating Nogo mRNA levels while downregulating all the enzymes involved in the synthesis of S1P. In line with this, we observed that S1P levels in the arcuate nucleus are downregulated during food deprivation. As the multitude of different S1P-mediated actions is linked to its capacity to be secreted, we found that S1P receptors are expressed in the neighboring anorexigenic POMC neurons where S1P significantly induced their activation by in vivo calcium imaging. Interestingly, we also observed that the expression of Nogo and several of the enzymes involved in the S1P de novo synthesis, together with S1P levels, are altered in diet-induced obesity (DIO). Altogether our data gave impetus to the central hypothesis that Nogo is a critical regulator of AgRP neuronal function and feeding behavior by regulating fatty acid metabolic pathways (catabolism versus anabolism) and that dysregulation of fatty acid metabolism during high fat diet (HFD) plays a role in DIO. Specifically, we hypothesize that when activated during fasting in AgRP neurons, Nogo by inhibiting S1P de novo biosynthesis will direct fatty acids to oxidation by the mitochondria (catabolic pathway) thus, activating AgRP neurons and inducing feeding behavior (Aim 1). On the other hand, Nogo downregulation in AgRP neurons during fed state will disinhibit S1P de novo biosynthesis (thus promoting the anabolic pathway), and by acting via its receptors, S1P will affect AgRP target neurons resulting in decreased food intake (Aim 2). Finally, dysregulation of this pathway and the resulting imbalance in sphingolipid metabolism (increased ceramides production but decreased S1P generation) during HFD plays a role in DIO (Aim 3).

我们最近的研究表明线粒体裂变与脂质代谢密切相关 更具体地说，线粒体裂变是长链脂肪酸氧化的固有因素 促食欲 AgRP 神经元 (Jin et al., 2021)。有趣的是，虽然线粒体裂变与脂质有关 在分解代谢过程中，线粒体融合与脂质合成代谢有关。更具体地说，线粒体融合蛋白 2，关键 线粒体融合蛋白，在内质网 (ER)-线粒体的形成中起着关键作用 接触位点，脂质代谢的相关位点，其中完整的脂肪酸被用作生成的前体， 例如，鞘脂。除了线粒体融合蛋白 2 外，其他蛋白质已被证明可以调节 ER- 线粒体相互作用。其中，神经突生长抑制剂（Nogo）是网状细胞家族的成员 位于内质网的蛋白质（Reticulon 4 基因；Rtn4），在调节鞘脂方面也发挥着关键作用 生产（Cantalupo 等人，2015）。在鞘脂中，1-磷酸鞘氨醇 (S1P) 已被证明可以 在许多生理过程中发挥着至关重要的作用，包括最近通过其进食行为 下丘脑的作用。然而，S1P 合成的具体位点及其在下丘脑内的靶点 尚未被识别。我们的初步数据表明 AgRP 神经元富含相关酶 S1P 从头生物合成，其 mRNA 水平受代谢状态调节，禁食时 上调 Nogo mRNA 水平，同时下调所有参与 S1P 合成的酶。排队 由此，我们观察到弓状核中的 S1P 水平在食物匮乏期间下调。作为 许多不同的 S1P 介导的作用与其分泌能力有关，我们发现 S1P 受体 在邻近的厌食 POMC 神经元中表达，其中 S1P 显着诱导其激活 通过体内钙成像。有趣的是，我们还观察到 Nogo 和几个 饮食引起的肥胖中参与 S1P 从头合成的酶以及 S1P 水平发生改变 （迪奥）。总而言之，我们的数据推动了中心假设，即 Nogo 是 AgRP 的关键调节因子 通过调节脂肪酸代谢途径（分解代谢与 合成代谢）以及高脂肪饮食（HFD）期间脂肪酸代谢失调在 DIO 中发挥作用。 具体来说，我们假设当 AgRP 神经元在禁食期间被激活时，Nogo 通过抑制 S1P de 新生物合成将引导脂肪酸通过线粒体氧化（分解代谢途径），从而激活 AgRP 神经元和诱导进食行为（目标 1）。另一方面，AgRP 中的 Nogo 下调 进食状态下的神经元将抑制 S1P 从头生物合成（从而促进合成代谢途径），并且通过 S1P 通过其受体发挥作用，将影响 AgRP 靶神经元，导致食物摄入量减少（目标 2）。最后， 该途径的失调以及由此导致的鞘脂代谢失衡（神经酰胺增加） HFD 期间的产量但 S1P 生成减少）在 DIO 中发挥作用（目标 3）。