Dorsal raphe nucleus melanocortin signaling regulates energy homeostasis

中缝背核黑皮质素信号传导调节能量稳态

• 批准号: 10664022
• 负责人: Sabrina Diano
• 金额: $ 62.83万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664022
• 关键词: Action Potentials; Affect; Agreement; Anatomy; Bathing; Behavior; Behavioral; Body Weight decreased; Brain Stem; Cell Nucleus; Data; Development; Dopamine; Dorsal; Emotional Stress; Energy Metabolism; Etiology; Fasting; Fiber; Food Intake Regulation; Frequencies; Genetic Models; Glutamates; Homeostasis; Hypothalamic structure; Injections; Lateral; Ligands; Melanocortin 4 Receptor; Metabolic Diseases; Metabolism; Midbrain structure; Molecular; Moods; Mus; Nature; Neurons; Obese Mice; Phenotype; Play; Process; Publishing; Regulation; Reporting; Role; Serotonin; Signal Pathway; Signal Transduction; Slice; Thermogenesis; Weight Gain; alpha-Melanocyte stimulating hormone; cell type; designer receptors exclusively activated by designer drugs; diet-induced obesity; dorsal raphe nucleus; experimental study; feeding; gamma-Aminobutyric Acid; immunoreactivity; insight; motivated behavior; neuronal circuitry; novel; obesity development; pharmacologic; postsynaptic; presynaptic; reduced food intake

Our recent studies have demonstrated that that activation of GABAergic MC4R neurons in the DRN increases feeding (Nectow et al., 2017; Bruschetta et al., 2020), thus suggesting that contrary to MC4R neurons located in the PVN, DRN GABAergic MC4R neurons are inhibited by its ligand, a-MSH. In support of this, we have observed that injection of a-MSH in the DRN reduces food intake (Bruschetta et al., 2020) and reduces DRN neuronal activation (Bruschetta et al., 2020) in overnight fasted mice. In agreement with these data, DREADD inhibition of DRN MC4R neurons reduces feeding in overnight fasted mice (Bruschetta et al., 2020) while DREADD activation of DRN MC4R neurons increases feeding in overnight fed mice (Bruschetta et al., 2020). Furthermore, bath application of a-MSH in DRN slice leads to hyperpolarization of MC4R neurons (Bruschetta et al., 2020) and a significant decreased of frequency of action potentials in DRN GABAerigic neurons (Nectow et al., 2017). Contrary to our published data, however, a recent study (Han et al., 2021) has reported that activation of MC4R neurons in the DRN does not affect feeding while induce decreased body weight by increasing energy expenditure and thermogenesis. While in this study the authors showed that activation of these MC4R neurons induced glutamate release, our studies found that the majority of the MC4R neurons are GABAergic in nature and their inhibition affects feeding, thus suggesting the existence of at least two DRN MC4R neuronal subpopulations, i.e. GABAergic vs glutamatergic MC4R neurons, with distinct roles in the regulation of metabolism. Notably, we have also found a significant increase in a-MSH immunoreactivity in the DRN of diet- induced obese (DIO) mice compared to standard chow-fed (SD) mice, suggesting a possible role for DRN melanocortin signaling in the development of diet-induced obesity. Thus, based on these data, we hypothesize that melanocortin signaling in the DRN plays a role in the regulation of metabolism (Nectow et al., 2017; Bruschetta et al., 2020) through the activity of 2 distinct MC4R subpopulations, GABAergic and glutamatergic MC4R neurons. In Aim 1 we will determine and compare the role of melanocortin signaling in DRN GABAergic neurons versus DRN glutamatergic neurons in the regulation of feeding and metabolism by affecting pharmacologically and genetically GABAergic and glutamatergic MC4R neurons. In Aim 2 we will profile POMC (and AgRP) projections to the DRN GABAergic and glutamatergic MC4R neuronal subpopulations and the intracellular signaling pathways in DRN (and PVN) GABAergic and glutamatergic MC4R neurons. In Aim 3 we will interrogate the role of DRN melanocortin signaling in diet-induced obesity. The proposed studies are a logical extension of our preliminary data and, their completion will unmask a novel mechanistic principle in the central regulation of metabolism.

我们最近的研究表明，DRN 中 GABA 能 MC4R 神经元的激活会增加 (Nectow et al., 2017; Bruschetta et al., 2020)，因此表明与位于 PVN、DRN GABA 能 MC4R 神经元受到其配体 a-MSH 的抑制。为了支持这一点，我们观察到 在 DRN 中注射 a-MSH 会减少食物摄入量 (Bruschetta et al., 2020) 并减少 DRN 神经元 在禁食过夜的小鼠中激活（Bruschetta 等人，2020）。与这些数据一致，DREADD 抑制 DRN MC4R 神经元减少过夜禁食小鼠的摄食 (Bruschetta et al., 2020)，而 DREADD DRN MC4R 神经元的激活会增加过夜喂养小鼠的进食量 (Bruschetta et al., 2020)。此外， 在 DRN 切片中沐浴应用 a-MSH 会导致 MC4R 神经元超极化 (Bruschetta et al., 2020) DRN GABAerigic 神经元的动作电位频率显着降低（Nectow et al., 2017）。 然而，与我们发布的数据相反，最近的一项研究（Han 等人，2021）报告说，MC4R 的激活 DRN 中的神经元不影响进食，同时通过增加能量诱导体重减轻 支出和产热作用。在这项研究中，作者表明这些 MC4R 神经元的激活 诱导谷氨酸释放，我们的研究发现大多数 MC4R 神经元本质上是 GABA 能的 并且它们的抑制会影响进食，因此表明至少存在两个 DRN MC4R 神经元 亚群，即 GABA 能神经元与谷氨酸能 MC4R 神经元，在调节中具有不同的作用 代谢。值得注意的是，我们还发现饮食 DRN 中的 a-MSH 免疫反应性显着增加 诱导肥胖 (DIO) 小鼠与标准食物喂养 (SD) 小鼠相比，表明 DRN 的可能作用 饮食引起的肥胖发展中的黑皮质素信号传导。因此，根据这些数据，我们假设 DRN 中的黑皮质素信号在代谢调节中发挥作用（Nectow 等，2017； Bruschetta 等人，2020）通过 2 个不同的 MC4R 亚群（GABAergic 和 谷氨酸能 MC4R 神经元。 在目标 1 中，我们将确定并比较黑皮质素信号传导在 DRN GABA 能神经元与 DRN 谷氨酸能神经元通过影响药理和代谢来调节摄食和代谢 遗传性 GABA 能和谷氨酸能 MC4R 神经元。在目标 2 中，我们将分析 POMC（和 AgRP）预测 DRN GABA 能和谷氨酸能 MC4R 神经元亚群和细胞内信号传导 DRN（和 PVN）GABA 能和谷氨酸能 MC4R 神经元中的通路。在目标 3 中，我们将询问角色 DRN 黑皮质素信号在饮食引起的肥胖中的作用。 拟议的研究是我们初步数据的逻辑延伸，它们的完成将揭示一个 代谢中枢调节的新机制原理。