Regulation of Lipolysis by Oxytocin

催产素对脂肪分解的调节

• 批准号: 10670865
• 负责人: Brigid Ellen Gregg
• 金额: $ 57.03万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670865
• 关键词: Ablation; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Adrenergic beta-Agonists; Adult Children; Affect; Agonist; Aminopeptidase; Anxiety Disorders; Area; Birth; Brain; Brown Fat; Cell surface; Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Drops; Ensure; Fasting; Fatty Acids; Fatty acid glycerol esters; Food; Functional disorder; Glycerol; Goals; Heart; Hepatic; Hormonal; Hormones; Human Milk; Hypothalamic Hormones; In Vitro; Insulin; Lactation; Learning; Licensing; Life; Light; Lipids; Lipolysis; Mediating; Metabolic; Metabolic Diseases; Metabolism; Milk; Minor; Mothers; Mus; Muscle; Natriuretic Factors; Nerve; Neurodegenerative Disorders; Neurons; Neuropeptides; Norepinephrine; Nutrient; Nutritional; Obesity; Organ; Oxytocin; Oxytocin Receptor; Paracrine Communication; Pathology; Pathway interactions; Peptides; Peripheral; Physiological; Physiology; Play; Process; Regulation; Reporting; Role; Side; Signal Pathway; Signal Transduction; Source; Surface; Sympathetic Nervous System; Techniques; Temperature; Testing; Text; Triglycerides; Weaning; Work; follow-up; glucose production; in vivo; insight; interest; milk production; neurotransmission; non-alcoholic fatty liver disease; novel; obesity treatment; offspring; pharmacologic; pup; response; side effect; thermal stress

ABSTRACT Adipose tissue lipolysis is a critical process that provides nutritional substrate to other organs during periods of fasting. Lipolysis also contributes to the metabolic pathology associated with obesity, as lipid species from adipose tissue promote hepatic glucose production and are also an important contributor to the excess fat seen in nonalcoholic fatty liver disease. Despite the importance of lipolysis in mammalian physiology and pathophysiology, there is still much to be learned about how it is regulated and what its consequences are. There have been reports over the years that the neuropeptide oxytocin (Oxt) is an inducer of lipolysis. Our preliminary data corroborates this, but goes much further in several important areas. First, we show that Oxt signaling is not only required for normal lipolysis in the setting of fasting and cold exposure, but is also needed for b-adrenergic agonists to exert their well-known pro-lipolytic effects. We also identify the relevant source of Oxt as a subpopulation of TH+ sympathetic neurons innervating white adipose depots. In this proposal we intend to fully characterize the intracellular signaling pathways by which Oxt promotes lipolysis. In addition, we will determine the local mechanism by which Oxt levels are controlled through degradation. Finally, we will follow up on preliminary data suggesting that maternal Oxt signaling in fat is required to ensure milk of proper nutritional content during lactation. Taken together, these studies will greatly advance our understanding of lipolysis. Furthermore, Oxt is being pursued as a pharmacological therapy for a variety of conditions, including anxiety and neurodegenerative disorders, and this work will provide important information about potential metabolic side effects.

抽象的 脂肪组织脂解是为其他器官提供营养基质的关键过程 禁食期间。脂肪分解也有助于与以下相关的代谢病理学： 肥胖，因为脂肪组织中的脂质种类促进肝葡萄糖的产生，也是一种 是非酒精性脂肪肝中脂肪过多的重要原因。尽管 尽管脂解作用在哺乳动物生理学和病理生理学中的重要性，但仍有许多工作要做 了解其监管方式及其后果。已有报道称 多年来，神经肽催产素（Oxt）是脂肪分解的诱导剂。我们的初步数据 证实了这一点，但在几个重要领域更进一步。首先，我们证明 Oxt 信号传导不仅是禁食和寒冷环境下正常脂肪分解所必需的，而且 β-肾上腺素能激动剂也需要发挥其众所周知的促脂肪分解作用。我们也 确定 Oxt 的相关来源为支配 TH+ 交感神经元的亚群 白色脂肪库。在本提案中，我们打算全面表征细胞内信号传导 Oxt 促进脂肪分解的途径。此外，我们将通过以下方式确定本地机制： Oxt 水平是通过降解来控制的。最后我们会跟进初步数据 表明母体脂肪中的 Oxt 信号是确保乳汁具有适当营养成分所必需的 哺乳期间。总而言之，这些研究将极大地增进我们对脂肪分解的理解。 此外，Oxt 正在被用作治疗多种疾病的药物疗法， 包括焦虑和神经退行性疾病，这项工作将为 有关潜在代谢副作用的信息。