Impact of Heme Homeostasis on Adipocyte Function

血红素稳态对脂肪细胞功能的影响

• 批准号: 9975170
• 负责人: Enrique Saez
• 金额: $ 52.87万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-09 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975170
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Antidiabetic Drugs; Binding; Biological Assay; Biological Process; Cell Nucleus; Cell physiology; Cells; Chemicals; Clinical; Defect; Degradation Pathway; Deposition; Diabetes Mellitus; Diabetic mouse; Electron Transport; Endoplasmic Reticulum; Enzymes; Exhibits; Fatty acid glycerol esters; Genetic; Genetic Transcription; Glucose; Goals; Heme; Hemeproteins; Homeostasis; Human; Hypertrophy; Insulin; Insulin Resistance; Integral Membrane Protein; Iron; Knockout Mice; Life; Ligands; Link; Lipids; Mammals; Membrane; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Molecular Chaperones; Movement; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Envelope; Nuclear Receptors; Null Lymphocytes; Obesity; Organelles; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Play; Process; Progesterone Receptors; Property; Prosthesis; Proteins; Proteome; Role; Signal Transduction; Signaling Molecule; Site; Testing; Therapeutic; Thermogenesis; Tissues; Work; adipocyte differentiation; adipokines; chemoproteomics; cytotoxic; gain of function; glucose metabolism; glucose tolerance; heme a; inhibitor/antagonist; innovation; insulin sensitivity; insulin sensitizing drugs; mitochondrial dysfunction; new therapeutic target; obesity treatment; programs; respiratory; screening; small molecule; tool; trafficking; transcriptome

ABSTRACT Defects in adipocyte function drive the onset of systemic insulin resistance and obesity-linked diabetes. Mitochondrial dysfunction is often associated with these obesity-induced abnormalities in adipocyte function. Agents that can revert these defects are clinically useful insulin sensitizers in humans. Using innovative tools, we recently isolated a small molecule that increased multiple aspects of adipocyte physiology and identified its target as Progesterone Receptor Membrane Component 2 (PGRMC2), a protein with no prior link to adipocyte function. The compound is not an inhibitor of PGRMC2, but rather, a gain-of-function ligand or activator. Treatment of obese-diabetic mice with a derivative of this molecule increased insulin sensitivity and glucose tolerance, indicating that activation of PGRMC2 function may be therapeutic. In contrast, adipose-specific PGRMC2-null mice exhibit profound defects in mitochondrial function, adaptive thermogenesis, and systemic glucose metabolism, highlighting the importance of PGRMC2 activity in adipocytes and systemic homeostasis. PGRMC2 is a poorly-characterized single-pass transmembrane protein with a putative heme-binding domain. It is localized in the endoplasmic reticulum and enriched in the nuclear envelope, and it reversibly binds heme. To stimulate adipocyte differentiation, chemical activation of PGRMC2 requires Rev-Erba, an adipogenic nuclear receptor whose natural ligand is heme, which suggests a role for PGRMC2 in heme trafficking. Heme is an essential prosthetic group for many proteins, and a signaling molecule in diverse biological processes. Because free heme is highly cytotoxic, heme-dependent processes require the rapid mobilization of heme to hemoproteins present in every organelle. Heme synthesis and degradation pathways are well known, but how heme synthesized in mitochondria reaches other organelles is not known. PGRMC2-null cells and tissues show alterations in intracellular heme partitioning, with decreased signaling heme in the nucleus. Thus, studying the function of PGRMC2 may provide the means to understand how heme is mobilized inside cells. Our hypothesis is that PGRMC2 plays a key role in intracellular heme homeostasis, facilitating heme delivery to the nucleus, and that this process is critical for adipocyte function and systemic physiology. This work may validate PGRMC2 as the first intracellular heme chaperone identified in mammals, one involved in transport of heme from mitochondria to the nucleus. It will also reveal the impact of heme metabolism on adipocyte function and systemic physiology. Further, because pharmacological activation of PGRMC2 has anti-diabetic effects, greater understanding of the function of PGRMC2 may provide the rationale to develop small-molecule PGRMC2 activators as insulin sensitizers.

抽象的 脂肪细胞功能缺陷会导致全身胰岛素抵抗和肥胖相关糖尿病的发生。 线粒体功能障碍通常与肥胖引起的脂肪细胞功能异常有关。 可以逆转这些缺陷的药物是临床上有用的人类胰岛素增敏剂。使用创新工具， 我们最近分离出一种小分子，它可以增强脂肪细胞生理学的多个方面，并确定了其 目标为黄体酮受体膜成分 2 (PGRMC2)，一种与脂肪细胞先前没有联系的蛋白质 功能。该化合物不是 PGRMC2 的抑制剂，而是一种功能获得性配体或激活剂。 用该分子的衍生物治疗肥胖糖尿病小鼠可增加胰岛素敏感性和血糖 耐受性，表明 PGRMC2 功能的激活可能具有治疗作用。相比之下，脂肪特异性 PGRMC2缺失小鼠在线粒体功能、适应性产热和全身功能方面表现出严重缺陷 葡萄糖代谢，强调了 PGRMC2 活性在脂肪细胞和全身稳态中的重要性。 PGRMC2 是一种特征较差的单次跨膜蛋白，具有假定的血红素结合结构域。它 定位于内质网并富集于核膜中，并且可逆地结合血红素。 为了刺激脂肪细胞分化，PGRMC2 的化学激活需要 Rev-Erba（一种脂肪生成剂） 其天然配体是血红素的核受体，这表明 PGRMC2 在血红素运输中发挥作用。血红素 是许多蛋白质的重要​​辅基，也是多种生物过程中的信号分子。 由于游离血红素具有高度细胞毒性，因此血红素依赖性过程需要血红素的快速动员 血红素蛋白存在于每个细胞器中。血红素合成和降解途径众所周知，但如何 线粒体中合成的血红素到达其他细胞器的情况尚不清楚。 PGRMC2 缺失细胞和组织 显示细胞内血红素分配的改变，细胞核内信号血红素减少。因此， 研究 PGRMC2 的功能可能提供了解血红素如何在细胞内动员的方法。 我们的假设是 PGRMC2 在细胞内血红素稳态中发挥关键作用，促进血红素输送 到细胞核，这个过程对于脂肪细胞功能和全身生理学至关重要。 这项工作可能验证 PGRMC2 是在哺乳动物中发现的第一个细胞内血红素伴侣，其中一个涉及 血红素从线粒体到细胞核的运输。它还将揭示血红素代谢对 脂肪细胞功能和全身生理学。此外，由于 PGRMC2 的药理学激活 抗糖尿病作用，更好地了解 PGRMC2 的功能可能为开发提供依据 小分子 PGRMC2 激活剂作为胰岛素增敏剂。