Impact of Heme Homeostasis on Adipocyte Function

摘要 脂肪细胞功能缺陷导致全身性胰岛素抵抗和肥胖相关糖尿病的发病。 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。 能够修复这些缺陷的药物是对人类临床有用的胰岛素增敏剂。使用创新的工具， 我们最近分离了一种小分子，它可以增加脂肪细胞生理的多个方面，并鉴定了它的 靶点为孕激素受体膜组分2(PGRMC2)，这是一种与脂肪细胞没有先前联系的蛋白质 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，表明激活PGRMC2功能可能具有治疗作用。相比之下，特定于脂肪的 PGRMC2基因缺失的小鼠在线粒体功能、适应性产热和全身性 葡萄糖代谢，突出了脂肪细胞中PGRMC2活性和全身动态平衡的重要性。 PGRMC2是一种功能较差的单程跨膜蛋白，具有可能的血红素结合区。它 定位于内质网，并富含在核膜中，它可逆地与血红素结合。 为了刺激脂肪细胞分化，PGRMC2的化学激活需要成脂因子REV-ERBA 核受体，其天然配体是血红素，这表明PGRMC2在血红素运输中发挥作用。血红素 是许多蛋白质必需的修复基团，也是多种生物过程中的信号分子。 由于游离的血红素具有高度的细胞毒性，因此依赖于血红素的过程需要快速动员血红素以 血球蛋白存在于每个细胞器中。血红素合成和降解途径是众所周知的，但如何 在线粒体中合成的血红素到达其他细胞器尚不清楚。PGRMC2缺失的细胞和组织 显示细胞内血红素分配的改变，细胞核内的信号血红素减少。因此， 研究PGRMC2的功能可能为理解血红素如何在细胞内动员提供手段。 我们的假设是，PGRMC2在细胞内血红素动态平衡中发挥关键作用，促进血红素的运输 这一过程对脂肪细胞的功能和系统生理学至关重要。 这项工作可能会证实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 在血红素从线粒体到细胞核的运输中。它还将揭示血红素代谢对 脂肪细胞功能和系统生理学。此外，由于PGRMC2的药理激活具有 抗糖尿病作用，更多地了解PGRMC2的功能可能为开发提供理论基础 小分子PGRMC2激活剂作为胰岛素增敏剂。

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.