Guarnieri Adrienne R, Benson Tyler W, Tranter Michael
University of Cincinnati College of Medicine, United States.
University of Cincinnati College of Medicine, United States
Mol Pharmacol. 2022 May 3;102(1):51-9. doi: 10.1124/molpharm.121.000465.
Canonical non-shivering thermogenesis (NST) in brown and beige fat relies on uncoupling protein 1 (UCP1)-mediated heat generation, although alternative mechanisms of NST have been identified, including sarcoplasmic reticulum (SR)-calcium cycling. Intracellular calcium is a crucial cell signaling molecule for which compartmentalization is tightly regulated, and the sarco-endoplasmic calcium ATPase (SERCA) actively pumps calcium from the cytosol into the SR. In this review, we discuss the capacity of SERCA-mediated calcium cycling as a significant mediator of thermogenesis in both brown and beige adipocytes. Here, we suggest two primary mechanisms of SR calcium mediated thermogenesis. The first mechanism is through direct uncoupling of the ATPase and calcium pump activity of SERCA, resulting in the energy of ATP catalysis being expended as heat in the absence of calcium transport. Regulins, a class of SR membrane proteins, act to decrease the calcium affinity of SERCA and uncouple the calcium transport function from ATPase activity, but remain largely unexplored in adipose tissue thermogenesis. A second mechanism is through futile cycling of SR calcium whereby SERCA-mediated SR calcium influx is equally offset by SR calcium efflux, resulting in ATP consumption without a net change in calcium compartmentalization. A fuller understanding of the functional and mechanistic role of calcium cycling as a mediator of adipose tissue thermogenesis and how manipulation of these pathways can be harnessed for therapeutic gain remains unexplored. Enhancing thermogenic metabolism in brown or beige adipose tissue may be of broad therapeutic utility to reduce obesity and metabolic syndrome. Canonical BAT-mediated thermogenesis occurs via uncoupling protein 1 (UCP1). However, UCP1-independent pathways of thermogenesis, such as sarcoplasmic (SR) calcium cycling, have also been identified, but the regulatory mechanisms and functional significance of these pathways remain largely unexplored. Thus, this mini-review discusses the state of the field with regard to calcium cycling as a thermogenic mediator in adipose tissue.
棕色和米色脂肪中的经典非颤抖性产热（NST）依赖于解偶联蛋白1（UCP1）介导的产热，尽管已经确定了NST的其他机制，包括肌浆网（SR）-钙循环。细胞内钙是一种关键的细胞信号分子，其区室化受到严格调控，而肌浆网/内质网钙ATP酶（SERCA）则将钙从细胞质主动泵入肌浆网。在这篇综述中，我们讨论了SERCA介导的钙循环作为棕色和米色脂肪细胞产热的重要介质的能力。在这里，我们提出了SR钙介导产热的两种主要机制。第一种机制是通过直接解偶联SERCA的ATP酶和钙泵活性，导致在没有钙转运的情况下，ATP催化的能量以热的形式消耗。调节蛋白是一类SR膜蛋白，其作用是降低SERCA对钙的亲和力，并使钙转运功能与ATP酶活性解偶联，但在脂肪组织产热中在很大程度上仍未被探索。第二种机制是通过SR钙的无效循环，即SERCA介导的SR钙内流被SR钙外流等量抵消，导致ATP消耗而钙区室化没有净变化。对钙循环作为脂肪组织产热介质的功能和机制作用以及如何操纵这些途径以获得治疗益处的更全面理解仍未被探索。增强棕色或米色脂肪组织中的产热代谢可能对减少肥胖和代谢综合征具有广泛的治疗用途。经典的褐色脂肪组织（BAT）介导的产热是通过解偶联蛋白1（UCP1）发生的。然而，也已经确定了不依赖UCP1的产热途径，如肌浆网（SR）钙循环，但这些途径的调节机制和功能意义在很大程度上仍未被探索。因此，这篇小型综述讨论了关于钙循环作为脂肪组织中产热介质的该领域现状。
