Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
Biochem J. 2020 Feb 14;477(3):709-725. doi: 10.1042/BCJ20190463.
Obesity results from energy imbalance, when energy intake exceeds energy expenditure. Brown adipose tissue (BAT) drives non-shivering thermogenesis which represents a powerful mechanism of enhancing the energy expenditure side of the energy balance equation. The best understood thermogenic system in BAT that evolved to protect the body from hypothermia is based on the uncoupling of protonmotive force from oxidative phosphorylation through the actions of uncoupling protein 1 (UCP1), a key regulator of cold-mediated thermogenesis. Similarly, energy expenditure is triggered in response to caloric excess, and animals with reduced thermogenic fat function can succumb to diet-induced obesity. Thus, it was surprising when inactivation of Ucp1 did not potentiate diet-induced obesity. In recent years, it has become clear that multiple thermogenic mechanisms exist, based on ATP sinks centered on creatine, lipid, or calcium cycling, along with Fatty acid-mediated UCP1-independent leak pathways driven by the ADP/ATP carrier (AAC). With a key difference between cold- and diet-induced thermogenesis being the dynamic changes in purine nucleotide (primarily ATP) levels, ATP-dependent thermogenic pathways may play a key role in diet-induced thermogenesis. Additionally, the ubiquitous expression of AAC may facilitate increased energy expenditure in many cell types, in the face of over feeding. Interest in UCP1-independent energy expenditure has begun to showcase the therapeutic potential that lies in refining our understanding of the diversity of biochemical pathways controlling thermogenic respiration.
肥胖是由能量失衡引起的，即能量摄入超过能量消耗。棕色脂肪组织（BAT）驱动非颤抖性产热，这是增强能量平衡方程中能量消耗方面的强大机制。BAT 中最被理解的产热系统是基于质子动力与氧化磷酸化的解偶联，通过解偶联蛋白 1（UCP1）的作用，UCP1 是冷介导产热的关键调节剂。同样，能量消耗是对热量过剩的反应触发的，并且具有减少的产热脂肪功能的动物可能会屈服于饮食诱导的肥胖。因此，当 Ucp1 的失活没有增强饮食诱导的肥胖时，这令人惊讶。近年来，已经清楚的是，存在多种基于以肌酸、脂质或钙循环为中心的 ATP 消耗的产热机制，以及由 ADP/ATP 载体（AAC）驱动的脂肪酸介导的 UCP1 独立泄漏途径。冷诱导和饮食诱导产热之间的一个关键区别在于嘌呤核苷酸（主要是 ATP）水平的动态变化，因此 ATP 依赖性产热途径可能在饮食诱导的产热中发挥关键作用。此外，AAC 的普遍表达可能有助于在面对过度喂养时，许多细胞类型增加能量消耗。对 UCP1 独立能量消耗的兴趣已经开始展示出治疗潜力，这在于细化我们对控制产热呼吸的生化途径多样性的理解。
