Janssen Research and Development, Spring House, Pennsylvania.
Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Am J Physiol Cell Physiol. 2022 Jun 1;322(6):C1085-C1094. doi: 10.1152/ajpcell.00034.2022. Epub 2022 Apr 27.
Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardiovascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ("yo-yo effect" or weight cycling). Strategies that increase REE are attractive treatment options. Brown fat tissue engages in nonshivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g., 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (chimeric antigen receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacological mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.
肥胖是一个广泛存在的公共卫生问题，具有深远的医学后果，其负担在全球范围内正在增加。肥胖会导致严重的发病率和死亡率，并与心血管疾病和糖尿病等疾病有关。传统的治疗选择要么不足，要么在减肥手术的情况下，相当具有侵入性。肥胖的病因很复杂，但核心通常是热量失衡，无法消耗足够的卡路里来超过热量摄入，导致储存。节食等干预措施通常会导致静息能量消耗 (REE) 减少，体重反弹（“溜溜球效应”或体重循环）。增加 REE 的策略是有吸引力的治疗选择。棕色脂肪组织参与非颤抖性产热，其中线粒体呼吸与 ATP 产生解耦联，从而增加 REE。通过线粒体解耦联复制棕色脂肪代谢的药物（例如，2,4-二硝基苯酚）有效地促进体重减轻，但受到毒性限制，治疗范围较窄。本综述探讨了一种新的治疗方法的可能性，即将自体 T 细胞工程化为获得类似于棕色脂肪的产热表型。经过多年的成功应用，工程化自体 T 细胞已被用于癌症治疗（嵌合抗原受体 T 细胞），并且体外工程化 T 细胞并将其转回患者体内的原理已经确立。工程化 T 细胞获得类似于棕色脂肪的代谢可以增加 REE，而不会有药理学线粒体解耦联的风险。这些产热 T 细胞可能会增加基础代谢率，因此是肥胖症的一种潜在新的治疗策略。
