Cardiovascular complications of diabetes and obesity remain a major cause for morbidity and mortality worldwide. Despite significant advances in the pharmacotherapy of metabolic disease, the available approaches do not prevent or slow the progression of complications. Moreover, a majority of patients present with significant vascular involvement at early stages of dysfunction prior to overt metabolic changes. The lack of disease-modifying therapies affects millions of patients globally, causing a massive economic burden due to these complications. Significantly, adipose tissue inflammation was implicated in the pathogenesis of metabolic syndrome, diabetes, and obesity. Specifically, perivascular adipose tissue (PVAT) and perirenal adipose tissue (PRAT) depots influence cardiovascular and renal structure and function. Accumulating evidence implicates localized PVAT/PRAT inflammation as the earliest response to metabolic impairment leading to cardiorenal dysfunction. Increased mitochondrial uncoupling protein 1 (UCP1) expression and function lead to PVAT/PRAT hypoxia and inflammation as well as vascular, cardiac, and renal dysfunction. As UCP1 function remains an undruggable target so far, modulation of the augmented UCP1-mediated PVAT/PRAT thermogenesis constitutes a lucrative target for drug development to mitigate early cardiorenal involvement. This can be achieved either by subtle targeted reduction in UCP-1 expression using innovative proteolysis activating chimeric molecules (PROTACs) or by supplementation with cyclocreatine phosphate, which augments the mitochondrial futile creatine cycling and thus decreases UCP1 activity, enhances the efficiency of oxygen use, and reduces hypoxia. Once developed, these molecules will be first-in-class therapeutic tools to directly interfere with and reverse the earliest pathology underlying cardiac, vascular, and renal dysfunction accompanying the early metabolic deterioration.

中文翻译：

---

脂肪库的产热调节：对代谢损伤早期心肾并发症的可能治疗干预的观点

糖尿病和肥胖的心血管并发症仍然是全世界发病和死亡的主要原因。尽管代谢疾病的药物治疗取得了重大进展，但现有的方法并不能预防或减缓并发症的进展。此外，大多数患者在明显的代谢变化之前的功能障碍早期阶段就表现出明显的血管受累。疾病缓解疗法的缺乏影响着全球数百万患者，这些并发症造成了巨大的经济负担。值得注意的是，脂肪组织炎症与代谢综合征、糖尿病和肥胖症的发病机制有关。具体而言，血管周围脂肪组织（PVAT）和肾周围脂肪组织（PRAT）库影响心血管和肾脏的结构和功能。越来越多的证据表明，局部 PVAT/PRAT 炎症是对导致心肾功能障碍的代谢损伤的最早反应。线粒体解偶联蛋白 1 (UCP1) 表达和功能增加导致 PVAT/PRAT 缺氧和炎症以及血管、心脏和肾功能障碍。由于迄今为止 UCP1 功能仍然是一个不可成药的靶点，因此增强 UCP1 介导的 PVAT/PRAT 生热作用的调节构成了减轻早期心肾受累的药物开发的一个有利可图的目标。这可以通过使用创新的蛋白水解激活嵌合分子 (PROTAC) 微妙地有针对性地减少 UCP-1 表达来实现，或者通过补充磷酸环肌酸来实现，环肌酸会增强线粒体的无用肌酸循环，从而降低 UCP1 活性，提高氧利用效率，并减少缺氧。一旦开发出来，这些分子将成为一流的治疗工具，可以直接干扰和逆转伴随早期代谢恶化的心脏、血管和肾功能障碍的最早病理学。