Abdillah Alfin Mohammad, Lee Jae Young, Lee Young Rok, Yun Jong Won
Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
Chem Biol Interact. 2025 Feb 1;407:111380. doi: 10.1016/j.cbi.2025.111380. Epub 2025 Jan 10.
Capsaicin, a polyphenol, is known to regulate energy expenditure and thermogenesis in adipocytes and muscles. However, its role in modulating uncoupling proteins (UCPs) and adenosine triphosphate (ATP)-dependent thermogenesis in muscles remains unclear. This study investigated the mechanisms underlying the role of capsaicin in modulating the UCP- and ATP-dependent thermogenesis in C2C12 myoblasts, as well as the gastrocnemius (GM) and soleus muscles (SM) of mice. We employed molecular dynamics (MD), quantitative real-time polymerase chain reactions (qRT-PCR), immunoblots, staining methods, and assay kits to investigate the role of capsaicin on thermogenesis and its modulatory roles on the transient receptor potential cation channel subfamily V member 1 (TRPV1) and α-/β-adrenergic receptors (ARs) using in vitro and in vivo models. Our findings demonstrate that capsaicin treatment in high-fat diet-induced obese mice reduces weight gain and elevates the expression of UCP- and ATP-dependent thermogenic effectors through ATP-consuming calcium and creatine futile cycles. In vitro and in vivo models capsaicin treatment elevated the expression of sarcoendoplasmic/endoplasmic reticulum calcium ATPases (SERCA-1 and -2), ryanodine receptors (RYR-1 and -2), uncoupling proteins (UCP-2 and -3), creatine kinase B (CKB), and creatine kinase mitochondrial 2 (CKMT2), through activation of TRPV1, α1-, β2-, and β3-AR as well as the suppressed expression of α2-AR. Furthermore, our results also indicate that capsaicin promotes myotube development and enhances lipid metabolism in C2C12 cells. We found that capsaicin increased intracellular Ca levels and the expression of the voltage-dependent anion channel (VDAC) and mitochondrial calcium uniporter (MCU), suggesting that elevated mitochondrial Ca levels boost the expression of oxidative phosphorylation protein complexes via the activation of the ATP-futile cycle. Mechanistic studies in C2C12 cells revealed that TRPV1 is likely dispensable for capsaicin-induced thermogenesis, and TRPV1 and α1-AR may synergistically induce thermogenesis. Collectively, our findings have uncovered a novel mechanism of UCP- and ATP-dependent thermogenesis and its associated pathways in both cellular and animal models which is crucial for designing therapeutic strategies to address obesity and associated metabolic diseases.
辣椒素是一种多酚类物质，已知其可调节脂肪细胞和肌肉中的能量消耗及产热作用。然而，其在调节肌肉中解偶联蛋白（UCPs）和三磷酸腺苷（ATP）依赖性产热方面的作用仍不清楚。本研究调查了辣椒素在调节C2C12成肌细胞以及小鼠腓肠肌（GM）和比目鱼肌（SM）中UCP依赖性和ATP依赖性产热作用的潜在机制。我们采用分子动力学（MD）、定量实时聚合酶链反应（qRT-PCR）、免疫印迹、染色方法和检测试剂盒，利用体外和体内模型研究辣椒素对产热的作用及其对瞬时受体电位阳离子通道亚家族V成员1（TRPV1）和α/β-肾上腺素能受体（ARs）的调节作用。我们的研究结果表明，在高脂饮食诱导的肥胖小鼠中，辣椒素治疗可减少体重增加，并通过消耗ATP的钙和肌酸无效循环提高UCP依赖性和ATP依赖性产热效应器的表达。在体外和体内模型中，辣椒素治疗通过激活TRPV1、α1-、β2-和β3-AR以及抑制α2-AR的表达，提高了肌浆网/内质网钙ATP酶（SERCA-1和-2）、兰尼碱受体（RYR-1和-2）、解偶联蛋白（UCP-2和-3）、肌酸激酶B（CKB）和肌酸激酶线粒体同工酶2（CKMT2）的表达。此外，我们的结果还表明，辣椒素可促进C2C12细胞中的肌管发育并增强脂质代谢。我们发现辣椒素可提高细胞内钙水平以及电压依赖性阴离子通道（VDAC）和线粒体钙单向转运体（MCU）的表达，这表明线粒体钙水平升高通过激活ATP无效循环促进氧化磷酸化蛋白复合物的表达。在C2C12细胞中的机制研究表明，TRPV1可能对辣椒素诱导的产热作用并非必需，并且TRPV1和α1-AR可能协同诱导产热。总的来说，我们的研究结果揭示了细胞和动物模型中UCP依赖性和ATP依赖性产热的新机制及其相关途径，这对于设计治疗肥胖症及相关代谢疾病的策略至关重要。
