5‑Heptadecylresorcinol Regulates the Metabolism of Thermogenic Fat and Improves the Thermogenic Capacity of Aging Mice via a Sirtuin 3–Adenosine Monophosphate-Activated Protein Kinase Pathway

5-Heptadecylresorcinol (AR-C17), a well-known biomarker for whole grain rye consumption, is a primary homolog of alkylresorcinols. In this study, the effects of AR-C17 on the thermogenesis of brown adipocytes and 3T3-L1 adipocytes were investigated. The results showed that AR-C17 increased sirtuin 3 (Sirt3) expression, and the expressions of specific thermogenic genes in adipocytes were increased. Furthermore, AR-C17 increased the mitochondrial functions during the thermogenic activation of adipocytes. In in vivo study, AR-C17 increased the cold tolerance and thermogenic capacity of adipose tissues in aging mice. In addition, Sirt3 activity was required for AR-C17-induced thermogenesis. Meanwhile, AR-C17 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and AMPK was involved in the regulation of AR-C17 on thermogenic adipocytes. Mechanically, AR-C17 upregulated a Sirt3–AMPK positive-feedback loop in adipocytes and further increased the expression of uncoupling protein 1 to activate thermogenesis. This study indicated that AR-C17 could be a promising thermogenic activator of adipocytes to alleviate obesity and aging-associated metabolic diseases.

5-十七烷基间苯二酚（5-Heptadecylresorcinol，AR-C17）是一种公认的全谷物黑麦摄入生物标志物，同时也是烷基间苯二酚类的主要同系物。本研究探究了AR-C17对棕色脂肪细胞与3T3-L1脂肪细胞产热作用的影响。结果显示，AR-C17可上调沉默信息调节因子3（Sirt3）的表达，并提升脂肪细胞中特异性产热基因的表达水平。进一步研究发现，AR-C17可增强脂肪细胞产热激活过程中的线粒体功能。在体内实验中，AR-C17可提升衰老小鼠的耐寒能力与脂肪组织产热能力。此外，Sirt3活性是AR-C17诱导产热作用所必需的。同时，AR-C17可促进腺苷酸活化蛋白激酶（AMPK）的磷酸化，而AMPK参与了AR-C17对产热脂肪细胞的调控。从分子机制层面来看，AR-C17在脂肪细胞中上调了Sirt3-AMPK正反馈环路，进而提升了解偶联蛋白1的表达以激活产热过程。本研究表明，AR-C17有望成为一种极具潜力的脂肪细胞产热激活剂，用于缓解肥胖及衰老相关代谢疾病。