We and others have shown that apple polyphenols decrease adipose tissue mass. To better understand the underlying mechanisms and to expand clinical applicability, we herein examine whether apple polyphenols induce adipose thermogenic adaptations (browning) and prevent diet-induced obesity and related insulin resistance. In mice fed a standard diet, daily apple polyphenol consumption induced thermogenic adaptations in inguinal white adipose tissue (iWAT), based on increases in the expression of brown/beige adipocyte selective genes (Ucp1, Cidea, Tbx1, Cd137) and protein content of uncoupling protein 1 and mitochondrial oxidative phosphorylation enzymes. Among the upstream regulatory factors of browning, fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptor gamma coactivator 1 α (PGC-1α) levels were concomitantly up-regulated by apple polyphenols. In the primary cell culture experiment, the results did not support a direct action of apple polyphenols on beige adipogenesis. Instead, apple polyphenols increased tyrosine hydroxylase (a rate-limiting enzyme of catecholamine synthesis) in iWAT, which activates the adipocyte thermogenic program possibly via intratissue cellular communications. In high-fat fed mice, apple polyphenols induced beige adipocyte development in iWAT, reduced fat accumulation, and increased glucose disposal rates in the glucose and insulin tolerance tests. Taken together, dietary administration of apple polyphenols induced beige adipocyte development in iWAT possibly via activation/induction of the peripheral catecholamine synthesis–FGF21–PGC-1α cascade. Results from diet-induced obese mice indicate that apple polyphenols have therapeutic potential for obesity and related metabolic disorders.

我们和其他人已经表明，苹果多酚可减少脂肪组织的质量。为了更好地理解其潜在机制并扩大临床适用性，我们在本文中研究了苹果多酚是否诱导脂肪的热适应性（褐变）并预防饮食引起的肥胖症和相关的胰岛素抵抗。在饲喂标准饮食的小鼠中，每天食用苹果多酚会导致腹股沟白脂肪组织（iWAT）发生热适应，这是基于棕色/米色脂肪细胞选择性基因（Ucp1，Cidea，Tbx1，Cd137）的表达增加以及解偶联的蛋白质含量引起的。蛋白1和线粒体氧化磷酸化酶。在褐变的上游调控因素中，苹果多酚同时上调了成纤维细胞生长因子21（FGF21）和过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的水平。在原代细胞培养实验中，结果不支持苹果多酚对米色脂肪形成的直接作用。相反，苹果多酚会增加iWAT中的酪氨酸羟化酶（儿茶酚胺合成的限速酶），从而可能激活脂肪细胞的产热程序通过组织内细胞通讯。在高脂喂养的小鼠中，苹果多酚在iWAT中诱导米色脂肪细胞发育，减少了脂肪积累，并在葡萄糖和胰岛素耐受性测试中提高了葡萄糖处置率。综上所述，苹果多酚的饮食管理可能通过激活/诱导周围儿茶酚胺合成–FGF21 –PGC-1α级联来诱导iWAT中的米黄色脂肪细胞发育。饮食诱导的肥胖小鼠的结果表明，苹果多酚对肥胖症和相关的代谢紊乱具有治疗潜力。