山竹子素透過抑制 HDAC11 表現減緩高脂飲食誘導之小鼠肥胖

Abstract

肥胖現今已是全球性的代謝疾病，過量脂肪蓄積可能造成心血管疾病，因此研究改善肥胖的手段是重要的議題。植化素預防肥胖的分子機制當中，包含了調控食慾、誘發米色與棕色脂肪非顫抖性產熱作用 (non-shivering thermogenesis, NST)，以及調節腸道菌相 (gut microbiota, GM)。山竹子素 (garcinol) 是一由印度鳳果 (Garcinia indica) 分離出的植化素。已有文獻證實garcinol 可降低組蛋白去乙醯酶11 (histone deacetylase 11, HDAC11) 的催化活性；先前文獻亦證實 HDAC11 的表現量與肥胖呈正相關、且與 NST 活性呈負相關。本實驗室先前研究指出，餵食 C57BL/6 小鼠混入 garcinol 粉末的飼料，可透過調節脂肪細胞相關因子表現量、增加 GM 中 Akarnania muciniphila 比例，減緩高脂飲食誘導的肥胖。因此，本研究將進一步探討降低 HDAC11 活性、促進 NST 活化與增加 GM 代謝物短鏈脂肪酸 (short chain fatty acids, SCFAs)，是否為 garcinol 抗肥胖的分子機制。本研究的動物實驗中，給予 0.25% 的 garcinol 具有減少攝食量並減緩攝食高脂飲食小鼠體重上升的效果，此現象可能與血清中升高的類升糖素胜肽-1 (Glucagon-like peptide-1, GLP-1) 與降低的瘦素 (leptin) 相關。garcinol 介入能有效降低肝臟重量，在 H&E 染色的影像中也能觀察出減少油滴累積的現象。另外，在白色脂肪相關實驗數據中，可觀察到 garcinol 顯著降低其重量與細胞粒徑大小，western blot 結果顯示，促進 ACC 磷酸化和 ATGL 蛋白表現量為其中機轉。經實驗測定，garcinol 使糞便中的丙酸 (propionic acid) 及丁酸 (butyric acid) 含量顯著增加。在細胞實驗模式下，3T3-L1 脂肪細胞在15 μM garcinol 介入後，不但能從油紅染色實驗觀察到油滴蓄積顯著降低，亦能從蛋白表現量的分析中得知 garcinol 透過活化 AMPK 促進 UCP1 與 PRDM16 之表現。綜上所述，本研究證實 garcinol 可透過抑制食慾、調節脂肪細胞代謝與促進 GM 生成 SCFAs，達到抗肥胖的效果。

Obesity is a global metabolic disease characterized by dysfunctional adipose tissue. Many phytochemicals prevent obesity by enhancing satiety, inducing non-shivering thermogenesis (NST) in adipocytes and regulating gut microbiota (GM) composition. garcinol, a polyisoprenylated benzophenone compound isolated from Garcinia indica, has been proven to inhibit histone deacetylase 11 (HDAC11), which positively correlates with obesity with its NST downregulating ability. A previous study also indicated garcinol could curb high-fat diet (HFD)-induced obesity in mice by affecting the expression of adipose associated factors and increasing Akkermansia muciniphila in GM. Whereas, whether garcinol exerts its anti-obesity ability via binding HDAC11, activating NST and increasing short-chain fatty acids (SCFAs) needs further research. Therefore, we aim to study the underlying anti-obesity molecular mechanisms of garcinol, especially lipids metabolism and NST activity in adipocytes and SCFAs generated by GM in mice. Our results show that 0.25% oral garcinol supplementation significantly decreases body weight and energy intake with higher GLP-1 and lower leptin levels in serum. garcinol reduces lipids accumulation in liver, and decreases the sizes of white adipocytes by upregulating phosphorylation levels of ACC and ATGL expressions in HFD-induced obese mice. Additionally, garcinol also increases fecal propionic and butyric acids. In vitro experiments indicate less triglyceride accumulation, and upregulate UCP1 and PRDM16 protein expression by AMPK activation within adipocytes with a 15 μM garcinol intervention in 3T3-L1 adipocytes. In conclusion, our study demonstrates that garcinol prevents obesity by suppressing appetite, modulating adipocyte metabolism and enhancing SCFAs synthesis.