Regulatory mechanisms of quercetin and zeranol on adipogenesis and insulin signaling

Ph.D.Obesity, the hallmark of metabolic syndromes, is now a major public health and economic problem worldwide. The role of calcium in adipocytes has been implicated by numerous studies. The increase in intracellular calcium has been shown to cause inhibition of adipogenesis and decreased insulin sensitivity in the 3T3-L1 fibroblast cell line. Transient Receptor Potential (TRP) channels, a group of non-selective cation channels with a high permeability to calcium, are known to be important to human health due to their abundance and contribution to many diseases. The modulation of Transient Receptor Potential (TRP) Channels may potentially regulate the intracellular calcium homeostasis and its downstream signaling, further regulate the adipocyte differentiation and insulin signaling. However, the role of TRP isoforms in adipocytes has not yet been fully elucidated. In this project, we showed that TRPC6 isoform activation could lead to the suppression of adipocyte differentiation while TRPV1 channel inhibition could improve adipose insulin sensitivity, making them novel targets for pharmacological modulation.Many flavonoids are known to have anti-obesogenic properties. In this study, five flavonoids found abundantly in diet, including epicatechin, naringenin, apigenin, quercetin and luteolin, were screened for their modulatory roles on adipocyte TRP channels. We delineated that quercetin exerts its anti-adipogenic effect through activating membrane TRPC6 channel in 3T3-L1 cell line and visceral adipocytes of C57/BL6J mice. An animal study revealed that quercetin treatment reversed high-fat-diet-induced obesity through upregulating TRPC6 protein expression and downregulating the phosphorylation of AKT (PKB) and PI3K. However, the modulation of TRPC6 and PKB axis only occurred in visceral adipose tissue, but not in subcutaneous adipose tissue.Research has shown that food toxicants promote the development of insulin resistance, the linkage between obesity and diabetes mellitus. The role of TRP channels in insulin signaling has also caught increasing research attention. Toxic plastics and mycotoxins are two groups of food contaminants that may cause adverse health effects. In this study, we illustrated that among the selected food contaminants, the potent mycotoxin a-Zeranol downregulated adipocyte TRPV1 and TRPC6 channels, and improved adipose insulin sensitivity and glucose homeostasis. Results further delineated that antagonizing TRPV1 channel in 3T3-L1 by using pharmacological modulator improved insulin signaling.Collectively, the results of this project provided a novel understanding of the roles of TRP isoforms in the process of adipogenesis and insulin signaling. Besides, the findings enriched our understanding of the mechanisms of food phytochemicals and contaminants in regulating adipogenic-related processes.由於世界肥胖人口比率的上升，肥胖症已成為全球性的趨勢。鈣離子通道由於在細胞中起著許多調節功能而備受關注。鈣離子在脂肪細胞生成及胰島素信號傳導過程中起著重要的作用，細胞內鈣離子濃度的增加可抑制3T3-L1脂肪細胞的分化及降低胰島素敏感性。暫態感受器電位（TRP）通道是一類在器官組織分佈廣泛的離子通道，對鈣離子擁有高通透性 。研究顯示暫態感受器電位元（TRP）通道在人體內分佈廣泛且與許多疾病的產生息息相關。在本研究中，我們探討了暫態感受器電位（TRP）通道在脂肪細胞中的作用，從而深入瞭解暫態感受器電位（TRP）通道與肥胖症及糖尿病的作用。我們發現在3T3-L1細胞啟動TRPC6通道可抑制脂肪的分化，從而達到抑制肥胖的作用。此外，我們研究了幾種常見的類黃酮化合物對脂肪細胞TRP通道的影響。在此研究中，我們發現TRPC6可被槲皮素啟動，從而抑制3T3-L1脂肪細胞的分化及預防高脂飲食誘導肥胖C57/BL6J小鼠內臟脂肪的含量。近年來，暫態感受器電位（TRP）通道在胰島素信號傳導中的作用引起了許多關注。 研究指出胰腺β細胞中的TRP通道可参与調節胰島素的分泌。由於脂肪細胞亦參與了體內胰島素信號的傳導，在這項研究中，我們使用了3T3-L1細胞来研究幾種食源污染物對脂肪細胞胰島素敏感性的影響以及在脂肪細胞中與TRP通道的作用。研究結果顯示在3T3-L1細胞及2型糖尿病小鼠模型 db/db中，a-玉米赤黴醇可改善脂肪細胞的胰島素敏感性，且下調3T3-L1細胞中TRPV1及TRPC6通道的表達。除此之外，我們發現在脂肪細胞中抑制TRPV1通道可改善胰島素敏感性，對血糖起到調控的作用。這項研究的意義在於增加了我們對於TRP通道在脂肪細胞中作用的理解。此外，亦增加了我們對於類黃酮化合物及食源污染物在調節脂肪相關過程機制的理解。Tan, Yan Qin.Thesis Ph.D. Chinese University of Hong Kong 2019.Includes bibliographical references (leaves 160-175).Abstracts also in Chinese.Title from PDF title page (viewed on 7, May 2021)