本實驗室之長期研究方向及目標為以轉殖基因小鼠及細胞系統，了解複雜的人類疾病之成因及結果，以研究其致病機轉。我們成功的轉殖了不同層次的PPARg於小鼠中，來測試PPARg的變化是否會導致代謝失常。而從小鼠的系統中，我們鑑定了PPARg一 些獨特的功能，包括其在維持個別脂肪功能的重要性，以及會與調控血管的完整性。另外，我們也開始著手於研究脂質發炎反應及胰島素抗性的成因；為了了解日常 飲食中是否有會引起發炎反應訊息的因子，我們主要研究由飲食成分所引起的TLR所調控的發炎信息傳遞，以及其所參與的代謝性疾病。今後我們想將研究重點轉 向透過近來相當熱門的分子影像技術，在不傷害活體下，進行體內分子影像來研究致病機轉，同時結合活體影像系統及數種轉殖冷光基因鼠，藉此在非侵入性的情形 下，來分析NF-kB及PPAR在各種不同的病理條件下的活性。而藉由結合基礎及轉譯的研究方法，可以幫助我們對人類疾病有更大的 了解。
Obese (ob/ob) mice were used to examine physical, morphological, and molecular changes in the aorta in response to obesity. ob/ob mice had increased aortic pulse wave velocity and tissue rigidity. ob/ob aorta exhibited decreases of lysyl oxidase (LOX) activity and cross-linked elastin, and increases of elastin fragmentation and elastolytic activity. The aortas of ob/ob mice were surrounded by a significant amount of proinflammatory and pro-oxidative perivascular adipose tissue. In vitro studies revealed that the conditioned medium from differentiated adipocytes or the perivascular adipose tissue of ob/ob mice attenuated LOX activity. Furthermore, inhibition of LOX in wild-type lean mice caused elastin fragmentation and induced a significant increase in pulse wave velocity. Finally, we found that obese humans had stiffer arteries and lower serum LOX levels than do normal-weight humans. Our results demonstrated that obesity resulted in aortic stiffening in both humans and mice, and established a causal relationship between LOX downregulation and aortic stiffening in obesity. (Arterioscler Thromb Vasc Biol. 2013;33:839-846.)
We revealed that excess palmitate (PA) induced mitochondrial fragmentation which was associated with increased oxidative stress, mitochondrial depolarization, loss of ATP production, and reduced insulin-stimulated glucose uptake. Inhibition of mitochondrial ?ssion improved the muscle insulin signaling and systemic insulin sensitivity of obese mice. Our ?ndings indicated that aberrant mitochondrial ?ssion is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle. Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.
The expression of TLR2 and inflammatory cytokines were elevated in white adipose tissue and liver of ob/ob mice. Mice lacking TLR2 exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. This is accompanied by reductions in expression of inflammatory cytokines and activation of extracellular signal-regulated kinase (ERK) in a liver-specific manner. The attenuated hepatic inflammatory cytokine expression and related signalling are correlated with increased insulin action specifically in the liver in TLR2-deficient mice, reflected by increased insulinstimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulinsuppressed hepatocyte glucose production. We concluded that the absence of TLR2 attenuates local inflammatory cytokine expression and related signalling and increases insulin action specifically in the liver. Thus, our work has identified TLR2 as a key mediator of hepatic inflammation-related signalling and insulin resistance.