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謝博軒教授學術分享---慢性發炎與肥胖相關脂肪組織、糖尿病的研究



   Po-Shiuan Hsieh MD, PhD

   Director, Institute of Preventive Medicine

   Editor in Chief, Chinese Journal of Physiology



Chronic inflammation in the pathogenesis of obesity-associated adipose tissue dysfunction and type 2 diabetes
 
    The main focus of our research is to investigate the pathological links between inflammation and the development of metabolic syndrome and T2DM (1, 2). In particular, we are interesting to explore the possible involvement of obesity-associated adipose tissue inflammation and also chronic hepatic inflammation in the development of insulin resistance and β cell dysfunction.  We not only established the gold standard techniques such as euglycemia, hyperinsulinemia clamp and hyperglycemia clamp assess insulin resistance but also insulin secretion in vivo. Accordingly, we published a series of papers regarding the impact of chronic liver diseases on the development of T2DM, indicating that at least in part of the detrimental effect of hepatic inflammation on the development of T2DM is due to impair insulin secretion.  More recently, our relevant study has shown that the NADPH oxidase-mediated redox signaling plays an important role in the detrimental effect of hepatic derived acute phase protein- CRP on pancreatic insulin secretion (3). In addition, our research also focuses on the relationship of COX2-mediated inflammation and the development of insulin resistance in diet-induced non-obesity and obesity-related insulin resistance. Our results demonstrated that COX2-mediated inflammation is crucially contributed to the development of fructose-induced insulin resistance in rats, an animal model of metabolic syndrome. Treatment with COX2 inhibitors could significantly attenuate fructose-induced insulin resistance and oxidative stress in rats. On the other hand, we also have a great progress in the study of the COX2-mediated inflammation and obesity-linked adipose tissue inflammation, insulin resistance and fatty liver. Our study indicated  that COX2 activation might play a pivotal role in chronic inflammation in fat and its subsequent effects on whole body metabolism. Our investigation also demonstrated suppressive effect of COX-2 inhibitor on the progression of adipose inflammation not only in visceral but also subcutaneous fat in different time-dependent manner in high-fat induced obese rats. The importance of cyclooxygenase 2 –mediated oxidative stress has been demonstrated in obesity-induced muscular insulin resistance in high-fat-fed rats. 
 
    Recently, we further developed the molecular genetic methods in vitro and in vivo such as doxycycline-regulated overexpression of a short hairpin RNA to knowdown adipocyte COX-2 activation and established adipocyte COX-2 overexpression method to clarify the adipocyte COX-2 activation in the development of obesity-associated adipose tissue inflammation and systemic insulin resistance (4). The vicious cycle between hypertrophic, hypoxic adipocytes and adipose macrophages in the pathogenesis of adipose tissue inflammation would be further clarified in our ongoing study.

References
  1. Pei-Chi Chan and Po-Shiuan Hsieh (2017). The Role of Adipocyte Hypertrophy and Hypoxia in the Development of Obesity-Associated Adipose Tissue Inflammation and Insulin Resistance, Adiposity - Omics and Molecular Understanding, Prof. Jan Gordeladze (Ed.), InTech, DOI: 10.5772/65458.
  2. Po-Shiuan Hsieh (2011). Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance, Role of the Adipocyte in Development of Type 2 Diabetes, Dr. Colleen Croniger (Ed.), InTech, DOI: 10.5772/20561.  
  3. Pei-Chi Chan, Ya-Chin Wang, Yi-Ling Chen, Wan-Ning Hsu, Yu-Feng Tian, Po-Shiuan Hsieh (2017, Aug). Importance of NADPH oxidase-mediated redox signaling in the detrimental effect of CRP on pancreatic insulin secretion. Free Radical Biology and Medicine, 112: 200-211.
  4. Pei-Chi Chan, Fone-Ching Hsiao, Hao-Ming Chang, Martin Wabitsch, Po Shiuan Hsieh (2016, Jun). Importance of adipocyte cyclooxygenase-2 and prostaglandin E2–prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. The FASEB Journal 30(6): 2282-2297.
 
 
 
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