肥胖發炎與糖尿病
國防醫學院生理學研究所
謝博軒教授兼所長
成人肥胖定義及分類
• 定義 肥胖是指體脂肪囤積過多
• 評估方式
– 身體質量指數 (body mass index, BMI) = Body
weight (kg) / height2 (m2) 與體脂肪有高度相關性
– BMI 易造成分類錯誤之個案，運動員(高估) 、
少女和年長者(低估)
– 合併腰圍和 BMI 測量，能減少錯誤分類
– 相同BMI ≠ 相同體脂率(男<女，年長>年輕)
“Thrifty gene” hypothesis
肥胖是全球性的問題
台灣成人過重與肥胖的盛行率
The prevalence of overweight (BMI>24 kg.m-2) and obesity
(BMI>27 kg.m-2) in Taiwanese adults categorized by gender
and calendar years (Obesity review 2008)
肥胖臨床併發症
6
肥胖對死亡率之影響
肥胖與糖尿病
肥胖與糖尿病的盛行率
肥胖發炎與糖尿病
免疫機制與營養狀態之關聯性
肥胖發炎與疾病的關聯性
肥胖和脂肪組織發炎
脂肪組織發炎和免疫細胞浸潤
肥胖組織發炎與胰島素抗性
Chronic inflammation in fat plays a crucial role in the
development of obesity-related insulin resistance
J Clin Invest. 112(12):1821-30 (2003).
Obesity is associated with macrophage accumulation
in adipose tissue
J. Clin. Invest. 112:1796–1808 (2003).
Crown-like structure
脂肪細胞與巨噬細胞在代謝與免疫反應的
共同機轉
肥胖誘發的發炎反應與胰島素抗性之關聯性
Adaptive immune system
19
Arterioscler Thromb Vasc Biol.
2008;28:1211-1213
T-cell and RANTES
Circulation. 2007;115:1029-1038
20
International Journal of Obesity (2008) 32, 451–463
後天免疫系統對脂肪組織發炎的影響
15 (8): 914-921, 2009
15 (8): 930-939, 2009
21
Adipose tissue cell interactions during High-fat diet induced
inflammation
CIITA, class II transactivator, the master transcriptional regulator of the MHCII pathway
MHCII, major histocompatibility complex II
Cell Metabolism 17:411-422, 2013
Obesity and Adipose Tissue Inflammation
肥胖造成發炎反應機轉及系統性胰島素抗性產生關係
抗發炎性藥物在肥胖治療上的開發與應用
Obesity and Inflammation
抗發炎性藥物在肥胖誘發胰島素抗性和心血
管疾病的治療潛力
■ Yuan MS et al. Reversal of obesity- and diet-induced insulin resistance
with salicylates or targeted disruption of IKKβ.
Science 2001 31:1673-1677
■ Hirosumi J et al. A central role for JNK in obesity and insulin resistance.
Nature 2002 420:333-337
JNK, c-jun amino-terminal kinase
The Importance of Adipose Cyclooxygenase 2 activation in the Development of
Obesity-induced Insulin Resistance and Fatty Liver
Circulation 2004;109;1729-1734
COX 2 Activation and Obesity-induced adipose inflammation
Obesity
COX-2
inhibitor
COX-2
↑
MCP-1↑
MCP-1↓
TNF-α、MCP-1
Improved
insulin
sensitivity
COX 2 Activation and Obesity-associated suppression
In adipocyte differentiation
Adipose tissue
inflammation
Pro-inflamatory cytokines and
chemokines
TNF-α, MCP-1
COX-2
COX-2 inhibitor
COX-2
Differentiation
Adipocyte
hypertrophy
European Journal of Clinical Investigation 2008 38
(11): 812-819.
Obesity 2009 17(6):1150-1157
European J Clinical Investigation 2010:40(2):164-171
Life Science 2011:89:107-114
肥胖與免疫治療
Arterioscler Thromb Vasc Biol. 2008;28:1211-1213
37
Nature Medince 15(8):921-930, 2009
Diet-induced obese mice
ob/ob obese mice
T helper type 1 (TH1) cells
T helper type 2 (TH2) cells
CD3-specific antibody 10 ug/d x 5
Lasting > 4 months
結論
I. 肥胖發炎在第二型糖尿病的發展上扮演重要角色
II. 肥胖發炎主要來自於脂肪組織發炎
III.先天(Innate immunity)和後天免疫(adaptive
immunity)系統在肥胖造成脂肪組織發炎中均扮演
重要角色
IV.特定抗發炎性藥物具有改善肥胖發炎和胰島素抗
性的潛力
V. 免疫治療具治療肥胖相關第二型糖尿病的潛力
身體對營養過剩與病原體感染之反應系統之
異同
肥胖病人都需要接受治療嗎?
肥胖治療策略
減重(飲食運動)
抗發炎性藥物??
脂肪組織無發炎
正常生理功能
脂肪組織發炎
系統性胰島素抗性
心血管疾病
(需積極治療族群)
Thank you for your attention
展望未來
Where will we be tomorrow?
• 肥胖盛行率往後可能會持續升高
• 學者依目前肥胖增加趨勢，預計到2030年
每個人都會變成肥胖