謝寶萱博士 2013/12/08 hsiehbs@gmail.com Adipocyte Fat body
Course outline: 一 肥胖流行病學 ( the epidemiology of obesity ) 二 脂肪細胞激素 ( adipocytokine ) 三 肥胖與免疫系統的關係 ( relationship between obesity and immune system ) 四 肥胖與疾病 ( obesity and diseases ) 五 熱量平衡 ( energy balance )
Obesity-associated diseases with immunological complication Nature Immunology 13:707-712, 2012 3
Underweight Normal Overweight Obese Extremely obese 身體質量指數 ( Body Mass Index ; BMI ) BMI = weight ( Kg ) height 2 ( m 2 )
Worldwide obesity has more than doubled since 1980.
腰圍 CVD: cardiovascular disease 6
Taiwan 4 %
台灣地區各縣市 98 至 100 年 18 歲以上過重及肥胖盛行率 ( 肥胖地圖 ) 衛生署國民健康局, 2012
What causes obesity and overweight? 卡路里 ( Calories ) 是熱量的單位 熱量密度 : 每公克食物所提供的熱量 康健雜誌選出 十大危險小吃, 前三名分別是鹽酥雞 蔥油餅和鍋貼 9
美研究..含糖飲料肥胖元凶 1 顆方糖 =5 公克 =20 大卡 含糖飲料是美國人飲食中最大卡路里來源, 且被視為造成美國三分之一兒童和青少年 逾三分之二成年人體重過重的主因 董氏基金會製
兩種脂肪分佈的體型 : Estimates of abdominal and gynoid fat mass by DEXA from the total body scan. 上身肥胖型 : android obesity 稱為蘋果型, 常見於男性血管疾病 高血壓 糖尿病 乳癌等的危險性較高 下身肥胖型 : gynoid obesity 稱為西洋梨型, 較常見於女性 男性腰臀圍比大於 0.9, 女性大於 0.8, 則罹患心血管疾病的機會增加
2-year-old children 29-year-old adult Stunkard, A., Sorensen, T., & Schlusinger, F. (1980) Newborn BMI: 3.5 kg/ 0.5X0.5 m 2 =14 J Pediatr Gastroenterol Nutr 52:90 95, 2011
Odds ratios for genes associated with obesity in genome-wide studies( 全基因組關聯研究 ). Fat mass and obesityassociated protein ( FTO ) Certain variants of the FTO gene appear to be correlated with obesity in humans. Nature Reviews Genetics 10:431-442, 2009
Obesity and depression The data come from 9,997 respondents to the National Health and Nutrition Examination Survey (NHANES), an interview survey of the US population. American Journal of Epidemiology 158:1139-1147, 2003
Serotonin ( 5-HT ) 血清素 : 人體的幸福分子 Serotonin converts to melatonin at night which controls our sleep/wake cycle and in turn promotes sleep. 飽食感 Nature Reviews Genetics 6:221-234, 2005
Adipose tissue depots. Nature Reviews Immunology 11:85-97, 2011
Brown adipose tissue(bat) * infants and small mammals * small lipid droplets * thermogenic organ * mitochondria rich * highly uncoupling protein 1 ( UCP1 ):dissipate energy White adipose tissue (WAT) * store energy: large lipid droplets * high vessel density * contribute immunity and inflammation triglycerides H/E stain UCP1 stain N Engl J Med 360:1500-1508, 2009 ; N Engl J Med 360:1518-1524, 2009
棕色脂肪組織 多功能幹細胞 多效性幹細胞 白色脂肪組織 AR: adrenergic receptors ( 腎上腺素接受體 ) T 3 : triiodothyronine ( 三碘甲狀腺素 ) TZD: Thiazolidinedione IGF-1: Insulin-like growth factor 1
老鼠皮下脂肪組織 剪碎後酵素分解 Fat accumulation during adipocyte maturation triglycerides ( fat ) Oil Red staining
間葉系幹細胞 PPAR γ CEBP α
Components of adipose tissue. Nature Reviews Immunology 11:85-97, 2011
Adipocytokine ( adipokine ) 脂肪組織具有內分泌功能, 能釋出游離脂肪酸及分泌數種激素, 統稱為脂肪細胞激素 ( adipocytokine ) (autonomic nervous system) 自主神經系統 白色脂肪細胞 J Clin Invest 106:473 481, 2000 23
Sources and functions of key adipokines Nature Reviews Immunology 11:85-97, 2011
Adipose tissue: cellular components and molecules synthesized. CC-chemokine ligand 2 (CCL2) Nature Reviews Immunology 6:772-783, 2006 25
Changes in adipose tissue in obesity * IL-6: interleukin-6 * PAI1: plasminogen activator inhibitor 1 26 * TNFα: tumur necrosis factor-α Nature Reviews Cancer 11:886-895, 2011
Phenotypic modulation of adipose tissue Nature Reviews Immunology 11:85-97, 2011
脂肪細胞激素 ( adipocytokine )- 瘦體素 ( leptin ) 1994 年發現 leptin 由 obese 基因調控表現 是 169 個胺基酸所組成的蛋白質 (16 kda ) 由脂肪組織合成, 主要作用在下視丘以抑制食慾, 可增加能量消耗, 藉此維持身體脂肪含量 作用機轉 : 是在下視丘中降低 neuropeptide Y( NPY ) 的作用, 而 NPY 可刺激食慾 抑制交感神經且增加副交感神經活性 給正常人注射瘦體素可使其體重下降, 但只有少部分肥胖者會有體重下降反應, 這可能是由於肥胖者有瘦體素抗阻現象 ( leptin resistance ) four-helix bundle *Y 型神經胜肽 ( neuropeptide Y, NPY ) 強力的飢餓信號, 可增進食慾
正常人之所以能維持正常體重, 是由於能量的攝取與消耗達到平衡 ; 而能量的攝取與消耗則靠下視丘來調控 下視丘側部 下視丘腹中核 飢餓中樞刺激食慾 飽食中樞抑制食慾 29
Leptin regulated adipose-tissue mass AGRP: agouti-related protein CART: cocaine and amphetamineregulated transcript NPY: neuropeptide Y POMC: pro-opiomelanocortin Nature Reviews Drug Discovery 1:276-286, 2002
Effects of leptin on the monocyte macrophage system. Nature Reviews Immunology 6:772-783, 2006 31
Leptin-deficient (ob/ob) mice Type 2 diabetes model hyperglycemia and obesity *Leptin is encoded by the obese gene.
脂肪細胞激素 ( adipocytokine )- 抵抗素 ( resistin ) 在 2001 年 Steppan, C. M. 等人發現並刊登於 Nature 期刊, 在誘導老鼠胰島素抗性時所表現出來的蛋白質, 故而稱之抵抗素 ( resistin ) 是 cysteine-rich protein 在人類是由 RETN 基因調控製造 108 amino acid polypeptide ( 約 12.5 kda ) 在動物實驗中被認為是肥胖的脂肪細胞所分泌而造成第二型糖尿病的重要因子 33
Effects of resistin on the monocyte macrophage system. Nature Reviews Immunology 6:772-783, 2006 34
脂肪細胞激素 ( adipocytokine )- 脂聯素 ( adiponectin ) 脂肪細胞 ( adipocytes ) 所製造及分泌 維持體內葡萄糖及脂質的代謝平衡有關 血漿中 adiponectin 的濃度非常高, 大約為 5-10 mg/l 與體脂肪 ( body fat mass ) 及身體質量指數 ( body mass index, BMI ) 成負相關, 體脂肪或是 BMI 高者, 其血清中的脂聯素濃度則偏低, 而體重的減輕也伴隨脂聯素濃度上升 第二型糖尿病的病人, 其血清中脂聯素的濃度比正常人來得低 增加脂聯素的生成, 可以增加葡萄糖的代謝且抑制肝臟中葡萄糖的合成而增加胰島素的敏感度, 脂聯素表現下降跟胰島素阻抗性有關 使肝臟及肌肉的三酸甘油脂 ( triglycerides, TG ) 下降, 刺激組織脂肪酸的氧化, 調節發炎反應 35
Adiponectin sources and structures. Nature Reviews Immunology 6:772-783, 2006 36
Effects of adiponectin on the monocyte macrophage system. IL-1RA: IL-1 receptor antagonist Nature Reviews Immunology 6:772-783, 2006 37
Adiponectin effects on anti-inflammatory cytokines. IL-1RA: IL-1 receptor antagonist Nature Reviews Immunology 6:772-783, 2006 38
窒息症 腦病變 The multiple functions of white adipose tissue. Nature Clinical Practice Rheumatology 3:716-724, 2007 39
schematic representation of the pleiotropic nature of leptin. Nature Clinical Practice Rheumatology 3:716-724, 2007 40
Summary of pathways that may link obesity to cancer development. Nature Reviews Cancer 11:886-895, 2011 41
Mechanisms through which WAT is proposed to promote cancer. Drug Discov Today, 2012
子宮內膜癌 Nature Reviews Cancer 4:579-591, 2004 43
Infertility is defined as the inability of a couple to conceive a child after 12 months of regular and unprotected sexual intercourse. According to this definition 15% of couples of reproductive age are infertile. Obesity and infertility
Leptin in reproduction Leptin stimulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. TRENDS in Endocrinology & Metabolism 12:65-72, 2001
Leptin is involved in embryo implantation, development and growth. Placenta 33:S63 S70, 2012
The effects of obesity on male infertility and the mechanisms involved. Asian Journal of Andrology 12:480 489, 2010
Expert Rev. Endocrinol. Metab. 5:229 251, 2010 DFI: DNA fragmentation index Nature Reviews Urology 7:153-161, 2010
Microbiota Nat Rev Immunol 9:313-323, 2009 PAMP: pathogen-associated molecular patter Nat Medicine 18:492 494, 2012
厚壁菌門擬桿菌門放線菌門變形菌門 Human microbiota( 人體消化道微生物相 ): onset and shaping through life stages and perturbations. Front. Cell. Inf. Microbio. 2:104-114, 2012
Relative proportion of firmicutes and bacteroidetes in lean and obese mice. 擬桿菌門 擬桿菌門 厚壁菌門 厚壁菌門 Arq Bras Endocrinol Metab. 53139-144, 2009 動物雙歧桿菌 植物乳酸桿菌副乾酪乳酸桿菌 洛德乳酸桿菌 L. reuteri was significantly linked with obesity. Nature Reviews Gastroenterology & Hepatology 8:537, 2011
肥胖症可能肇因於腸內細菌肥胖有可能是由腸內細菌所導致, 而不僅僅只是過度飲食 運動不足或遺傳因素 Features of the gut microbiota that promote obesity and insulin resistance. Nature 489:242 249, 2012
能源需求 (energy requirements) Insulin-like Growth Factor 1 靜態能量消耗 (resting energy expenditure) 身體活動量 (physical activity)
靜態能量消耗 ( Resting Energy Expenditure ) 基礎代謝率 ( basal metabolic rate ; BMR ) 相近於休息代謝率 ( resting metabolic rate ; RMR ) 在自然溫度環境下且處於消化末期 ( 進食後 12 小時 ) 的能量消耗, 包括維持生命的器官運作, 例如心臟 肝臟 肺臟 神經系統 小腸 肌肉 皮膚等 能量消耗表 ( energy expenditure table ) Liver ( 肝臟 ) 27 % Brain ( 腦 ) 19 % Skeletal muscle ( 骨骼肌肉 ) 18 % Kidneys ( 腎臟 ) 10 % Heart ( 心臟 ) 7 % Other organs ( 其他器官 ) 19 %
下列因素影響 BMR 值 : Genetics: 先天基因決定代謝快或是慢 Gender: 男性肌肉組織較多, 故有較高的基礎代謝率男性比女性高 10-15 % BMR Age: BMR 隨著年齡增加而降低, 每增加 10 歲降低 2 % Weight: 體重越重,BMR 越高 Body Surface Area: 高個子 ( 體表面積大 ) 較矮個子的 BMR 高 Body Fat Percentage: 脂肪比例越高,BMR 越低 Diet: 禁食或是嚴格熱量限制下,BMR 會降低約 30 % Body Temperature:. 體溫上升 0.5,BMR 上升 7 % Glands: 甲狀腺素增加會大量增加代謝速度 Exercise: 運動會增加卡路里的消耗, 也會提高 BMR http://www.calculator.org/calculate-online/health-fitness/basal-metabolic-rate.aspx
營養素身高體重熱量 (2)(3) 單位 公分 公斤 大卡 年齡 (1) (cm) (kg) (kcal) 男 女 男 女 0-6 月 61 60 6 6 7-12 月 72 70 9 8 90/ 公斤男女 1-3 歲 92 91 13 13 ( 稍低 ) 100/ 公斤 1150 1150 ( 適度 ) 1350 1350 國人熱量參考攝取量 ( 第七版 ) (Dietary Reference Intakes,DRIs) 4-6 歲 ( 稍低 ) ( 適度 ) 7-9 歲 ( 稍低 ) ( 適度 ) 10-12 歲 113 112 20 19 130 130 28 27 147 148 38 39 1550 1400 1800 1650 1800 1650 2100 1900 ( 稍低 ) 2050 1950 ( 適度 ) 2350 2250 13-15 歲 168 158 55 49 1 大卡 (kcal)=4.186 仟焦耳 (kj); 油脂熱量以不超過總熱量的 30% 為宜 ( 稍低 ) ( 適度 ) 16-18 歲 ( 低 ) ( 稍低 ) ( 適度 ) ( 高 ) 19-30 歲 172 160 62 51 171 159 64 52 2400 2050 2800 2350 2150 1650 2500 1900 2900 2250 3350 2550 ( 低 ) 1850 1450 低 稍低 適度 高 表示生活活動強度之程度 ( 稍低 ) ( 適度 ) ( 高 ) 31-50 歲 ( 低 ) ( 稍低 ) 170 157 64 54 2150 1650 2400 1900 2700 2100 1800 1450 2100 1650 ( 適度 ) 2400 1900 ( 高 ) 51-70 歲 165 153 60 52 2650 2100 ( 低 ) 1700 1400 ( 稍低 ) 1950 1600 ( 適度 ) 2250 1800 ( 高 ) 71 歲 - 163 150 58 50 2500 2000 ( 低 ) 1650 1300 ( 稍低 ) 1900 1500 ( 適度 ) 2150 1700 懷孕 第一期第二期 +0 +300 第三期 +300 哺 乳 期 +500
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總熱量需求 = 基礎代謝量 + 活動量 + 食物熱效應 使用骨骼和肌肉導致身體移動所消耗的熱量 在自然溫度環境下且處於消化末期 ( 進食後 12 小時 ) 的能量消耗, 包括維持生命的器官運作, 例如肝臟 (27 %) 腦(19%) 腎臟(10%) 心臟 (7 %) 等 58
身體活動量 ( Physical activity ) 身體活動所需的能量 世界衛生組織 ( WHO ) 定義 : 使用骨骼和肌肉導致身體移動所消耗的熱量 Physical inactivity, (a lack of physical activity) is an independent risk factor for chronic diseases, and overall is estimated to cause 1.9 million deaths globally. Regular physical activity such as walking, cycling, or dancing has significant benefits for health. For instance, it can reduce the risk of cardiovascular disease, diabetes and osteoporosis, help control weight, and promote psychological well-being. More activity may be required for weight control.
Inactivity and obesity sedentary lifestyle physical exercise exercise chronically Incidence of chronic diseases Inactivity and obesity as risk factors for developing chronic diseases. Sedentary Lifestyle: 坐式生活型態 Nature 454:463-469, 2008 60
Genetic predisposition( 基因易感性 ) obesity can be reduced by an average of 40% through increased physical activity.
Interplay between adipokines and myokines represent a yin yang balance. Nature Reviews Endocrinology 8:457-465, 2012
Myokines Functions of secretory factors from skeletal muscle. Advances in Biological Regulation 52:340 350, 2012
Inflammation and chronic diseases. Nature 454:463-469, 2008 64
* Peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) Effect of PGC1α on chronic systemic inflammation. Nature 454:463-469, 2008 65
McCay and colleagues concluded that caloric intake modulates the rate of aging since 1935. J. Nutr. 10:63-97, 1935 Caloric restriction retards aging and extend lifespan in yeast, worms, fish, flies, mice, rats, monkeys. Cell Mol. Life. Sci. 62:320-343, 2005 Caloric restriction is the only known non-genetic intervention that robustly extends lifespan in mammals. Nat. Rev. 8:835-844, 2007 Caloric restriction : a 20-40 % lowering of caloric intake
Caloric restriction Normal diet
The expression of mitochondrial genes and Sirt1 are also increased by caloric restriction. In white adipose tissue and other mouse tissues, caloric restriction (CR) induces cgmp production through an increase in enos levels. Nature Chemical Biology 1:355 356,2005
Nature Rev. Drug Discovery 7: 841-853, 2008
Nature 444: 868-874, 2006
均衡飲食 一份水果 : 一份水果約 1 個拳頭大或約 1 個飯碗切好的水果 一份蔬菜 : 生蔬菜 : 每份 100 克 ( 可食部分 ) 熟蔬菜 : 每份約等於 2/3 碗
謝謝聆聽 敬請指教