肥胖型高血压的临床特征及血管紧张素Ⅱ受体拮抗剂干预的机制研究
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摘要
背景和目的:
研究表明,肥胖人群更容易发生高血压,以各种肥胖指标(体重指数、腰围(WC)、腰-臀比等)评定的肥胖程度均与血压水平有较好的相关性。肥胖与高血压合并存在,更易发生糖尿病、高脂血症、冠状动脉、脑动脉粥样硬化及外周血管病变。腹内脂肪堆积是腹型肥胖的重要临床特征和病理生理基础,与胰岛素抵抗、高血压、代谢异常等心血管危险因素密切相关。但应用腹内脂肪指标专门观察对高血压患者的代谢影响的研究较少。
腹型肥胖时,常伴有内脏脂肪大量堆积,其分泌的众多炎症介质、细胞和脂肪因子在心血管和代谢病的发病中起重要作用。研究证实,亚洲地区人群的腹内脂肪面积(Visceral fat area,VA)≥100cm2可诊断为内脏脂肪型肥胖(visceral fat obesity,VFO)。达到此切点,心血管代谢危险性明显增加。目前临床诊断腹型肥胖主要依据测量腰围和腰臀比,但这两个体脂指标与内脏脂肪量存在一定程度的不一致。因此,这将出现几种应用常规体脂参数测量不能准确评价的情况,如WC正常、VA超标或WC超标、而VA正常,我们将前者称之为“隐性内脏脂肪型肥胖”(Masked visceral fat obesity,隐性VFO),后者称之为“假性内脏脂肪型肥胖”(Pseudo visceral fat obesity,假性VFO),但这二种特殊的腹型肥胖与高血压患者心血管代谢危险性及靶器官损害的关系如何尚不清楚。
对于高血压合并非糖尿病肥胖者,目前各国高血压指南均无推荐用药。血管紧张素II受体拮抗剂(ARB)类药物除了降压作用之外,还可以改善糖尿病患者、代谢综合征患者的代谢指标。激活过氧化物酶体增生物激活受体(PPAR)γ可引起脂肪分化和脂肪形成,增加体重;而激活PPARδ则可促进脂肪组织游离脂肪酸氧化分解,可预防高脂诱导的肥胖和体重增加。有报道某些ARB如替米沙坦、坎地沙坦可预防实验动物体重增加及高脂诱导的肥胖,但机制不明:已知ARB可激活PPARγ,尚不清楚替米沙坦是否通过激活PPARδ预防体重增加及高脂诱导的肥胖。此外,ARB干预对非糖尿病的肥胖型高血压患者是否也有改善脂肪代谢、减轻体重的作用,也不得而知。
因此,本研究从临床到基础再到临床,分为三部分进行研究,首先探索腹内脂肪堆积对于高血压患者的代谢指标、心血管代谢危险性和靶器官损害的影响,进一步观察替米沙坦是否能预防实验动物体重增加及高脂诱导的肥胖并探索其机制,最后再回到临床,观察替米沙坦干预能否改善肥胖型高血压患者的肥胖程度及腹内脂肪堆积;为探索肥胖型高血压的优化治疗方案提供依据。
方法:
1、临床横断面研究:检测住院高血压患者的肥胖相关指标、腹部脂肪分布情况,通过统计分析,探索腹内脂肪堆积对代谢指标、心血管代谢危险性和靶器官损害的影响。
2、动物实验研究:采用SHR大鼠、C57BL/6J小鼠及PPARδ基因敲除小鼠等多种动物模型,分别给予正常/高脂饮食,并给予替米沙坦/氨氯地平灌胃,观察ARB对实验动物体重和肥胖的影响;并采用实验动物肠系膜脂肪组织及皮下脂肪组织、正常及PPARδ过表达的3T3-L1细胞作为研究对象,对其分子机制作初步探讨。
3、临床试验:开展随机对照、双盲双模拟的临床试验,纳入60例非糖尿病的肥胖型高血压患者,随机分为替米沙坦组和氨氯地平组,分别给予替米沙坦/氨氯地平干预12周,观察其血压、肥胖相关体脂指数及腹部脂肪分布情况变化,探索替米沙坦能否改善肥胖型高血压患者的肥胖程度及腹内脂肪堆积。
主要研究结果
1、临床横断面研究:
1)腹内脂肪堆积对高血压患者代谢指标的影响:
在年龄、性别、血压水平匹配的条件下,腰围超标组舒张压、体重指数(BMI)、腹内脂肪面积均显著高于腰围正常组,空腹血糖、负荷后2h血糖、糖化血红蛋白、总胆固醇(TC)、甘油三酯(TG)、空腹胰岛素和胰岛素抵抗指数(HOMA-IR)也显著高于腰围正常组(P<0.01);但其高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-c)与腰围正常组比较无显著差异。与腰围超标+腹内脂肪堆积组比较,单纯腹内脂肪堆积组和正常组的空腹血糖、负荷后2h血糖、HOMA-IR、TC均显著降低;单纯腰围超标组和正常组的TG与腰围超标+腹内脂肪堆积组比较也显著降低;空腹胰岛素水平则仅有正常组与腰围超标+腹内脂肪堆积组有显著差异。与正常组比较,其余三组的空腹胰岛素均显著增高,腰围超标+腹内脂肪堆积组和单纯腰围超标组HOMA-IR显著增高;其余指标(空腹血糖、负荷后2h血糖、糖化血红蛋白、TC、TG)仅腰围超标+腹内脂肪堆积组与正常组比较有显著差异。校正了年龄、性别之后,高血压患者腰围与空腹血糖、负荷后2h血糖、糖化血红蛋白、HOMA-IR和空腹胰岛素均呈显著正相关(P<0.05或0.01),腹内脂肪面积与HOMA-IR和空腹胰岛素也呈显著正相关(P<0.01)
2)腹型肥胖的类型与高血压患者心血管代谢危险性的关系
男性隐性内脏性肥胖(VFO)检出率(10.9%)显著高于女性(4.8%)。2)男性隐性VFO组和假性VFO组≥3项以上心血管代谢危险因素聚集率(43.1%,78.7%)显著高于非肥胖组(25.0%)。女性隐性VFO组≥3项以上危险因素聚集率(33.3%)与非肥胖组(31.2%)无显著差异,但显著低于假性VFO组(78.7%)和真性VFO组(90.9%)。腰围增加和腹内脂肪堆积是多重心血管代谢危险因素聚集的独立危险因素(OR 1.13(1.10-1.17),1.01(1.006-1.02))。
3)内脏脂肪堆积对肥胖型高血压靶器官损害的影响
假性VFO组和真性VFO组左室肥厚检出率(46.5%,53.6%)显著高于非肥胖组(32%),颈动脉壁病变检出率(22%)显著低于隐性VFO组(40.4%)和真性VFO组(35.0%);隐性VFO组肾功轻度受损检出率(20.9%)显著高于非肥胖组(11.1%)。隐性VFO组和真性VFO组的靶器官损害检出率(75%,75.2%)均比非肥胖组(52.5%)和假性VFO组(56.1%)显著增高。年龄和腹内脂肪是高血压患者是否合并靶器官损害的独立危险因素(OR: 1.021(95%CI:1.002-1.040),1.008(95%CI:1.002-1.014))。
2、动物实验研究
1)普食及高脂喂养SHR大鼠并接受ARB(替米沙坦和坎地沙坦)干预后体重均显著低于普食/高脂对照组和普食/高脂+氨氯地平组(P<0.05或P<0.01);各部位内脏脂肪总量及内脏脂肪量/体重显著低于普食/高脂+氨氯地平组(P<0.05或P<0.01)。ARB及氨氯地平干预后血压均明显低于普食/高脂对照组(P<0.01),但干预组间无显著差异。各组间代谢指标无显著差异。普食喂养SHR,加用ARB后其肠系膜及皮下脂肪脂肪细胞的平均面积均非常显著小于普食/高脂对照组和普食/高脂+氨氯地平组(P<0.01)。高脂喂养的SHR,加用替米沙坦或坎地沙坦后其肠系膜脂肪细胞面积小于高脂组及高脂+氨氯地平组(P<0.01)。
2) C57BL/6J野生型小鼠(WT)予以普食+替米沙坦干预后,其体重、皮下脂肪、棕脂、各部位内脏脂肪及内脏脂肪总量和内脏脂肪量/体重、皮下脂肪量/体重以及血甘油三酯及游离脂肪酸、肠系膜脂肪、皮下脂肪细胞平均面积均明显低于普食组(P<0.05或P<0.01)。过氧化物酶体增殖体激活受体(PPAR)δ基因敲除小鼠(PPARδ-/-)普食组与普食+替米沙坦组无上述差异。各组间血压均无显著差异。
3)替米沙坦(10μmol/L)和PPARδ激动剂GW0742干预3T3-L1细胞24小时后,可见PPARδ基因活性明显高于对照组。油红染色提示PPARδ过表达组细胞的脂滴沉积较3T3-L1对照组和3T3-L1空病毒组明显改善,PPARδ蛋白表达明显增加(P<0.05),三组间AT1R蛋白表达无明显差异。
4) SHR喂养16周后,普食/高脂+替米沙坦组肠系膜脂肪组织PPARδ蛋白、mRNA表达显著高于普食/高脂对照组(P<0.05);皮下脂肪组织PPARδ蛋白表达有增高趋势,但无统计学意义;PPARγmRNA表达无明显差异。
3、临床试验研究
1)替米沙坦/氨氯地平干预12周后,与基线水平相比,两组收缩压、舒张压均显著降低(P<0.001),但干预后组间差异无统计学意义。
2)干预12周后,与基线水平相比,替米沙坦组腹壁脂肪厚度无显著差异,腹内脂肪厚度显著减少(P=0.012),腹壁/腹内脂肪厚度比显著增加(P=0.009);但氨氯地平组上述各项指标均无显著差异。干预后组间比较,替米沙坦组腹内脂肪减少程度更为显著(-3.38±6.08cm vs -0.08±5.80cm,P=0.045)。替米沙坦组腹部脂肪分布情况显著改变(腹壁/腹内脂肪比变化:0.10±0.16),与氨氯地平组(-0.02±0.17)比较有显著差异。
主要结论
1.高血压患者同时伴有腹围超标和腹内脂肪堆积时,胰岛素抵抗、血糖异常、血脂异常最为严重。
2.不同腹型肥胖类型高血压患者的心血管代谢危险和靶器官损害有显著差异;隐性内脏脂肪型肥胖和假性内脏脂肪型肥胖患者同样有较高的心血管代谢风险。男性隐性内脏脂肪型肥胖检出率显著高于女性。
3.替米沙坦干预可减少C57BL/6J小鼠和SHR大鼠体重增加,减少其脂肪细胞面积和脂肪量,预防高脂诱导的肥胖,这一作用与过氧化物酶体增殖激活受体(PPAR)δ被激活有关。
4.替米沙坦和氨氯地平干预非糖尿病、肥胖型高血压患者12周,均可显著降低血压,但仅替米沙坦可显著减少患者腹内脂肪。
BACKGROUDS
A large number of researches had showed that those obese people were more prone to hypertension and degree of obesity assessed by a variety of indicators (e.g. body mass index, waist circumference, waist-hip ratio, et al.) was correlated with blood pressure. Obesity and hypertension were often co-existed, which induced higher susceptibility to diabetes, hyperlipidemia, coronary and cerebral atherosclerosis and peripheral vascular disease. Intra-abdominal fat accumulation was an important clinical features and pathophysiological basis of abdominal obesity (AO) and closely related to the cardiovascular risk factors such as insulin resistance, hypertension, metabolic abnormalities, and so on. Nevertheless, the metabolic effects of visceral fat tissue in hypertensive patients were relatively seldom discussed.
Abdominal obesity was often accompanied by visceral fat accumulation and increase of the secretion of the many inflammatory mediators, cytokines and adipocytokines, which played an important role in cardiovascular and metabolic disease. Many studies had confirmed that visceral fat area(VA)≥100cm2 can be diagnosed as visceral fat obesity (VFO) and predict higher cardiometabolic risk. At present, clinical diagnosis of abdominal obesity was mainly based on waist measurement (WC) and waist-hip ratio, but there is a degree of inconsistency between these two indicators of body fat and visceral fat volume. As a result, there will be several cohorts which can not be accurately classified, such as the patients with normal WC but elevated VA, or with abnormal WC but normal VA. We then defined the former as Masked visceral fat obesity (Masked VFO) and the latter as Pseudo- visceral fat obesity (Pseudo-VFO). But the relationships between these two special types of abdominal obesity and cardiometabolic risk and target organ damage in patients with hypertension remain still unclear.
For non-diabetic, obese hypertensive patients, there is still no recommend medication in all current hypertension guidelines. In addition to its anti-hypertensive role, angiotensin II receptor blockers (ARB) can also improve metabolic profiles in patients with diabetes or metabolic syndrome, which made it a promising drug as the first choice for obesity related hypertension. ARBs were reported to activate peroxisome proliferator-activated receptor (PPAR)γ, which can induce the formation and differentiation of fat tissue and increase body weight. However, there were some reports showed some ARB, such as Telmisartan and Candesartan, could prevent weight gain and high-fat diet-induced obesity. On the other hand, PPARδcan promote free fatty acid oxidation in fatty tissue and prevent high-fat diet-induced obesity and weight gain when it be activated. Now we are interested in whether Telmisartan can prevent weight gain and high-fat diet-induced obesity by activating PPARδ; and whether Telmisartan can improve the fat metabolism and reduce body weight in non- diabetes obese patients with hypertension.
The present study was divided into three parts to explore the impact of abdominal adiposity on metabolism profile, cardiometabolic risk and target organ damages in patients with hypertension and obesity, and to observe whether Telmisartan can prevent weight gain and obesity induced by high-fat diet in animals and explore its mechanism. Furthermore, a clinical trial was performed to observe whether Telmisartan could improve the degree of obesity and accumulation of visceral fat in obese hypertensive patients.
METHODS
1. Clinical cross-sectional study: A cross-sectional study was performed in hypertensive patients to explore effects of obesity-related indicators and abdominal fat distribution on metabolic profile, cardiometabolic risk and target organ damages.
2. Experimental study: Several animal models, including SHR rats, C57BL/6J mice and PPARδ-knockout mice, were fed by the normal/high-fat diet, accompanied intragastric administration of Telmisartan or Amlodipine, to observed impact of Telmisartan on the weight and the degree of obesity. 3T3-L1 cells with normal and over-expression of PPARδ, SHR mesenteric adipose tissue and subcutaneous tissue were also used to explore the molecular mechanism of Telmisartan-induced metabolic effects.
3. Clinical trial: A random, double-blinded, double-dummy, controlled trial was performed in 60 no-diabetes, obese hypertensive cases. The eligible patients were randomized into two groups, followed by a 12-week intervention of Telmisartan / Amlodipine. Blood pressure, obesity-related parameters and abdominal fat distribution were observed to explore whether Telmisartan can improve the degree of obesity and abdominal fat accumulation in patients with hypertension and obesity.
RESULTS
1. Clinical cross-sectional study:
1) Impact of visceral adipose on metabolic profiles in patients with hypertension
After adjusted by age, gender and blood pressure, there were significant differences of diastolic blood pressure (DBP), BMI, VA between patients with abnormal (AO(+)) and normal (AO(-)) waist circunference. Compared with AO(-) group, fasting plasma glucose (FPG), post-prandial plasma glucose (2hPG), HbAlC, total cholesterol (TC), triglyceride (TG), fasting insulin (FIN) and HOMA-IR were significantly higher in AO(+) group. However, no significant difference of high density lipoprotein cholesterol (HDL-c) and low density lipoprotein cholesterol (LDL-c) was detected between the two groups. Compared with the patients with increased WC and VA, FPG, 2hPG, HOMA-IR and TC level in patients with increased VA only and patients with normal WC and VA were significantly decreased, whereas TG level in patients with increased WC only or with normal WC and VA was significantly decreased.. As for FIN level, those patients with normal WC and VA showed lowest serum concentration than the other three groups. Compared with patients with normal WC and VA, HOMA-IR in patients with increased WC and VA and with increased WC only was significantly higher. Nevertheless, only patients with increased WC and VA were detected significantly higher FPG, 2hPG, HbA1C, TC, TG level than patients with normal WC and VA. After controlled by age and gender, partial correlation analysis showed that WC was significantly positively correlated with FPG, 2hPG, HbA1C, HOMA-IR and FIN level, whereas VA was significantly positively correlated with HOMA-IR and FINs.
2) Relationship between different type of abdominal obesity and cardiometabolic risk
Firstly, there was significantly higher prevalence of Masked VFO in male (10.9%) than that in female (4.8%). Secondly, those male patients in Masked and Psudo- VFO group had higher prevalence of clustering of more than 3 cardiometabolic risk factors (CMR) (43.1%, 78.7%) than those in Non-obesity group (25.0%). On the other hand, those female patients with Masked VFO had similar prevalence (33.3%) with those in Non-obesity group (31.2%), and lower prevalence than those with Pseudo- VFO (78.7%) and VFO (90.9%). Moreover, logistic regression analysis showed that WC and VA were independent risk factors for multiple risk factors clustering(OR(95%CI) was 1.13(1.10-1.17) ,1.01(1.01-1.02),respectively)。
3) Relationship between the characteristics of target organ damage and visceral fat in patients with obesity-related hypertension
There was significantly higher prevalence of left ventricular hypertrophy in Pseudo VFO (46.5%) and VFO group (53.6%) than that in Non-Obesity group (32%). The prevalence of left carotid artery wall lesions in Pseudo VFO group (22%) was significantly lower than that in Masked VFO group (40.4%) and VFO group (35.0%). There were also significantly lower prevalence of renal damage in Non-Obesity group (11.1%) than that in Masked VFO group (20.9%). The Masked VFO (75%) and VFO group (75.2%) had higher prevalence of TOD than Non-Obesity(52.5%) and Pseudo VFO group (56.1%). Also, the logistic regression analysis showed that age and VA were independent risk factors for TOD (OR (95%CI) was 1.021(1.002-1.040), 1.008(1.002-1.014), respectively).
2. Experimental study
1) SHR rats were fed by normal- (ND) or high-fat diet (HD) and intragastric administrated by ARB (Telmisartan (Tel) or Candesartan (Can)) or amlodipine (Aml). After the intervention, there is significantly lower body weight and less visceral fat in ND/HD+Tel group than that in ND/HD control and ND/HD+Aml group (P <0.05 or P < 0.01). Blood pressure was observed significantly lower in ARB groups and amlodipine group than that in after the intervention were significantly lower than that in ND/HD control group (P <0.01), but no significant difference was detected among the intervention groups. Metabolic parameters between the groups were also not significantly different. The average fat cell size of the mesentery and subcutaneous adipose were significantly smaller in ARB-intervention groups than that in ND control and ND+Aml group. On the other hand, similar decrease changes were only seen in mesentery adipose tissue in ARB groups compared with HD control and HD+Aml group.
2) Wild-type C57 mice (WT) intervened with ND+Telmisartan showed significantly decreased weight, subcutaneous fat, brown fat, various visceral fat, total visceral fat and visceral fat / weight, subcutaneous fat / Weight, as well as serum triglyceride and free fatty acids, mesenteric fat, subcutaneous fat cell size than that in the ND group (P <0.05 or P <0.01). There were no same difference in PPARδknockout mice (PPARδ-/-). There was also no significant difference of blood pressure among all groups.
3) PPARδgene activity was significantly higher after intervened with telmisartan (10μmol/L) than that with PPARδagonist GW0742., Oil Red O staining showed that deposition of lipid droplets in PPARδover-expressed cells was significantly reduced than that in 3T3-L1 Control and 3T3-L1 Vecto cells. PPARδprotein expression was observed significantly increased in PPARδover-expressed cells (P<0.05), but there were no significant differences in all three groups.
4) PPARδprotein and mRNA expression in mesenteric adipose tissue was significantly higher in ND/HD+Tel group than that in ND/HD control group (P<0.05). Similar but not significant trend of PPARδprotein expression was observed in ND/HD+Tel group. There were no significant difference of PPARγmRNA expression in all groups.
3. Clinical trial
1) After intervention with Telmisartan or amlodipine for 12 weeks, systolic blood pressure, diastolic blood pressure were significantly lower (P<0.001) compared with the baseline level of the two groups, but no significant difference were observed between two groups after intervention.
2) There were no significant differences of subcutaneous fat thickness but a significant reduction of visceral fat thickness (P = 0.012) and subcutaneous/visceral fat thickness (P= 0.009) between pre- and post-intervention in Telmisartan group. As for Amlodipine group, these indicators were no significant difference. After the intervention, Telmisartan group showed more decrease of visceral fat thickness compared with Amlodipine group (-3.38±6.08cm2 vs -0.08±5.80, P =0.045). There was also significantly improved abdominal fat distribution in Amlodipine group compared with Telmisartan group.
CONCLUSIONS
1. The most aggravated insulin resistance, hyperglycaemia and dyslipidemia are accompanied by abnormal waist circumference and visceral adiposity simultaneously in hypertensive patients.
2. There is significantly impact of different types of abdominal obesity on cardiometabolic risk and target organ damages in patients with hypertension. Patients with masked visceral fat obesity (VFO) and pseudo- visceral fat obesity also have a considerably higher risk of cardiometabolic risk. The prevalence of masked VFO is significantly higher in men than that in women.
3. Telmisartan reduces weight gain, fat cell area and fat volume in C57BL/6J mice and SHR rats and prevents high-fat diet-induced obesity mainly by activating the PPARδ.
4. Either Telmisartan or Amlodipine can decrease blood pressure in non-diabetic, obese hypertensive patients after 12-week intervention, whereas only Telmisartan can reduce visceral fat thickness significantly.
研究表明,肥胖人群更容易发生高血压,以各种肥胖指标(体重指数、腰围(WC)、腰-臀比等)评定的肥胖程度均与血压水平有较好的相关性。肥胖与高血压合并存在,更易发生糖尿病、高脂血症、冠状动脉、脑动脉粥样硬化及外周血管病变。腹内脂肪堆积是腹型肥胖的重要临床特征和病理生理基础,与胰岛素抵抗、高血压、代谢异常等心血管危险因素密切相关。但应用腹内脂肪指标专门观察对高血压患者的代谢影响的研究较少。
腹型肥胖时,常伴有内脏脂肪大量堆积,其分泌的众多炎症介质、细胞和脂肪因子在心血管和代谢病的发病中起重要作用。研究证实,亚洲地区人群的腹内脂肪面积(Visceral fat area,VA)≥100cm2可诊断为内脏脂肪型肥胖(visceral fat obesity,VFO)。达到此切点,心血管代谢危险性明显增加。目前临床诊断腹型肥胖主要依据测量腰围和腰臀比,但这两个体脂指标与内脏脂肪量存在一定程度的不一致。因此,这将出现几种应用常规体脂参数测量不能准确评价的情况,如WC正常、VA超标或WC超标、而VA正常,我们将前者称之为“隐性内脏脂肪型肥胖”(Masked visceral fat obesity,隐性VFO),后者称之为“假性内脏脂肪型肥胖”(Pseudo visceral fat obesity,假性VFO),但这二种特殊的腹型肥胖与高血压患者心血管代谢危险性及靶器官损害的关系如何尚不清楚。
对于高血压合并非糖尿病肥胖者,目前各国高血压指南均无推荐用药。血管紧张素II受体拮抗剂(ARB)类药物除了降压作用之外,还可以改善糖尿病患者、代谢综合征患者的代谢指标。激活过氧化物酶体增生物激活受体(PPAR)γ可引起脂肪分化和脂肪形成,增加体重;而激活PPARδ则可促进脂肪组织游离脂肪酸氧化分解,可预防高脂诱导的肥胖和体重增加。有报道某些ARB如替米沙坦、坎地沙坦可预防实验动物体重增加及高脂诱导的肥胖,但机制不明:已知ARB可激活PPARγ,尚不清楚替米沙坦是否通过激活PPARδ预防体重增加及高脂诱导的肥胖。此外,ARB干预对非糖尿病的肥胖型高血压患者是否也有改善脂肪代谢、减轻体重的作用,也不得而知。
因此,本研究从临床到基础再到临床,分为三部分进行研究,首先探索腹内脂肪堆积对于高血压患者的代谢指标、心血管代谢危险性和靶器官损害的影响,进一步观察替米沙坦是否能预防实验动物体重增加及高脂诱导的肥胖并探索其机制,最后再回到临床,观察替米沙坦干预能否改善肥胖型高血压患者的肥胖程度及腹内脂肪堆积;为探索肥胖型高血压的优化治疗方案提供依据。
方法:
1、临床横断面研究:检测住院高血压患者的肥胖相关指标、腹部脂肪分布情况,通过统计分析,探索腹内脂肪堆积对代谢指标、心血管代谢危险性和靶器官损害的影响。
2、动物实验研究:采用SHR大鼠、C57BL/6J小鼠及PPARδ基因敲除小鼠等多种动物模型,分别给予正常/高脂饮食,并给予替米沙坦/氨氯地平灌胃,观察ARB对实验动物体重和肥胖的影响;并采用实验动物肠系膜脂肪组织及皮下脂肪组织、正常及PPARδ过表达的3T3-L1细胞作为研究对象,对其分子机制作初步探讨。
3、临床试验:开展随机对照、双盲双模拟的临床试验,纳入60例非糖尿病的肥胖型高血压患者,随机分为替米沙坦组和氨氯地平组,分别给予替米沙坦/氨氯地平干预12周,观察其血压、肥胖相关体脂指数及腹部脂肪分布情况变化,探索替米沙坦能否改善肥胖型高血压患者的肥胖程度及腹内脂肪堆积。
主要研究结果
1、临床横断面研究:
1)腹内脂肪堆积对高血压患者代谢指标的影响:
在年龄、性别、血压水平匹配的条件下,腰围超标组舒张压、体重指数(BMI)、腹内脂肪面积均显著高于腰围正常组,空腹血糖、负荷后2h血糖、糖化血红蛋白、总胆固醇(TC)、甘油三酯(TG)、空腹胰岛素和胰岛素抵抗指数(HOMA-IR)也显著高于腰围正常组(P<0.01);但其高密度脂蛋白胆固醇(HDL-c)、低密度脂蛋白胆固醇(LDL-c)与腰围正常组比较无显著差异。与腰围超标+腹内脂肪堆积组比较,单纯腹内脂肪堆积组和正常组的空腹血糖、负荷后2h血糖、HOMA-IR、TC均显著降低;单纯腰围超标组和正常组的TG与腰围超标+腹内脂肪堆积组比较也显著降低;空腹胰岛素水平则仅有正常组与腰围超标+腹内脂肪堆积组有显著差异。与正常组比较,其余三组的空腹胰岛素均显著增高,腰围超标+腹内脂肪堆积组和单纯腰围超标组HOMA-IR显著增高;其余指标(空腹血糖、负荷后2h血糖、糖化血红蛋白、TC、TG)仅腰围超标+腹内脂肪堆积组与正常组比较有显著差异。校正了年龄、性别之后,高血压患者腰围与空腹血糖、负荷后2h血糖、糖化血红蛋白、HOMA-IR和空腹胰岛素均呈显著正相关(P<0.05或0.01),腹内脂肪面积与HOMA-IR和空腹胰岛素也呈显著正相关(P<0.01)
2)腹型肥胖的类型与高血压患者心血管代谢危险性的关系
男性隐性内脏性肥胖(VFO)检出率(10.9%)显著高于女性(4.8%)。2)男性隐性VFO组和假性VFO组≥3项以上心血管代谢危险因素聚集率(43.1%,78.7%)显著高于非肥胖组(25.0%)。女性隐性VFO组≥3项以上危险因素聚集率(33.3%)与非肥胖组(31.2%)无显著差异,但显著低于假性VFO组(78.7%)和真性VFO组(90.9%)。腰围增加和腹内脂肪堆积是多重心血管代谢危险因素聚集的独立危险因素(OR 1.13(1.10-1.17),1.01(1.006-1.02))。
3)内脏脂肪堆积对肥胖型高血压靶器官损害的影响
假性VFO组和真性VFO组左室肥厚检出率(46.5%,53.6%)显著高于非肥胖组(32%),颈动脉壁病变检出率(22%)显著低于隐性VFO组(40.4%)和真性VFO组(35.0%);隐性VFO组肾功轻度受损检出率(20.9%)显著高于非肥胖组(11.1%)。隐性VFO组和真性VFO组的靶器官损害检出率(75%,75.2%)均比非肥胖组(52.5%)和假性VFO组(56.1%)显著增高。年龄和腹内脂肪是高血压患者是否合并靶器官损害的独立危险因素(OR: 1.021(95%CI:1.002-1.040),1.008(95%CI:1.002-1.014))。
2、动物实验研究
1)普食及高脂喂养SHR大鼠并接受ARB(替米沙坦和坎地沙坦)干预后体重均显著低于普食/高脂对照组和普食/高脂+氨氯地平组(P<0.05或P<0.01);各部位内脏脂肪总量及内脏脂肪量/体重显著低于普食/高脂+氨氯地平组(P<0.05或P<0.01)。ARB及氨氯地平干预后血压均明显低于普食/高脂对照组(P<0.01),但干预组间无显著差异。各组间代谢指标无显著差异。普食喂养SHR,加用ARB后其肠系膜及皮下脂肪脂肪细胞的平均面积均非常显著小于普食/高脂对照组和普食/高脂+氨氯地平组(P<0.01)。高脂喂养的SHR,加用替米沙坦或坎地沙坦后其肠系膜脂肪细胞面积小于高脂组及高脂+氨氯地平组(P<0.01)。
2) C57BL/6J野生型小鼠(WT)予以普食+替米沙坦干预后,其体重、皮下脂肪、棕脂、各部位内脏脂肪及内脏脂肪总量和内脏脂肪量/体重、皮下脂肪量/体重以及血甘油三酯及游离脂肪酸、肠系膜脂肪、皮下脂肪细胞平均面积均明显低于普食组(P<0.05或P<0.01)。过氧化物酶体增殖体激活受体(PPAR)δ基因敲除小鼠(PPARδ-/-)普食组与普食+替米沙坦组无上述差异。各组间血压均无显著差异。
3)替米沙坦(10μmol/L)和PPARδ激动剂GW0742干预3T3-L1细胞24小时后,可见PPARδ基因活性明显高于对照组。油红染色提示PPARδ过表达组细胞的脂滴沉积较3T3-L1对照组和3T3-L1空病毒组明显改善,PPARδ蛋白表达明显增加(P<0.05),三组间AT1R蛋白表达无明显差异。
4) SHR喂养16周后,普食/高脂+替米沙坦组肠系膜脂肪组织PPARδ蛋白、mRNA表达显著高于普食/高脂对照组(P<0.05);皮下脂肪组织PPARδ蛋白表达有增高趋势,但无统计学意义;PPARγmRNA表达无明显差异。
3、临床试验研究
1)替米沙坦/氨氯地平干预12周后,与基线水平相比,两组收缩压、舒张压均显著降低(P<0.001),但干预后组间差异无统计学意义。
2)干预12周后,与基线水平相比,替米沙坦组腹壁脂肪厚度无显著差异,腹内脂肪厚度显著减少(P=0.012),腹壁/腹内脂肪厚度比显著增加(P=0.009);但氨氯地平组上述各项指标均无显著差异。干预后组间比较,替米沙坦组腹内脂肪减少程度更为显著(-3.38±6.08cm vs -0.08±5.80cm,P=0.045)。替米沙坦组腹部脂肪分布情况显著改变(腹壁/腹内脂肪比变化:0.10±0.16),与氨氯地平组(-0.02±0.17)比较有显著差异。
主要结论
1.高血压患者同时伴有腹围超标和腹内脂肪堆积时,胰岛素抵抗、血糖异常、血脂异常最为严重。
2.不同腹型肥胖类型高血压患者的心血管代谢危险和靶器官损害有显著差异;隐性内脏脂肪型肥胖和假性内脏脂肪型肥胖患者同样有较高的心血管代谢风险。男性隐性内脏脂肪型肥胖检出率显著高于女性。
3.替米沙坦干预可减少C57BL/6J小鼠和SHR大鼠体重增加,减少其脂肪细胞面积和脂肪量,预防高脂诱导的肥胖,这一作用与过氧化物酶体增殖激活受体(PPAR)δ被激活有关。
4.替米沙坦和氨氯地平干预非糖尿病、肥胖型高血压患者12周,均可显著降低血压,但仅替米沙坦可显著减少患者腹内脂肪。
BACKGROUDS
A large number of researches had showed that those obese people were more prone to hypertension and degree of obesity assessed by a variety of indicators (e.g. body mass index, waist circumference, waist-hip ratio, et al.) was correlated with blood pressure. Obesity and hypertension were often co-existed, which induced higher susceptibility to diabetes, hyperlipidemia, coronary and cerebral atherosclerosis and peripheral vascular disease. Intra-abdominal fat accumulation was an important clinical features and pathophysiological basis of abdominal obesity (AO) and closely related to the cardiovascular risk factors such as insulin resistance, hypertension, metabolic abnormalities, and so on. Nevertheless, the metabolic effects of visceral fat tissue in hypertensive patients were relatively seldom discussed.
Abdominal obesity was often accompanied by visceral fat accumulation and increase of the secretion of the many inflammatory mediators, cytokines and adipocytokines, which played an important role in cardiovascular and metabolic disease. Many studies had confirmed that visceral fat area(VA)≥100cm2 can be diagnosed as visceral fat obesity (VFO) and predict higher cardiometabolic risk. At present, clinical diagnosis of abdominal obesity was mainly based on waist measurement (WC) and waist-hip ratio, but there is a degree of inconsistency between these two indicators of body fat and visceral fat volume. As a result, there will be several cohorts which can not be accurately classified, such as the patients with normal WC but elevated VA, or with abnormal WC but normal VA. We then defined the former as Masked visceral fat obesity (Masked VFO) and the latter as Pseudo- visceral fat obesity (Pseudo-VFO). But the relationships between these two special types of abdominal obesity and cardiometabolic risk and target organ damage in patients with hypertension remain still unclear.
For non-diabetic, obese hypertensive patients, there is still no recommend medication in all current hypertension guidelines. In addition to its anti-hypertensive role, angiotensin II receptor blockers (ARB) can also improve metabolic profiles in patients with diabetes or metabolic syndrome, which made it a promising drug as the first choice for obesity related hypertension. ARBs were reported to activate peroxisome proliferator-activated receptor (PPAR)γ, which can induce the formation and differentiation of fat tissue and increase body weight. However, there were some reports showed some ARB, such as Telmisartan and Candesartan, could prevent weight gain and high-fat diet-induced obesity. On the other hand, PPARδcan promote free fatty acid oxidation in fatty tissue and prevent high-fat diet-induced obesity and weight gain when it be activated. Now we are interested in whether Telmisartan can prevent weight gain and high-fat diet-induced obesity by activating PPARδ; and whether Telmisartan can improve the fat metabolism and reduce body weight in non- diabetes obese patients with hypertension.
The present study was divided into three parts to explore the impact of abdominal adiposity on metabolism profile, cardiometabolic risk and target organ damages in patients with hypertension and obesity, and to observe whether Telmisartan can prevent weight gain and obesity induced by high-fat diet in animals and explore its mechanism. Furthermore, a clinical trial was performed to observe whether Telmisartan could improve the degree of obesity and accumulation of visceral fat in obese hypertensive patients.
METHODS
1. Clinical cross-sectional study: A cross-sectional study was performed in hypertensive patients to explore effects of obesity-related indicators and abdominal fat distribution on metabolic profile, cardiometabolic risk and target organ damages.
2. Experimental study: Several animal models, including SHR rats, C57BL/6J mice and PPARδ-knockout mice, were fed by the normal/high-fat diet, accompanied intragastric administration of Telmisartan or Amlodipine, to observed impact of Telmisartan on the weight and the degree of obesity. 3T3-L1 cells with normal and over-expression of PPARδ, SHR mesenteric adipose tissue and subcutaneous tissue were also used to explore the molecular mechanism of Telmisartan-induced metabolic effects.
3. Clinical trial: A random, double-blinded, double-dummy, controlled trial was performed in 60 no-diabetes, obese hypertensive cases. The eligible patients were randomized into two groups, followed by a 12-week intervention of Telmisartan / Amlodipine. Blood pressure, obesity-related parameters and abdominal fat distribution were observed to explore whether Telmisartan can improve the degree of obesity and abdominal fat accumulation in patients with hypertension and obesity.
RESULTS
1. Clinical cross-sectional study:
1) Impact of visceral adipose on metabolic profiles in patients with hypertension
After adjusted by age, gender and blood pressure, there were significant differences of diastolic blood pressure (DBP), BMI, VA between patients with abnormal (AO(+)) and normal (AO(-)) waist circunference. Compared with AO(-) group, fasting plasma glucose (FPG), post-prandial plasma glucose (2hPG), HbAlC, total cholesterol (TC), triglyceride (TG), fasting insulin (FIN) and HOMA-IR were significantly higher in AO(+) group. However, no significant difference of high density lipoprotein cholesterol (HDL-c) and low density lipoprotein cholesterol (LDL-c) was detected between the two groups. Compared with the patients with increased WC and VA, FPG, 2hPG, HOMA-IR and TC level in patients with increased VA only and patients with normal WC and VA were significantly decreased, whereas TG level in patients with increased WC only or with normal WC and VA was significantly decreased.. As for FIN level, those patients with normal WC and VA showed lowest serum concentration than the other three groups. Compared with patients with normal WC and VA, HOMA-IR in patients with increased WC and VA and with increased WC only was significantly higher. Nevertheless, only patients with increased WC and VA were detected significantly higher FPG, 2hPG, HbA1C, TC, TG level than patients with normal WC and VA. After controlled by age and gender, partial correlation analysis showed that WC was significantly positively correlated with FPG, 2hPG, HbA1C, HOMA-IR and FIN level, whereas VA was significantly positively correlated with HOMA-IR and FINs.
2) Relationship between different type of abdominal obesity and cardiometabolic risk
Firstly, there was significantly higher prevalence of Masked VFO in male (10.9%) than that in female (4.8%). Secondly, those male patients in Masked and Psudo- VFO group had higher prevalence of clustering of more than 3 cardiometabolic risk factors (CMR) (43.1%, 78.7%) than those in Non-obesity group (25.0%). On the other hand, those female patients with Masked VFO had similar prevalence (33.3%) with those in Non-obesity group (31.2%), and lower prevalence than those with Pseudo- VFO (78.7%) and VFO (90.9%). Moreover, logistic regression analysis showed that WC and VA were independent risk factors for multiple risk factors clustering(OR(95%CI) was 1.13(1.10-1.17) ,1.01(1.01-1.02),respectively)。
3) Relationship between the characteristics of target organ damage and visceral fat in patients with obesity-related hypertension
There was significantly higher prevalence of left ventricular hypertrophy in Pseudo VFO (46.5%) and VFO group (53.6%) than that in Non-Obesity group (32%). The prevalence of left carotid artery wall lesions in Pseudo VFO group (22%) was significantly lower than that in Masked VFO group (40.4%) and VFO group (35.0%). There were also significantly lower prevalence of renal damage in Non-Obesity group (11.1%) than that in Masked VFO group (20.9%). The Masked VFO (75%) and VFO group (75.2%) had higher prevalence of TOD than Non-Obesity(52.5%) and Pseudo VFO group (56.1%). Also, the logistic regression analysis showed that age and VA were independent risk factors for TOD (OR (95%CI) was 1.021(1.002-1.040), 1.008(1.002-1.014), respectively).
2. Experimental study
1) SHR rats were fed by normal- (ND) or high-fat diet (HD) and intragastric administrated by ARB (Telmisartan (Tel) or Candesartan (Can)) or amlodipine (Aml). After the intervention, there is significantly lower body weight and less visceral fat in ND/HD+Tel group than that in ND/HD control and ND/HD+Aml group (P <0.05 or P < 0.01). Blood pressure was observed significantly lower in ARB groups and amlodipine group than that in after the intervention were significantly lower than that in ND/HD control group (P <0.01), but no significant difference was detected among the intervention groups. Metabolic parameters between the groups were also not significantly different. The average fat cell size of the mesentery and subcutaneous adipose were significantly smaller in ARB-intervention groups than that in ND control and ND+Aml group. On the other hand, similar decrease changes were only seen in mesentery adipose tissue in ARB groups compared with HD control and HD+Aml group.
2) Wild-type C57 mice (WT) intervened with ND+Telmisartan showed significantly decreased weight, subcutaneous fat, brown fat, various visceral fat, total visceral fat and visceral fat / weight, subcutaneous fat / Weight, as well as serum triglyceride and free fatty acids, mesenteric fat, subcutaneous fat cell size than that in the ND group (P <0.05 or P <0.01). There were no same difference in PPARδknockout mice (PPARδ-/-). There was also no significant difference of blood pressure among all groups.
3) PPARδgene activity was significantly higher after intervened with telmisartan (10μmol/L) than that with PPARδagonist GW0742., Oil Red O staining showed that deposition of lipid droplets in PPARδover-expressed cells was significantly reduced than that in 3T3-L1 Control and 3T3-L1 Vecto cells. PPARδprotein expression was observed significantly increased in PPARδover-expressed cells (P<0.05), but there were no significant differences in all three groups.
4) PPARδprotein and mRNA expression in mesenteric adipose tissue was significantly higher in ND/HD+Tel group than that in ND/HD control group (P<0.05). Similar but not significant trend of PPARδprotein expression was observed in ND/HD+Tel group. There were no significant difference of PPARγmRNA expression in all groups.
3. Clinical trial
1) After intervention with Telmisartan or amlodipine for 12 weeks, systolic blood pressure, diastolic blood pressure were significantly lower (P<0.001) compared with the baseline level of the two groups, but no significant difference were observed between two groups after intervention.
2) There were no significant differences of subcutaneous fat thickness but a significant reduction of visceral fat thickness (P = 0.012) and subcutaneous/visceral fat thickness (P= 0.009) between pre- and post-intervention in Telmisartan group. As for Amlodipine group, these indicators were no significant difference. After the intervention, Telmisartan group showed more decrease of visceral fat thickness compared with Amlodipine group (-3.38±6.08cm2 vs -0.08±5.80, P =0.045). There was also significantly improved abdominal fat distribution in Amlodipine group compared with Telmisartan group.
CONCLUSIONS
1. The most aggravated insulin resistance, hyperglycaemia and dyslipidemia are accompanied by abnormal waist circumference and visceral adiposity simultaneously in hypertensive patients.
2. There is significantly impact of different types of abdominal obesity on cardiometabolic risk and target organ damages in patients with hypertension. Patients with masked visceral fat obesity (VFO) and pseudo- visceral fat obesity also have a considerably higher risk of cardiometabolic risk. The prevalence of masked VFO is significantly higher in men than that in women.
3. Telmisartan reduces weight gain, fat cell area and fat volume in C57BL/6J mice and SHR rats and prevents high-fat diet-induced obesity mainly by activating the PPARδ.
4. Either Telmisartan or Amlodipine can decrease blood pressure in non-diabetic, obese hypertensive patients after 12-week intervention, whereas only Telmisartan can reduce visceral fat thickness significantly.
引文
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