| BACKGROUDSA 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.METHODS1. 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.RESULTS1. Clinical cross-sectional study:1) Impact of visceral adipose on metabolic profiles in patients with hypertensionAfter 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 riskFirstly, 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 hypertensionThere 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 study1) 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 trial1) 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.CONCLUSIONS1. 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. |
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