Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH) Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH), endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide) were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD) and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity.

Association between leptin and its soluble receptor with cardiometabolic risk factors in a Brazilian population.

BACKGROUND: Most studies evaluating the conjoint effects of leptin and human soluble leptin receptor (hs-LR) on cardiometabolic risk factors have been conducted in well-characterized ethnic groups. We aimed to assess the associations of leptin and hs-LR with the cardiometabolic risk factors that reflect the components of metabolic syndrome (MetS) in a Brazilian population with varying degrees of adiposity. METHODS: This is a cross-sectional analysis of adult subjects (n=173, age 45 ± 12 years, 124 women; body mass index [BMI] 35.6 ± 9.5 kg/m(2)) for association of leptin and its soluble receptor with cardiometabolic risk factors (glucose, BMI, waist circumference, hip circumference, blood pressure, insulin, cholesterol and triglycerides). Plasma hs-LR was measured by ELISA; insulin and leptin were determined by RIA. Metabolic syndrome was defined by NCEP/ATP III. RESULTS: Leptin was positively associated with blood pressure, BMI, waist circumference, hip circumference, triglycerides, glucose, insulin and HOMA and inversely correlated with HDL-cholesterol. The hs-LR exhibited inverse relationship with cardiometabolic risk factors (P ≤ 0.006), except for glucose and lipid parameters. Leptin increased, whereas hs-LR decreased, with increasing number of MetS components (P for trend<0.001). In multivariable models, sex, BMI and insulin were independently associated with leptin, whereas age, sex, BMI and systolic blood pressure were the independent correlates of hs-LR. CONCLUSION: In a Brazilian population with complex interethnic admixture, levels of hs-LR and leptin were independently associated with systolic blood pressure and insulin, respectively. Leptin increased with increasing number of MetS components. In turn, hs-LR decreased as the number of MetS components increased.

Hypoadiponectinemia is associated with prehypertension in obese individuals of multiethnic origin.

BACKGROUND: Considering that prehypertension is associated with an increase in cardiovascular risk, hypoadiponectinemia seems to be a predictor of hypertension. HYPOTHESIS: This study investigated whether adiponectin plasma levels are affected in Brazilian obese prehypertensives compared with those in normotensives and hypertensives. METHODS: The study involved 96 multiethnic obese subjects (mean age = 42.8-11.9 years; BMI = 35.7-7.3 kg/m(2)). Fasting plasma adiponectin and serum insulin were determined by radioimmunoassay. Insulin resistance was estimated by HOMA-IR. Blood pressure was recorded using a calibrated automated sphygmomanometer. RESULTS: Adiponectin concentrations were significantly lower in prehypertensives compared with those in normotensives, but hypertensives exhibited the lowest adiponectin concentrations of all. Regarding the values of HOMA-IR, both prehypertensives and hypertensives were significantly more insulin resistant when compared with normotensives. When normotensives and prehypertensives were classified according to the 50th percentile of adiponectin (< or = vs > 6.5 mg/ml) a logistic regression was performed to estimate the association of this adipokine with hypertension, the lower the plasma adiponectin values, the greater the association. A multivariate linear regression analysis adjusted for cardiometabolic factors showed that systolic blood pressure increased by 1.612 mm Hg for 1 microg/mL reduction in adiponectin plasma levels (P < 0.01). CONCLUSION: Our findings have shown that hypoadiponectinemia is associated with prehypertension in obese individuals of multiethnic origin.

Not all obese subjects of multiethnic origin are at similar risk for developing hypertension and type 2 diabetes.

BACKGROUND: Whether insulin resistance and not obesity per se is the major contributor to clinical outcomes associated with obesity has not been fully established. This study evaluated in a group of obese Brazilians of multiethnic origin to what extent the prevalence of hypertension and other cardiometabolic risk factors varies as a function of the degree of insulin sensitivity. METHODS: The study involved 118 individuals (mean age of 44+/-12 years; BMI=38.6+/-7.9 kg/m(2)) without evidence of diabetes or cardiovascular disease. Insulin resistance was assessed by HOMA-IR index, which was used to stratify patients into tertiles. RESULTS: The mean HOMA-IR in tertile 1, the most insulin-sensitive group, was 2.7+/-0.8 and in tertile 3, the most insulin-resistant group, 9.1+/-2.4 (P<0.001). Mean arterial pressure showed a linear and significant variation across the HOMA-IR tertiles 1, 2, and 3 (94.3+/-11.7; 98.7+/-11.4; 105.0+/-12.4 mm Hg), as did fasting plasma glucose (93.6+/-12.1; 98.1+/-12.7; 100.0+/-11.0 mg/dL), uric acid (4.7+/-1.4; 5.9+/-1.9; 6.3+/-1.4 mg/dL), HDL-cholesterol (48.1+/-11.6; 46.5+/-10.5; 42.2+/-8.0 mg/dL), and plasma adiponectin (7.8+/-3.3; 7.0+/-2.8; 6.3+/-6.5 microg/mL), respectively. The results indicated that 27.5% of our patients had dysglicemia, 28.2% had hypertriglyceridemia, and 30.7% had arterial hypertension in the most insulin-sensitive tertile, when compared with 51%, 53.8% and 79.4%, respectively, in the most insulin-resistant tertile. A stepwise regression analysis showed that only HOMA-IR and age independently affected the risk for increased systolic blood pressure. CONCLUSION: In conclusion, our findings have shown that the risk of developing essential hypertension, type 2 diabetes, and cardiovascular disease is accentuated in obese individuals who are also more insulin resistant.

Association of a common variant of the leptin gene with blood pressure in an obese Brazilian population.

BACKGROUND: This study assessed in obese Brazilians subjects whether a common variant of leptin gene, -2548G>A, is associated with blood pressure changes. METHODS: A total of 140 subjects, 99 women; mean age of 45.2 +/- 12.4 years; body mass index (BMI) = 38.5 +/- 8.0 kg/m2 were included. Blood pressure was recorded using Dinamap 1846 (Critikon, Tampa, FL). Molecular analysis was made by use of PCR and restriction fragment-length polymorphism analysis. Plasma insulin and leptin concentrations were determined by radioimmunoassay. RESULTS: AA homozygotes, in comparison with the G-allele carriers, showed significant lower levels of systolic, diastolic, and mean arterial pressure (120 +/- 10 vs. 132 +/- 17 mm Hg, P = 0.01; 75 +/- 6 vs. 84 +/- 12 mm Hg, P = 0.009; 92 +/- 7 vs. 100 +/- 12 mm Hg, P = 0.007, respectively). The differences in blood pressure remained significant after adjusting for the influence of gender, age, obesity, and body fat distribution as well as for leptin, insulin, and homeostasis model assessment of insulin resistance. A stepwise regression analysis confirmed that the LEP AA genotype independently predicted blood pressure changes. On the other hand, in GG homozygotes, insulinemia showed a significant association with blood pressure values. This suggests that common LEP genotype carriers exhibiting high insulin levels, reflecting an insulin-resistant state, were particularly prone to higher blood pressure levels. CONCLUSIONS: Our results showing that higher blood pressure levels were found with the most prevalent -2548G>A genotype, whereas patients with the AA genotype seemed to be protected from hypertension, indicate that the -2548G>A polymorphism of LEP appears to be an important mediator of obesity hypertension.

Treatment of hypertension in individuals with the cardiometabolic syndrome: role of an angiotensin II receptor blocker, telmisartan.

Arterial hypertension is a global public health problem owing to its high prevalence and association with increased risk for cerebral, cardiac and renal events. Hypertension frequently clusters with other cardiometabolic risk factors, such as dysglycemia, low levels of high-density lipoprotein cholesterol and high triglyceride levels. These, along with other factors such as central obesity, increased inflammation, endothelial dysfunction and thrombosis, are components of the metabolic syndrome. All guidelines recommend that the first-line therapy in metabolic syndrome should be based on lifestyle modification, consisting of diet and moderate exercise for at least 30 min/day. Concerning drug treatment of hypertension associated with other cardiometabolic risk factors, many results of head-to-head studies have demonstrated a reduction in new-onset Type 2 diabetes in hypertensive patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, when compared with conventional antihypertensive therapy. The explanations of the different actions of both these drugs include several mechanisms related to pancreatic insulin release and insulin sensitivity improvement. Another mechanism by which the inhibition of the renin-angiotensin system may improve insulin sensitivity is through the partial peroxisome proliferator-activated receptor-gamma agonism of telmisartan. For that reason, telmisartan has been considered by some experts to be an antihypertensive agent that is particularly useful in the treatment of hypertension associated with cardiometabolic risk factors. The impact of the promising metabolic action exhibited by telmisartan on the outcome of hypertensive patients aggregating other cardiometabolic risk factors waits for adequately randomized and powered clinical trials.

Hypoadiponectinemia is associated with blood pressure increase in obese insulin-resistant individuals.

Adiponectin is a major adipocytokine and has been considered as an independent risk factor for arterial hypertension. Most studies on the subject have been restricted to biracial (white-black) and Asian groups. The present report examined whether adiponectin affects blood pressure in a sample of untreated obese Brazilians of multiethnic origin. Fasting plasma adiponectin and serum insulin were determined by radioimmunoassay. Insulin resistance was estimated by homeostatic model assessment of insulin resistance (HOMA-IR). Blood pressure was recorded using Dinamap 1846 (Critikon, Tampa, FL). Adiponectin was significantly lower in obese hypertensive individuals than in obese normotensive ones. Blood pressure, insulin, and HOMA-IR were significantly higher in obese hypertensive than in obese normotensive individuals. Plasma adiponectin was negatively associated with waist-to-hip ratio, blood pressure, insulin, and HOMA-IR. The comparison of obese individuals who markedly differed in their HOMA-IR (> vs 6. 5 microg/mL), a 3 x 2 analysis of variance showed an independent contribution of adiponectin in the variation of mean arterial pressure. These results support the notion that HOMA-IR and adiponectin independently predict blood pressure variation in obese insulin-resistant Brazilians.

An 18-mo randomized trial of a low-glycemic-index diet and weight change in Brazilian women.

BACKGROUND: Despite interest in the glycemic index diets as an approach to weight control, few long-term evaluations are available. OBJECTIVE: The objective was to investigate the long-term effect of a low-glycemic-index (LGI) diet compared with that of a high-glycemic-index (HGI) diet; all other dietary components were equal. DESIGN: After a 6-wk run-in, we randomly assigned 203 healthy women [body mass index (in kg/m2): 23-30] aged 25-45 y to an LGI or an HGI diet with a small energy restriction. The primary outcome measure was weight change at 18 mo. Secondary outcomes included hunger and fasting insulin and lipids. RESULTS: Despite requiring a run-in and the use of multiple incentives, only 60% of the subjects completed the study. The difference in glycemic index between the diets was approximately 35-40 units (40 compared with 79) during all 18 mo of follow-up, and the carbohydrate intake from energy remained at approximately 60% in both groups. The LGI group had a slightly greater weight loss in the first 2 mo of follow-up (-0.72 compared with -0.31 kg), but after 12 mo of follow-up both groups began to regain weight. After 18 mo, the weight change was not significantly different (P = 0.93) between groups (LGI: -0.41 kg; HGI: -0.26 kg). A greater reduction was observed in the LGI diet group for triacylglycerol (difference = -16.4 mg/dL; P = 0.11) and VLDL cholesterol (difference = -3.7 mg/dL; P = 0.03). CONCLUSIONS: Long-term weight changes were not significantly different between the HGI and LGI diet groups; therefore, this study does not support a benefit of an LGI diet for weight control. Favorable changes in lipids confirmed previous results.

[Effects of greater-than-5% weight reduction on hemodynamic, metabolic and neuroendocrine profiles of grade I obese subjects]. / Efeitos da redução de peso superior a 5% nos perfis hemodinâmico, metabólico e neuroendócrino de obesos grau I.

OBJECTIVE: To evaluate the effects of a greater-than-5% weight reduction in hemodynamic, metabolic, and neuroendocrine profiles of grade I obese subjects. METHODS: Observational study with 47 grade I obese subjects, with mean age of 33 years who received monthly orientation regarding diet, physical exercises, and eating behavior for four months. Blood pressure using the auscultatory method and pulse rate were assessed monthly, whereas the following variables (and respective methods) were measured at the beginning and at the end of the study: total cholesterol, triglycerides, HDL-cholesterol (enzymatic method), LDL-cholesterol (Friedewald formula), blood glucose (hexokinase method), leptin, adiponectin, renin, aldosterone, insulin (radioimmunoassay) and insulin-resistance index (HOMA). RESULTS: After adjustment for other variables, significant reductions of 6 mmHg in diastolic blood pressure, 7 pg/ml in renin, 13 mg/dl in total cholesterol and 12 mg/dl in LDL-cholesterol were observed in the greater-than-5% weight reduction group. Also, a tendency to a higher increase in adiponectin levels by the end of the study, as well as a three-fold higher reduction in blood glucose, insulin, and HOMA levels, and a six-fold higher reduction in leptin levels were observed in this group. CONCLUSION: Non-pharmacological measures that promote a greater-than-5% weight reduction produce hemodynamic, metabolic, and neuroendocrine effects that improve the cardiovascular risk of obese subjects.

Efeitos da redução de peso superior a 5 por cento nos perfis hemodinâmico, metabólico e neuroendócrino de obesos grau I / Effects of greater-than-5 percent weight reduction on hemodynamic, metabolic and neuroendocrine profiles of grade I obese subjects

OBJETIVO: Avaliar os efeitos da redução de peso superior a 5 por cento nos perfis hemodinâmico, metabólico e neuroendócrino de obesos grau I. MÉTODOS: Estudo observacional com 47 obesos grau I, média de idade de 33 anos, submetidos a orientação mensal quanto a dieta, exercício físico e comportamento alimentar, durante quatro meses. A pressão arterial, pelo método auscultatório, e a freqüência cardíaca, pelo método palpatório, foram avaliadas mensalmente, enquanto as seguintes variáveis (e respectivos métodos) foram medidas no início e final do estudo: colesterol total, triglicerídeos, HDL-colesterol (enzimático), LDL-colesterol (fórmula de Friedwald), glicemia (enzimático hexoquinase), leptina, adiponectina, renina, aldosterona, insulina (radioimunoensaio) e índice de resistência à insulina (HOMA). RESULTADOS: Observamos, após ajuste para outras variáveis, reduções significativas de 6 mmHg na pressão arterial diastólica, 7 pg/ml na renina, 13 mg/dl no colesterol total e 12 mg/dl no LDL-colesterol, no grupo com redução de peso superior a 5 por cento. Notamos, também nesse grupo, tendência ao aumento de maior magnitude da adiponectina ao final do estudo, bem como diminuição três vezes maior dos níveis de glicemia, insulina e HOMA, e seis vezes maior da leptina. CONCLUSÃO: Medidas não-farmacológicas capazes de promover redução de peso superior a 5 por cento produzem efeitos hemodinâmicos, metabólicos e neuroendócrinos que melhoram o risco cardiovascular de obesos.