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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.

In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed “the adiponectin paradox”. Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.

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.

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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 (≤ 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 μg/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. IntroductionThe data from the participants in the Framingham Heart Study demonstrate the increased risk seen in people at any blood pressure (BP) level above optimal (below 120/80 mm Hg) to normal (120-129/80-84 mm Hg) to high normal (130-139/85-89 mm Hg). 1 Over a 12-year followup, the cumulative incidence of cardiovascular events in the enrolled men rose from 6% in those who started as optimal, to 8% in the normal, and 13% in the high normal. In 2003, the Seventh Report of the Joint National Committee (JNC) identified prehypertension as a new category of BP in adults for those with BP from 120 to 139 mm Hg systolic and/or 80 to 89 mm Hg diastolic, encompassing both the normal and high-normal classifications of prior JNC reports. 2 A review of recent published data relating prehypertension to cardiovascular damage includes reports showing an increase in coronary heart disease, cardiac procedure, silent myocardial infarction, or ischemic stroke in middleaged adults followed for an average of 11.6 years, 3 and significant progress of coronary atherosclerosis determined by intravascular ultrasound. 4

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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.