The endocannabinoid system--back to the scene of cardiometabolic risk factors control?

This review examines the impact of the endocannabinoid signaling system on metabolic and cardiovascular health and the new therapeutic strategies that selectively target dysfunctional endocannabinoid action in peripheral tissues, without causing the undesirable central nervous system effects that occurred with the first-generation of CB1 receptor blockers. We first review the components of the endocannabinoid system and the enzymes that synthesize and degrade the endocannabinoids, the critical role of the system in the homeostasis of energy balance, and its hedonic aspects related to the incentive and motivational value of food. Second, we describe the central and peripheral actions of the endocannabinoid system and its interactions with other biological modulators, such as ghrelin and leptin. Third, we summarize data from human clinical trials with the CB1 inverse agonist rimonabant, showing that the drug, although effective in increasing weight loss with accompanying improvements in the metabolic profile of the participants in the RIO (Rimonabant In Obesity) trials, was withdrawn from the market because of the risk of serious adverse events. Finally, we describe: 1) the development of new selective peripheral blockers that interrupt endocannabinoid action selectively in peripheral tissues and that have been suggested as an alternative approach to treat the metabolic consequences of obesity and related diseases, without undesirable central nervous system effects, and 2) the potential for inhibition of enzymes of synthesis, as well as the possible role of endocannabinoid congeners, with opposing effects as compared to CB1 receptor agonists, in the control of metabolic disorders.

Beta3-adrenergic receptor polymorphism is related to cardiometabolic risk factors in obese Brazilian subjects.

We determined whether ADRbeta3 polymorphism is associated with obesity-related traits in 140 obese patients. Molecular analysis was performed by PCR and RFLP. Individuals carrying the Arg64 allele had a lower waist-to-hip ratio, higher adiponectin and high-density lipoprotein cholesterol levels, and a tendency towards lower blood pressure. In contrast, Trp64/Trp64 carriers were at greater risk for dysmetabolic phenotypes (odds ratio = 2.88, P = 0.03).

Effect of a high-calcium energy-reduced diet on abdominal obesity and cardiometabolic risk factors in obese Brazilian subjects.

BACKGROUND: Clinical trials designed to examine the effects of calcium supplementation on abdominal obesity have had ambiguous results. AIMS: This study aimed to evaluate, during energy restriction, the effects of a high-calcium diet (HCD) on measures of abdominal obesity and cardiometabolic risk factors in Brazilian obese subjects of multiethnic origin. METHODS: We conducted a randomised clinical trial. Fifty obese subjects of both sexes, aged 22-55 years, with stable body weight and a low calcium intake were randomised into the following outpatient dietary regimens: (i) a low-calcium diet (LCD; < 500 mg/day) or (ii) a HCD [1200-1300 mg/day, supplemented with non-fat powdered milk (60 g/day)]. Both groups followed an energy-restricted diet (-800 kcal/day) throughout the study (16 weeks). RESULTS: Thirty-nine participants completed the study. After 16 weeks of energy restriction, a significant reduction was observed in all anthropometric parameters, metabolic variables (except for high-density lipoprotein cholesterol) and blood pressure levels in both the groups. Insulin was significantly reduced only in the HCD group. Subjects on the HCD compared with those on the LCD exhibited a greater reduction in waist circumference (p = 0.002), waist-to-hip ratio (p = 0.0001), diastolic blood pressure (p = 0.04) and mean blood pressure (p = 0.03). CONCLUSIONS: Our study suggests that increased calcium intake may enhance the beneficial effects of energy restriction on abdominal obesity and blood pressure.

Obesity-hypertension: an ongoing pandemic.

Considerable evidence has suggested that excessive weight gain is the most common cause of arterial hypertension. This association has been observed in several populations, in different regions of the world. Obesity-hypertension, a term that underscores the link between these two deleterious conditions, is an important public health challenge, because of its high frequency and concomitant risk of cardiovascular and kidney diseases. The obesity-hypertension pandemic imposes a considerable economic burden on societies, directly reflecting on healthcare system costs. Increased renal sodium reabsorption and blood volume expansion are central features in the development of obesity-hypertension. Overweight is also associated with increased sympathetic activity. Leptin, a protein expressed in and secreted by adipocytes, is the main factor linking obesity, increased sympathetic nervous system activity and hypertension. The renin-angiotensin-aldosterone system has also been causally implicated in obesity-hypertension, because angiotensinogen is expressed in and secreted by adipose tissue. Hypoadiponectinemia, high circulating levels of free fatty acids and increased vascular production of endothelin-1 (ET-1) have been reported as potential mechanisms for obesity-hypertension. Lifestyle changes are effective in obesity-hypertension control, though pharmacological treatment is frequently necessary. Despite the consistency of the mechanistic approach in explaining the causal relation between hypertension and obesity, there is yet no evidence that one class of drug is superior to the others in controlling obesity-hypertension. In this review, we present the current knowledge and research in obesity-hypertension, exploring the epidemiologic evidence of the association, its probable pathophysiological mechanisms and treatment issues.

LEPR p.Q223R, beta3-AR p.W64R and LEP c.-2548G>A gene variants in obese Brazilian subjects.

Obesity is due to the combined effects of genes, environment, lifestyle, and the interactions of these factors. The adrenergic receptor beta3 (beta3-AR), leptin (LEP) and leptin receptor (LEPR) genes have been intensively evaluated in the search of variants that could be related to obesity and its cardiometabolic complications. The results of most of these studies have been controversial. In the present study, we investigated the relationship of the beta3-AR p.W64R, LEP c.-2548G>A and LEPR p.Q223R gene variants with body mass index (BMI), in Brazilian subjects of different genetic backgrounds and ethnic origins. Two hundred obese patients (60 males, 140 females, BMI > or = 30 kg/m2) were screened and compared to 150 lean healthy subjects (63 males, 87 females, BMI < or = 24 kg/m2). Genomic DNA was extracted and amplified by polymerase chain reaction. Polymerase chain reaction products were digested with specific restriction enzymes and separated by electrophoresis. There was no significant difference in the genotype frequency of the beta3-AR p.W64R and the LEP c.-2548G>A polymorphisms, between lean and obese subjects. However, the genotype and allele frequencies of the LEPR p.Q223R variant were significantly different between the normal weight and obese groups. Haplotype analysis has shown an association between the G/G allelic combination of c.-2548G>A LEP and c.668A>G LEPR, in obese subjects. Our results suggest that genetic variability in the leptin receptor is associated with body weight regulation, the LEPR p.Q223R variant being related to BMI increase. The haplotype combination of LEP c.-2548G>A and LEPR p.Q223R variants was related to a 58% increase in obesity risk.

LEPR p. Q223R, Beta 3-AR p. W64R and LEPc. -2548G>A gene variants in obese Brazilian subjects

Obesity is due to the combined effects of genes, environment, lifestyle, and the interactions of these factors. The adrenergic receptor ¦Â3 (¦Â3-AR), leptin (LEP) and leptin receptor (LEPR) genes have been intensively evaluated in the search of variants that could be related to obesity and its cardiometabolic complications. The results of most of these studies have been controversial. In the present study, we investigated the relationship of the ¦Â3-AR p.W64R, LEP c.-2548G>A and LEPR p.Q223R gene variants with body mass index (BMI), in Brazilian subjects of different genetic backgrounds and ethnic origins. Two hundred obese patients (60 males, 140 females, BMI ¡Ý 30 kg/m2) were screened and compared to 150 lean healthy subjects (63 males, 87 females, BMI ¡Ü 24 kg/m2). Genomic DNA was extracted and amplified by polymerase chain reaction. Polymerase chain reaction products were digested with specific restriction enzymes and separated by electrophoresis. There was no significant difference in the genotype frequency of the ¦Â3-AR p.W64R and the LEP c.-2548G>A polymorphisms, between lean and obese subjects. However, the genotype and allele frequencies of the LEPR p.Q223R variant were significantly different between the normal weight and obese groups. Haplotype analysis has shown an association between the G/G allelic combination of c.-2548G>A LEP and c.668A>G LEPR, in obese subjects. Our results suggest that genetic variability in the leptin receptor is associated with body weight regulation, the LEPR p.Q223R variant being related to BMI increase. The haplotype combination of LEP c.-2548G>A and LEPR p.Q223R variants was related to a 58% increase in obesity risk.

Renal functional reserve in obesity hypertension.

The capacity to increase glomerular filtration rate in response to an acute oral protein load is known as the renal functional reserve; the loss of such capacity is used as a marker of hyperfiltration. This physiological response in obese hypertensives is not yet fully understood. We aimed to study the interdependent effects of obesity and hypertension on renal reserve, taking into account renal kallikrein and nitric oxide in the modulation of that parameter. Fourteen obese hypertensives (mean age, 50.5 +/- 0.9 years) and nine lean hypertensives (mean age, 50.6 +/- 2.7 years) were evaluated. Renal haemodynamics and the levels of serum nitric oxide and urinary kallikrein were assessed at baseline and after a protein load (1 g/kg of body weight). An increase in the following parameters was observed when comparing obese and lean hypertensives: basal glomerular filtration rate; renal plasma flow; and urinary kallikrein and nitric oxide levels (129.2 +/- 2.9 vs. 101.4 +/- 3.4 ml/min/1.73 m2; 587.5 +/- 18.2 vs. 502.8 +/- 16.7 ml/min/1.73 m2; 0.120 +/- 0.02 vs. 0.113 +/- 0.02 mU/ml; 23.2 +/- 0.8 vs. 19.5 +/- 1.2 mmol/ml, respectively). The renal reserve was lower in obese hypertensives when compared with that of lean hypertensives (4.1 +/- 0.5 vs. 11.8 +/- 0.8 ml/min, p < 0.005). After a protein load, contrasting with the lean group, inability to elevate the nitric oxide serum levels and a lower increase in urinary kallikrein were observed in the obese group. These data suggest that obese hypertensives lose renal reserve earlier in the evolution to renal dysfunction. This may be due to the defective modulation of renal vasodilatation mechanisms by renal kallikrein and nitric oxide production.

Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.

AIM: To evaluate the effects of combined treatment of an ACE inhibitor and an angiotensin II receptor antagonist on parameters related to the progression of renal disease in type 2 diabetic patients. METHODS: 20 hypertensive type 2 diabetic patients with non-nephrotic proteinuria (0.5 - 3.0 g/day) and estimated creatinine clearance > or = 40 ml/min/1.73m2 were randomly assigned to be treated with perindopril 8 mg/day (Per), irbesartan 300 mg/day (Irb) or a combination of both with the same doses (Per + Irb). Each treatment phase lasting 16 weeks was preceded by a four-week washout period. Diuretics, clonidine and hydralazine were used as supplementary drugs for blood pressure control. Patients were evaluated at baseline and at the end of each treatment phase. RESULTS: 15 (3M/12F) patients completed all the phases. Use of Per, Irb and Per + Irb led to a reduction in 24-hour mean blood pressure of 6 mmHg, 4 mmHg and 4 mmHg, respectively. Changes in glomerular filtration rate were not significant at any phase. Renal plasma flow was significantly more elevated with Irb than Per. Treatment with both Irb and Per + Irb induced similar plasma renin elevation, but treatment with Per did not, suggesting escape. Plasma aldosterone was reduced only by treatment with Per + Irb (-36%, p < 0.02). Reduction in proteinuria during Per + Irb (-33%) was not significantly different from Per (-34%) or Irb (-22%). Urinary transforming growth factor beta1 (TGF-beta1) excretion was significantly reduced with both Irb (-24%, p < 0.05) and Per + Irb (-36%, p < 0.05) but not with Per (-11%, p = 0.60). CONCLUSION: Only combined therapy with irbesartan plus perindopril concurrently reduces plasma aldosterone, proteinuria and urinary TGF-beta1.