Stefan Engeli

Weight Loss and the Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system has been causally implicated in obesity-associated hypertension. We studied the influence of obesity and weight reduction on the circulating and adipose tissue renin-angiotensin-aldosterone system in menopausal women. Blood samples were analyzed for angiotensinogen, renin, aldosterone, angiotensin-converting enzyme activity, and angiotensin II. In adipose tissue biopsy samples, we analyzed angiotensinogen, renin, renin-receptor, angiotensin-converting enzyme, and angiotensin II type-1 receptor gene expression. Obese women (n=19) had higher circulating angiotensinogen, renin, aldosterone, and angiotensin-converting enzyme than lean women (n=19), and lower angiotensinogen gene expression in adipose tissue. Seventeen women successfully participated in a weight reduction protocol over 13 weeks to reduce daily caloric intake by 600 kcal. Body weight was reduced by −5%, as were angiotensinogen levels by −27%, renin by −43%, aldosterone by −31%, angiotensin-converting enzyme activity by −12%, and angiotensinogen expression by −20% in adipose tissue (all P<0.05). The plasma angiotensinogen decrease was highly correlated with the waist circumference decline (r=0.74; P<0.001). Weight and renin-angiotensin-aldosterone system reductions were accompanied by a −7-mm Hg reduced systolic ambulatory blood pressure. These data suggest that a 5% reduction in body weight can lead to a meaningfully reduced renin-angiotensin-aldosterone system in plasma and adipose tissue, which may contribute to the reduced blood pressure.

Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity

The endocannabinoid system has been suspected to contribute to the association of visceral fat accumulation with metabolic diseases. We determined whether circulating endocannabinoids are related to visceral adipose tissue mass in lean, subcutaneous obese, and visceral obese subjects (10 men and 10 women in each group). We further measured expression of the cannabinoid type 1 (CB1) receptor and fatty acid amide hydrolase (FAAH) genes in paired samples of subcutaneous and visceral adipose tissue in all 60 subjects. Circulating 2-arachidonoyl glycerol (2-AG) was significantly correlated with body fat (r = 0.45, P = 0.03), visceral fat mass (r = 0.44, P = 0.003), and fasting plasma insulin concentrations (r = 0.41, P = 0.001) but negatively correlated to glucose infusion rate during clamp (r = 0.39, P = 0.009). In visceral adipose tissue, CB1 mRNA expression was negatively correlated with visceral fat mass (r = 0.32, P = 0.01), fasting insulin (r = 0.48, P < 0.001), and circulating 2-AG (r = 0.5, P < 0.001), whereas FAAH gene expression was negatively correlated with visceral fat mass (r = 0.39, P = 0.01) and circulating 2-AG (r = 0.77, P < 0.001). Our findings suggest that abdominal fat accumulation is a critical correlate of the dysregulation of the peripheral endocannabinoid system in human obesity. Thus, the endocannabinoid system may represent a primary target for the treatment of abdominal obesity and associated metabolic changes.

The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome?

Overfeeding of rodents leads to increased local formation of angiotensin II due to increased secretion of angiotensinogen from adipocytes. Whereas angiotensin II promotes adipocyte growth and preadipocyte recruitment, increased secretion of angiotensinogen from adipocytes also directly contributes to the close relationship between adipose-tissue mass and blood pressure in mice. In contrast, angiotensin II acts as an antiadipogenic substance in human adipose tissue, and the total increase in adipose-tissue mass may be more important in determining human plasma angiotensinogen levels than changes within the single adipocyte. However, as increased local formation of angiotensin II in adipose tissue may be increased especially in obese hypertensive subjects, a contribution of the adipose-tissue renin-angiotensin system to the development of insulin resistance and hypertension is conceivable in humans, but not yet proven. Insulin resistance may be aggravated by the inhibition of preadipocyte recruitment, which results in the redistribution of triglycerides to the liver and skeletal muscle, and blood pressure may be influenced by local formation of angiotensin II in perivascular adipose tissue. Thus, although the mechanisms are still speculative, the beneficial effects of ACE-inhibition and angiotensin-receptor blockade on the development of type 2 diabetes in large clinical trials suggest a pathophysiological role of the adipose-tissue renin-angiotensin system in the metabolic syndrome.

Retinol-Binding Protein 4 in Human Obesity

Studies in mice suggest that adipocytes serve as glucose sensors and regulate systemic glucose metabolism through release of serum retinol-binding protein 4 (RBP4). This model has not been validated in humans. RBP4 was highly expressed in isolated mature human adipocytes and secreted by differentiating human adipocytes. In contrast to the animal data, RBP4 mRNA was downregulated in subcutaneous adipose tissue of obese women, and circulating RBP4 concentrations were similar in normal weight, overweight, and obese women (n = 74). RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable. Five percent weight loss slightly decreased adipose RBP4 expression but did not influence circulating RBP4. In another set of experiments, we stratified patients (n = 14) by low or high basal fasting interstitial glucose concentrations, as determined by the microdialysis technique. Venous glucose concentrations were similar throughout oral glucose tolerance testing, and basal RBP4 expression in adipose tissue and serum RBP4 concentrations were similar in the groups with higher and lower interstitial glucose levels. Our findings point to profound differences between rodents and humans in the regulation of adipose or circulating RBP4 and challenge the notion that glucose uptake by adipocytes has a dominant role in the regulation of RBP4.

Carotid Baroreceptor Stimulation, Sympathetic Activity, Baroreflex Function, and Blood Pressure in Hypertensive Patients

In animals, electric field stimulation of carotid baroreceptors elicits a depressor response through sympathetic inhibition. We tested the hypothesis that the stimulation acutely reduces sympathetic vasomotor tone and blood pressure in patients with drug treatment–resistant arterial hypertension. Furthermore, we tested whether the stimulation impairs the physiological baroreflex regulation. We studied 7 men and 5 women (ages 43 to 69 years) with treatment-resistant arterial hypertension. A bilateral electric baroreflex stimulator at the level of the carotid sinus (Rheos) was implanted ≥1 month before the study. We measured intra-arterial blood pressure, heart rate, muscle sympathetic nerve activity (microneurography), cardiac baroreflex sensitivity (cross-spectral analysis and sequence method), sympathetic baroreflex sensitivity (threshold technique), plasma renin, and norepinephrine concentrations. Measurements were performed under resting conditions, with and without electric baroreflex stimulation, for ≥6 minutes during the same experiment. Intra-arterial blood pressure was 193±9/94±5 mm Hg on medications. Acute electric baroreflex stimulation decreased systolic blood pressure by 32±10 mm Hg (range: +7 to −108 mm Hg; P=0.01). The depressor response was correlated with a muscle sympathetic nerve activity reduction (r2=0.42; P<0.05). In responders, muscle sympathetic nerve activity decreased sharply when electric stimulation started. Then, muscle sympathetic nerve activity increased but remained below the baseline level throughout the stimulation period. Heart rate decreased 4.5±1.5 bpm with stimulation (P<0.05). Plasma renin concentration decreased 20±8% (P<0.05). Electric field stimulation of carotid sinus baroreflex afferents acutely decreased arterial blood pressure in hypertensive patients, without negative effects on physiological baroreflex regulation. The depressor response was mediated through sympathetic inhibition.

Angiotensin Blockade Prevents Type 2 Diabetes by Formation of Fat Cells

Obesity is the prime risk factor for the development of type 2 diabetes. Recent clinical trials have shown that blockade of the renin-angiotensin system, either by inhibiting the angiotensin-converting enzyme or blocking the angiotensin type 1 receptor, may substantially lower the risk for type 2 diabetes. The mechanism underlying this effect is unknown. Based on our recent observation that angiotensin II markedly inhibits adipogenic differentiation of human adipocytes via the angiotensin type I receptor and that expression of angiotensin II-forming enzymes in adipose tissue is inversely correlated with insulin sensitivity, we propose the hypothesis that blockade of the renin-angiotensin system prevents diabetes by promoting the recruitment and differentiation of adipocytes. Increased formation of adipocytes would counteract the ectopic deposition of lipids in other tissues (muscle, liver, pancreas), thereby improving insulin sensitivity and preventing the development of type 2 diabetes.

Novel Baroreflex Activation Therapy in Resistant Hypertension Results of a European Multi-Center Feasibility Study

OBJECTIVES This study assessed the safety and efficacy of a novel implantable device therapy in resistant hypertension patients. BACKGROUND Despite the availability of potent antihypertensive drugs, a substantial proportion of patients remain hypertensive. A new implantable device (Rheos system, CVRx, Inc., Minneapolis, Minnesota) that activates the carotid baroreflex may help these patients. METHODS Forty-five subjects with systolic blood pressure ≥160 mm Hg or diastolic ≥90 mm Hg despite at least 3 antihypertensive drugs were enrolled in a prospective, nonrandomized feasibility study to assess whether Rheos therapy could safely lower blood pressure. Subjects were followed up for as long as 2 years. An external programmer was used to optimize and individualize efficacy. RESULTS Baseline mean blood pressure was 179/105 mm Hg and heart rate was 80 beats/min, with a median of 5 antihypertensive drugs. After 3 months of device therapy, mean blood pressure was reduced by 21/12 mm Hg. This result was sustained in 17 subjects who completed 2 years of follow-up, with a mean reduction of 33/22 mm Hg. The device exhibited a favorable safety profile. CONCLUSIONS The Rheos device sustainably reduces blood pressure in resistant hypertensive subjects with multiple comorbidities receiving numerous medications. This unique therapy offers a safe individualized treatment option for these high-risk subjects. This novel approach holds promise for patients with resistant hypertension and is currently under evaluation in a prospective, placebo-controlled clinical trial.

Co-expression of renin-angiotensin system genes in human adipose tissue.

OBJECTIVE The renin-angiotensin system plays a central role in blood pressure regulation, both by affecting renal function and by modulating vascular tone and structure. Recent studies in rodents demonstrated the existence of several components of this system in adipose tissue. The activity of the renin-angiotensin system appears to be regulated by food intake, suggesting that it may be involved in obesity-associated hypertension. Few data are available on the presence of renin-angiotensin system components in human adipose tissue. MATERIALS AND METHODS In order to explore the expression of renin-angiotensin system genes in human adipose tissue and adipocytes, total RNA was isolated from whole adipose tissue (subcutaneous and omental) or cultured adipocytes (mammary) and subjected to reverse-transcriptase polymerase chain reaction with primers specific for human angiotensinogen, renin, renin-binding protein, angiotensin converting enzyme, chymase and type 1 and type 2 angiotensin receptors. RESULTS Angiotensinogen, angiotensin converting enzyme and type 1 angiotensin receptor genes were widely expressed, both in human adipose tissue and in cultured human adipocytes. Furthermore, we found expression of the chymase and renin-binding protein genes in these samples. CONCLUSIONS Our findings suggest the presence of a local renin -angiotensin system in human adipose tissue, with adipocytes being an important part of this system, and prompt speculation that this local renin-angiotensin system may be involved in obesity-related disorders, including hypertension and the metabolic syndrome.

Hormonal regulation of the human adipose-tissue renin-angiotensin system: relationship to obesity and hypertension.

Objective Adipose tissue secretes vasoactive substances which may contribute to the development of obesity-related hypertension. The aim of this work was to study the expression of renin–angiotensin system genes in adipose tissue of obese hypertensive subjects and the hormonal regulation of these genes. Design Differential expression of renin–angiotensin system genes in subcutaneous abdominal adipocytes of 12 lean normotensive, eight obese normotensive, and 10 obese hypertensive women was determined in a cross-sectional study. In vitro hormonal regulation of these genes was studied in primary human adipocytes obtained by breast reduction from healthy women. Methods In the clinical study, 24-h ambulatory blood pressure measurement and anthropometry were used to characterize the volunteers, and adipocytes were obtained by subcutaneous needle biopsy. The in vitro regulation of renin–angiotensin system genes by hydrocortisone, insulin, thyroxin, estradiol and angiotensin II on primary cultured human mammary adipocytes was studied by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Results While expression of the angiotensinogen gene was significantly lower in adipocytes from both obese groups, the renin, angiotensin-converting enzyme and angiotensin II type 1 receptor genes were significantly upregulated in obese hypertensives. Hydrocortisone increased angiotensin II type 1 receptor gene and protein expression in a time- and dose-dependent manner in human adipocytes, but had no significant influence on other renin–angiotensin system genes. Expression of these genes was not significantly affected by any of the other tested hormones. Conclusions Renin–angiotensin system genes are differentially regulated in human obesity and hypertension. The role of the adipose-tissue renin–angiotensin system in the development of obesity-associated hypertension or metabolic disease clearly warrants further study.

The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension

Abstract. Excessive accumulation of adipose tissue is associated with profound alterations in the cardiovascular system, including an increase in systemic blood pressure. It now appears clear that a central feature of obesity-associated hypertension is related to changes in sodium handling that may result from abnormalities in sympathetic nervous system activity, the renin-angiotensin-aldosterone system, natriuretic peptides, and kidney function. In this paper we review the role of these factors in the development of obesity-associated hypertension, thereby focusing on the potential role of adipose tissue in these alterations.