Physiology and pathophysiology of the adipose tissue renin-angiotensin system

The renin-angiotensin system has long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis, and local renin-angiotensin systems have also been implicated in pathological changes of organ structure and function by modulation of gene expression, growth, fibrosis, and inflammatory response. Recently, substantial data have been accumulated in support of the notion that adipose tissue, besides other endocrine functions, also hosts a local renin-angiotensin system. In the first part of this review, we describe the components of the adipose tissue renin-angiotensin system in human and rodent animal models with respect to regulation of angiotensinogen expression and secretion, formation of angiotensin peptides, and the existence of angiotensin II receptors. In the second part, we describe the role of the adipose tissue renin-angiotensin system in the process of adipogenic differentiation and in the regulation of body weight. We also detail the differential regulation of the adipose tissue renin-angiotensin system in obesity and hypertension and thereby also speculate on its possible role in the development of obesity-associated hypertension. Although some findings on the adipose tissue renin-angiotensin system appear to be confusing, its involvement in the physiology and pathophysiology of adipose tissue has been confirmed by several functional studies. Nevertheless, future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.     

White adipose tissue mitochondrial metabolism in health and in obesity

White adipose tissue is one of the largest organs of the body. It plays a key role in whole‐body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well‐being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity‐associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole‐body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long‐term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue.     

Beneficial effects of losartan or telmisartan on the local hepatic renin-angiotensin system to counter obesity in an experimental model

BACKGROUND Obesity has been associated with hepatic overexpression of the renin-angiotensin system(RAS).AIM To evaluate the action of two angiotensin II(ANGII) receptor blockers(losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model.METHODS Twenty C57 BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group(C, n = 5, 10% of energy as fat) or high-fat group(HF, n = 15,50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group(n = 5), HF treated with losartan(HFL, n = 5) and HF treated with telmisartan(HFT, n = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass.RESULTS HF diet induced body mass gain(+28%, P 0.0001), insulin resistance(+69%, P =0.0079), high hepatic triacylglycerol(+127%, P = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme(ACE) 1/ANGII type 1 receptor(AT1 r)(+569.02% and +141.40%, respectively, P 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group(ACE2: +465.57%, P = 0.0002 for HFL and +345.17%, P = 0.0049 for HFT; rMAS:+711.39%, P 0.0001 for HFL and +539.75%, P 0.0001 for HFT), followed by reduced insulin/glucose ratio(-30% for HFL and-33% for HFT, P = 0.0181),hepatic triacylglycerol levels(-28%, P = 0.0381 for HFL; and-45%, P = 0.0010 for HFT, and Plin2 expression.CONCLUSION Modulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1 r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.     

Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance

In-vitro studies have implicated the A(1) adenosine receptor (A(1)AR) of adipocytes in inhibition of lipolysis, stimulation of lipogenesis and enhancement of the action of insulin on glucose metabolism. To determine whether any of these activities were physiologically relevant in an intact animal, A(1)AR was overexpressed in adipose tissue of transgenic mice. Lower plasma free fatty acid (FFA) levels were observed in the transgenic mice relative to the litter-matched controls, supporting a significant physiological role for adipocyte A(1)AR in the control of lipolysis. However, no differences were observed in body weights or body composition. On a high fat diet, both the transgenic mice and the litter matched controls, male and female, became equally obese. Unlike the control mice, however, the transgenic mice did not develop insulin resistance, as demonstrated by serum glucose and insulin levels and glucose and insulin tolerance tests. These findings demonstrate that adipocyte A(1)AR plays an important physiological role in the control of insulin sensitivity in an intact animal and therefore should be considered to be a potential therapeutic target for the treatment of obesity-related insulin resistance and type 2 diabetes.     

Potential role of the tissue renin-angiotensin system in the pathophysiology of congestive heart failure

The circulating renin-angiotensin system (RAS) plays an important role in the maintenance of cardiovascular homeostasis. It has recently been demonstrated that endogenous RAS exist in target tissues that are important in cardiovascular regulation. This article reviews the multiple effects of angiotensin II in target tissues, the evidence for the presence of functional tissue RAS and the data that suggest a role for these tissue RAS in the pathophysiology of heart failure. Activation of circulating neurohormones is predictive of worsened survival in heart failure; however, cardiac and renal tissue RAS activities are also increased in the compensated stage of heart failure, when plasma renin-angiotensin activity is normal. It is hypothesized that the plasma RAS maintains circulatory homeostasis during acute cardiac decompensation, while changes in tissue RAS contribute to homeostatic responses during chronic sustained cardiac impairment. This concept of different functions of circulating and tissue RAS in the pathophysiology of heart failure may have important pharmacologic implications.     

Childhood obesity: Implications on adipose tissue dynamics and metabolic health

Obesity is the leading risk factor for the development of type 2 diabetes and cardiovascular diseases. Childhood obesity represents an alarming health challenge because children with obesity are prone to remain with obesity throughout their life and have an increased morbidity and mortality risk. The ability of adipose tissue to store lipids and expand in size during excessive calorie intake is its most remarkable characteristic. Cellular and lipid turnovers determine adipose tissue size and are closely related with metabolic status. The mechanisms through which adipose tissue expands and how this affects systemic metabolic homeostasis are still poorly characterized. Furthermore, the mechanism through which increased adiposity extends from childhood to adulthood and its implications in metabolic health are in most part, still unknown. More studies on adipose tissue development in healthy and children with obesity are urgently needed. In the present review, we summarize the dynamics of white adipose tissue, from developmental origins to the mechanisms that allows it to grow and expand throughout lifetime and during obesity in children and in different mouse models used to address this largely unknown field. Specially, highlighting the role that excessive adiposity during the early life has on future's adipose tissue dynamics and individual's health.      

Protracted glucose fall in subcutaneous adipose tissue and skeletal muscle compared with blood during insulin-induced hypoglycaemia

Summary The absolute glucose concentrations in subcutaneous adipose tissue and skeletal muscle were determined with microdialysis in 10 normal-weight, healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The concentration of tissue dialysate glucose was measured in 15-min fractions and compared with that in arterialized venous plasma. Insulin (0.15 U · kg^-1· h⁻¹) was infused i. v. to lower the plasma glucose level to 2.5 mmol/l over 30 min. This level was maintained for 30 min by using a variable glucose infusion. Thereafter, the insulin infusion was stopped and the plasma glucose level was gradually increased to baseline levels over 120 min. During a 60-min basal period, the glucose levels in muscle were 0.6 mmol/l lower than those in plasma (p = 0.002), whereas the levels in adipose tissue and plasma were similar. The glucose nadirs in muscle (1.6 ± 0.1 mmol/l) and adipose tissue (2.0 ± 0.1 mmol/l) were significantly lower than that in plasma (2.4 ± 0.1 mmol/l) (p = 0.001 and 0.02, respectively), and the time-to-nadir was substantially longer in muscle (69 ± 5 min) and adipose tissue (57 ± 2 min) than in plasma (39 ± 3 min) (p = 0.0004). When the insulin infusion was stopped, the increases in adipose tissue and muscle glucose concentrations were delayed by approximately 25 and 45 min, respectively, as compared to the increase in plasma glucose. Thus, it seems that glucose measurements in adipose tissue and muscle more adequately reflect overall tissue homeostasis than do measurements in blood and that clinically relevant tissue glucopenia may be overlooked by conventional blood glucose measurements. [Diabetologia (1997) 40: 1320–1326] Received: 21 January 1997 and in final revised form: 2 July 1997     

Down-regulation of cardiac apelin system in hypertrophied and failing hearts: Possible role of angiotensin II-angiotensin type 1 receptor system

Cardiac apelin has recently been suggested to contribute to the pathophysiology of heart failure (HF) in humans. In animal experiments, its infusion acutely improved systolic as well as diastolic LV function. Although its deficit could critically determine the cardiac dysfunction, its regulatory mechanism is unknown. Accordingly, we investigated the role and regulation of the cardiac apelin system in the diseased heart using Dahl salt-sensitive rats, which show a distinctive transition from compensatory LV hypertrophy (LVH) to HF. In the compensatory LVH stage, apelin and its receptor APJ mRNA showed no change compared with control animals, while these were markedly down-regulated in the HF stage (72% and 57% decrease, respectively). The rats were chronically treated with telmisartan (angiotensin type 1 receptor blocker [ARB], 5 mg/kg/day, n=9), ONO-4817 (matrix metalloproteinase [MMP] inhibitor, 200 mg/kg/day, n=9), bisoprolol (beta blocker, 3 mg/kg/day, n=6) or vehicle (0.5%CMC, n=9) from the LVH stage. Although the functional improvements were similar among the three treated groups 6 weeks after treatment, restoration of cardiac apelin and APJ expression was observed only in the ARB group. Furthermore, in angiotensin II-infused rats, cardiac apelin mRNA was decreased after 24 h of treatment and its restoration was achieved by treatment with ARB. These results indicate that the cardiac apelin system is markedly down-regulated in experimental HF and may be regulated by the angiotensin II-angiotensin type 1 receptor system directly. Inhibition of the renin-angiotensin system may have beneficial effects, at least in part, through restoration of the cardiac apelin system in the treatment of HF.     

Persistent organic pollutants in adipose tissue should be considered in obesity research

Although low doses of persistent organic pollutants (POPs), strong lipophilic chemicals with long half‐lives, have been linked to various endocrine, immune, nervous and reproductive system diseases, few obesity studies have considered adipose tissue as an important POPs exposure source. Because the toxicodynamics of POPs relate directly to the dynamics of adiposity, POPs might explain puzzling findings in obesity research. In two people exposed to the same amounts of environmental POPs, the one having more adipose tissue may be advantaged because POPs storage in adipose tissue can reduce burden on other critical organs. Therefore, adipose tissue can play a protective role against the POPs effects. However, two situations increase the POPs release from adipose tissue into the circulation, thereby increasing the risk that they will reach critical organs: (i) weight loss and (ii) insulin resistance. In contrast, weight gain reduces this possibility. Therefore, avoiding harmful health effects of POPs may mostly contradict conventional judgments about obesity and weight change. These contradictory situations can explain the obesity paradox, the adverse effects of intensive intentional weight loss and the protective effects of obesity against dementia. Future studies should consider that adipose tissue is widely contaminated with POPs in modern society.     

Possible involvement of the local renin-angiotensin system in exocrine pancreas responses to food components

The functioning of the exocrine and endocrine pancreas is strictly co-ordinated through an interdependent array of neural and endocrine, paracrine and autocrine hormonal factors. The responses of the exocrine pancreas to food are primarily initiated via hormones secreted by neuroendocrine cells in the gut. No role for the pancreatic renin-angiotensin system in these mechanisms has so far been established. However, because of its distribution throughout the pancreas, the renin-angiotensin system could have a function in fine-tuning of secretory responses or in integrating some of the actions of the endocrine and exocrine pancreas. In the normal diet, we are exposed to an array of bioactive (lectins, protease inhibitors, hormone-mimics, tannins, etc). Some can profoundly alter pancreas metabolism both in a beneficial or detrimental manner. Others could have beneficial effects on the pancreas renin-angiotensin system. The effects of these compounds need to be evaluated.     

Fine particulate matter induces adipose tissue expansion and weight gain: Pathophysiology

Dysregulations in energy balance represent a major driver of obesity. Recent evidence suggests that environmental factors also play a pivotal role in inducing weight gain. Chronic exposure to fine particulate matter (PM_2.5) is associated with white adipose tissue (WAT) expansion in animals and higher rates of obesity in humans. This review discusses metabolic adaptions in central and peripheral tissues that promote energy storage and WAT accumulation in PM_2.5-exposed animals and humans. Chronic PM_2.5 exposure produces inflammation and leptin resistance in the hypothalamus, decreasing energy expenditure and increasing food intake. PM_2.5 promotes the conversion of brown adipocytes toward the white phenotype, resulting in decreased energy expenditure. The development of inflammation in WAT can stimulate adipogenesis and hampers catecholamine-induced lipolysis. PM_2.5 exposure affects the thyroid, reducing the release of thyroxine and tetraiodothyronine. In addition, PM_2.5 exposure compromises skeletal muscle fitness by inhibiting Nitric oxide (NO)-dependent microvessel dilation and impairing mitochondrial oxidative capacity, with negative effects on energy expenditure. This evidence suggests that pathological alterations in the hypothalamus, brown adipose tissue, WAT, thyroid, and skeletal muscle can alter energy homeostasis, increasing lipid storage and weight gain in PM_2.5-exposed animals and humans. Further studies will enrich this pathophysiological model.     

脂肪组织局部肾素血管紧张素系统与代谢综合征

肾素-血管紧张素系统相关成分陆续在脂肪组织中发现,它们主要受能量代谢调节,与代谢综合征的发生发展有密切关系。在机体发生肥胖、高血压、高血糖和高胰岛素血症时,脂肪组织内肾素-血管紧张素系统表达增加;应用血管紧张素受体拮抗剂或血管紧张素转换酶抑制剂,通过改变脂肪细胞功能等作用,改善代谢综合征的状态。     

肾素-血管紧张素系统与支气管哮喘

支气管哮喘(哮喘)是全球范围内严重威胁公众健康的慢性疾病之一,是以气道慢性炎症和气道重塑为基本病理特征的慢性疾病.近年来,大量研究显示肾素一血管紧张素系统(renin-angiotensin system,RAS)参与了哮喘的急性发作和气道重塑过程.因此,应用血管紧张素转换酶抑制剂和血管紧张素受体阻断剂治疗和预防哮喘发作,可望成为哮喘治疗的一个重要方法.本文综述了RAS在哮喘发生、发展过程中的作用.     

Determination of Body Fat Distribution by Dual-Energy X-ray Absorptiometry and Attenuation of Visceral Fat Vasoconstriction by Enalapril

Use of dual-energy X-ray absorptiometry (DEXA) data to calculate the percent of body fat in the visceral (%VF) and subcutaneous (%SF) compartments and the mechanism of visceral fat vasoconstriction when intestinal mucosal afferent nerves are stimulated has not been reported. The aim of this sudy was to compare visceral fat weight determined by DEXA and direct weighing and determine whether enalapril attenuates visceral fat vasoconstriction induced by stimulation of intestinal mucosal afferent nerves. We performed two studies. Study 1: In euthanized mice, DEXA scans were obtained before and after visceral fat dissection. The dissected fat weight was determined by DEXA (VF) and by direct weighing. Study 2: In anesthetized rat preparations, visceral (mesenteric) fat blood flow was monitored by laser Doppler flowmetry (LDF). After baseline, vehicle or 3 mg/kg enalapril (angiotensin-converting enzyme inhibitor) was administered intravenously, followed by 2 ml/kg of 640 μm capsaicin intraduodenally. In study 1, there was agreement between visceral fat weight determined by the DEXA (y) and direct weighing (x): y = 0.98x, r = 0.99, n = 10. In study 2, LDF signals showed an instantaneous decline when capsaicin was administered into the duodenal lumen. After enalapril treatment, the reductions were significantly attenuated compared with those after vehicle treatment. DEXA results combined with visceral fat dissection permit determination of body fat distribution. The instantaneous decline in visceral fat blood flow suggests that the reduction is a neural- rather than a hormone-mediated event, and attenuation by enalapril suggests angiotensin II plays a role. Presented at the Digestive Disease Week Meetings, Washington D.C., USA, May 2007 and published as Abstract S1688 in Gastroenterology 2007;132(4):Suppl 2, p. 248.