瘦素和肥胖相关性高血压

动物试验和临床研究等表明瘦素与高血压存在一定的联系。肥胖者往往存在瘦素抵抗 ,此种抵抗发生于调节代谢的作用而不是兴奋交感神经的作用。瘦素通过交感神经系统、一氧化氮等调节血管张力和血压 ,在肥胖相关性高血压的发病机制中起着重要作用。     

瘦素和肥胖相关性高血压

动物试验和临床研究等表明瘦素与高血压存在一定的联系。肥胖者往往存在瘦素抵抗，此种抵抗发生于调节代谢的作用而不是兴奋交感神经的作用。瘦素通过交感神经系统、一氧化氮等调节血管张力和血压，在肥胖相关性高血压的发病机制中起着重要作用。     

蛋白酪氨酸磷酸酶1B的普遍激活:胰岛素抵抗和瘦素抵抗可能的共同发病机制

近年研究发现蛋白酪氨酸磷酸酶1B(PTP1B)是胰岛素信号转导和瘦素信号转导的负性调控因子;肥胖相关胰岛素抵抗及瘦素抵抗中均存在PTP1B的过度表达。PTP1B活化可能是胰岛素抵抗和瘦素抵抗的共同机制。因此,抑制PTP1B为治疗2型糖尿病和肥胖开辟了新的途径。     

瘦素抵抗的机制及其临床意义

瘦素的发现揭示了控制食欲和能量代谢平衡的神经内分泌机制,标志着肥胖研究的巨大突破.瘦素通过降低热量摄入以及增加能量消耗,调节自主神经系统、内分泌系统以及免疫系统,从而将能量平衡的神经内分泌调节作用与体内脂肪水平联系在一起.由瘦素引发的细胞内信号转导机制非常复杂,涉及到很多与瘦素各种功能活性相关的信号通路.肥胖和代谢综合征患者普遍存在高瘦素血症,瘦素抵抗及其机制近年来成为研究热点,而对于瘦素抵抗的药物治疗也将成为相关疾病的治疗新靶点.     

肥胖高血压患者血清瘦素与血压的临床分析

流行病学研究表明，肥胖合并高血压者占30％～50％；肥胖者较体重正常者患高血压的危险高6倍。肥胖引起高血压的确切机制尚不清楚，可能与胰岛素抵抗、盐敏感、交感神经激活及一些细胞因子有关。1994年人们成功克隆了肥胖基因，随后发现了其蛋白产物瘦素，瘦素和瘦素抵抗成为最近研究的热点。2002～2003年，我们检测了肥胖高血压患者的血清瘦素水平，探讨肥胖高血压患者瘦素水平与血压、糖脂代谢及体脂的关系。     

肥胖相关高血压的发病机制

肥胖与高血压密切相关,是高血压的独立危险因素之一。肥胖相关高血压的发病有多种可能机制,包括瘦素通路改变、胰岛素抵抗、微血管功能紊乱、肾素-血管紧张素-醛固酮系统和交感神经系统激活、中枢神经系统功能失调、肾脏损伤等。对肥胖相关高血压发病机制的研究有助于制定合理的治疗措施,以控制此类患者的血压水平,降低心脑血管事件发生率。     

选择性瘦素抵抗与肥胖相关性高血压病

肥胖是原发性高血压病的一个重要发病因素,在大多数西方国家,高血压病患者中约65％-75％为肥胖者⑴。1994年瘦素(leptin)的发现使人们对肥胖的研究真正进入分子时代⑵。研究表明:瘦素通过多种途径调节能量代谢及血压,由于选择性瘦素抵抗,导致肥胖及肥胖相关性高血压病的发生。     

瘦素生理作用研究现状

瘦素受体广泛分布于中枢和外周组织 ,瘦素与其受体结合后 ,发挥一系列生理作用。除影响体脂和能量代谢过程外 ,尚可促进生殖系统成熟 ,始动青春发育 ;影响骨骼发育和重建 ;调节血管张力和血小板的粘附性 ,与肥胖相关性高血压和血栓形成的关系密切。在机体应激和免疫防御系统中 ,瘦素也显示了一定的作用。     

瘦素致高血压左心室重构机制的研究新进展

长期高血压可导致不可逆性左心室重构，严重影响心脏功能，可引起心力衰竭。如何减缓甚至逆转高血压引起的左心室重构，受到国内外研究者的关注。瘦素是一种具有多种生物学功能的肽类激素，其生理作用复杂。研究表明，瘦素通过直接作用于瘦素受体,激活交感神经及肾素-血管紧张素-醛固酮系统，引起瘦素抵抗及胰岛素抵抗等作用。目前,在瘦素致高血压左心室重构机制方面取得了很大的进展，这为其干预治疗提供了新的思路。     

原发性高血压血清瘦素水平变化

将76例原发性高血压患者按有无糖代谢异常及肥胖分为单纯高血压组、高血压 糖代谢异常组及高血压 肥胖组;健康体检者68例按体质量指数(BMI)分为正常对照组、单纯肥胖组.检测各组血清瘦素、空腹胰岛素(FINS)、空腹血糖(FBG)及餐后血糖(PBG)、总胆固醇、甘油三酯水平.发现高血压各亚组血清瘦素水平均高于正常对照组;直线相关分析显示,瘦素分别与BMI、SBP、DBP、FINS呈正相关;多元逐步回归分析示,瘦素与性别、FBG、FINS、SBP、BMI、WHR相关.认为原发性高血压患者血清瘦素水平明显高于正常人群,血清瘦素水平增高与高血压、胰岛素抵抗关系密切.     

Obesity-associated hypertension: new insights into mechanisms

Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.     

Emerging concepts in the pathophysiology and treatment of obesity-associated hypertension

The dramatic increase in the prevalence of obesity is a global phenomenon associated with increased risk of the development of cardiovascular and renal disease. Changes in renal structure and function that occur early in the development of obesity may lead to urine outflow obstruction and increased intrarenal pressure, mechanisms sufficient to shift the pressure-natriuresis relation to higher blood pressure levels. Another important alteration that may lead to hypertension with obesity is the increase in sympathetic nervous system activity. Several studies point to higher leptin levels associated with hypertension in humans, and animal data now convincingly suggest that leptin has direct central effects that increase sympathetic outflow to the kidneys, associated with increases in blood pressure. Although understanding of the pathophysiology of obesity-associated hypertension has made substantial progress during the past years, treatment of obese hypertensives remains largely empirical and clearly deserves to be addressed in larger randomized, controlled trials.     

Hypothalamic endoplasmic reticulum stress as a key mediator of obesity‐induced leptin resistance

Obesity is an epidemic disease that is increasing worldwide and is a major risk factor for many metabolic diseases. However, effective agents for the prevention or treatment of obesity remain limited. Therefore, it is urgent to clarify the pathophysiological mechanisms underlying the development and progression of obesity and exploit potential agents to cure and prevent this disease. According to a recent study series, obesity is associated with the development of endoplasmic reticulum stress and the activation of its stress responses (unfolded protein response) in metabolically active tissues, which contribute to the development of obesity‐related insulin and leptin resistance, inflammation and energy imbalance. Hypothalamic endoplasmic reticulum stress is the central mechanism underlying the development of obesity‐associated leptin resistance and disruption of energy homeostasis; thus, targeting endoplasmic reticulum stress offers a promising therapeutic strategy for improving leptin sensitivity, increasing energy expenditure and ultimately combating obesity. In this review, we highlight the relationship between and mechanism underlying hypothalamic endoplasmic reticulum stress and obesity‐associated leptin resistance and energy imbalance and provide new insight regarding strategies for the treatment of obesity.     

Animal Models in Obesity and Hypertension

Although obesity is a well-known risk factor for hypertension, the mechanisms by which hypertension develops in obese patients are not entirely clear. Animal models of obesity and their different susceptibilities to develop hypertension have revealed some of the mechanisms linking obesity and hypertension. Adipose tissue is an endocrine organ secreting hormones that impact blood pressure, such as elements of the renin-angiotensin system whose role in hypertension have been established. In addition, the appetite-suppressing adipokine leptin activates the sympathetic nervous system via the melanocortin system, and this activation, especially in the kidney, increases blood pressure. Leptin secretion from adipocytes is increased in most models of obesity due to leptin resistance, although the resistance is often selective to the anorexigenic effect, while the susceptibility to the hypertensive effect remains intact. Understanding the pathways by which obesity contributes to increased blood pressure will hopefully pave the way to and better define the appropriate treatment for obesity-induced hypertension.     

Obesity-related hypertension: Is there a role for selective leptin resistance?

Obesity is a risk factor for cardiovascular diseases, in particular for hypertension. Serum leptin levels and sympathetic nerve activity are both increased in obesity. Leptin has been demonstrated to increase sympathetic nerve activity. Thus, leptin-dependent sympathoactivation might contribute to obesity-related hypertension. However, leptin resistance occurs in obesity. One possibility is that leptin resistance is selective to the metabolic effects of leptin, sparing its sympathoexcitatory actions. In this article, we review experimental evidence supporting the novel concept of selective leptin resistance. We also discuss the sympathetic actions of leptin that are relevant to blood pressure modulation and potential mechanisms of leptin resistance. Disruption of leptin intracellular signaling pathways and resistance of specific leptin-responsive neural networks provide theoretic models of selective leptin resistance. However, most information about leptin-sympathetic actions and leptin-resistance mechanisms derive from in vitro and animal studies. Future research in humans is widely awaited.     

Obesity and cardiovascular disease. Pathogenetic role of the metabolic syndrome and therapeutic implications

Since obesity is a major risk factor for cardiovascular disease (CVD), the increasing prevalence and degree of obesity in all developed countries has the potential to significantly offset the current efforts to decrease CVD burden in our population. Obesity is pathogenetically related to several clinical and sub-clinical abnormalities that contribute to the development of atherosclerotic placks and their complication, leading to the onset of cardiovascular events. Obesity seems to interact with inheritable factors in determining the onset of insulin resistance, a metabolic abnormality that is responsible for altered glucose metabolism and predisposition to type 2 diabetes, but that also has a major role in the development of dyslipidemia, hypertension and many other sub-clinical abnormalities that contribute to the atherosclerotic process and onset of cardiovascular events. Inheritable factors seem to modulate the onset of type 2 diabetes, dyslipidemia, hypertension and various insulin resistance-related sub-clinical abnormalities, often in a clustering pattern that is commonly referred to as the "metabolic syndrome." Inheritable factors also are involved in the onset of CVD in a given population or individuals with various components of the metabolic syndrome. Intense research is currently undergoing to better understand the molecular mechanisms that could explain the relationship between environmental and inheritable factors that lead from obesity to atherosclerosis and cardiovascular event. The elucidation of these mechanisms will provide improved therapeutic strategies to reduce cardiovascular risk in the obese patients. However, effective therapeutic tools that control each of the known pathophysiological steps mediating CVD in obese patients are already available and should be used more aggressively. Patient education and coordinated approach of physicians, nurses and other health care providers in a multidisciplinary treatment of the obese patient is of fundamental importance to reduce CVD burden in our population.     

Exercise, insulin resistance, and hypertension: a complex relationship

More than 300,000 deaths occur annually in the United States alone as a result of obesity, poor dietary habits, or physical inactivity. Obesity is now an increasingly recognized independent risk factor for cardiovascular disease and leads to numerous other comorbidities. The causal relationships between obesity and both insulin resistance and hypertension have been consistently demonstrated in numerous studies. The relationships consist of cascading events involving insulin, leptin, adiponectin, and other hormones that often precipitate the development of metabolic syndrome. As we learn more about the metabolic activity of the adipose tissue, we can better identify the mechanisms that associate weight reduction with a decrease in health risks. Evidence suggests that exercise produces a positive effect on weight reduction, insulin sensitivity, and blood pressure. Therefore, weight reduction and therapeutic changes in lifestyle should be encouraged in all overweight and obese patients. It is imperative to increase the awareness of the obesity epidemic and to emphasize the importance of exercise as both treatment and prevention of metabolic disease.     

Cardiovascular and sympathetic effects of leptin

Several studies have shown the association between obesity and hypertension. The pathophysiologic mechanisms of obesity-related hypertension remain unknown. Clinical and experimental studies have shown that obesity is associated with enhanced sympathetic nervous activity. Thus, sympathetic nerve activation seems to play a major role in obesity-associated hypertension. However, the factors responsible for this sympathoactivation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and food intake and by increasing energy expenditure through sympathetic stimulation to brown adipose tissue. Leptin also produces sympathoactivation to kidneys, hindlimb, and adrenal glands, indicating that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, obesity is associated with leptin resistance, since high circulating levels of leptin were observed in obese subjects. Recent evidences indicate that this leptin resistance could be selective with preservation of sympathetic effects despite the loss of metabolic action of leptin. This suggests divergent central pathways underlying metabolic and sympathetic effects of leptin. Several neuropeptides have emerged as potent candidate mediators of leptin action in the central nervous system, including the melanocortin system, neuropeptide Y, and cortico-trophin releasing factor. A detailed understanding of the multitude and complexity of integrated neuronal circuits and neuropeptide-containing pathways in leptin action will help in understanding the pathogenesis of obesity and related disorders.     

Leptin as a Potential Treatment for Obesity

Despite significant reductions in the consumption of dietary fat, the prevalence of obesity is steadily rising in western civilization. Of particular concern is the recent epidemic of childhood obesity, which is expected to increase the incidence of obesity-related disorders. The obese gene (ob) protein product leptin is a hormone that is secreted from adipocytes and functions to suppress appetite and increase energy expenditure. Leptin is an attractive candidate for the treatment of obesity as it is an endogenous protein and has been demonstrated to have potent effects on bodyweight and adiposity in rodents. Whereas leptin has been successfully used in the treatment of leptin-deficient obese patients, trials in hyperleptinemic obese patients have yielded variable results. Long-acting leptins have been tried but with no greater success. Other strategies including the use of leptin analogs and other factors that bypass normal leptin delivery systems are being developed. Identifying the mechanisms at the molecular level by which leptin functions will create new avenues for pharmaceutical targeting to simulate the intracellular effects of leptin.