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Masuo K.,Nucleus Network Ltd. | Masuo K.,Baker IDI Heart and Diabetes Research Institute | Rakugi H.,Osaka University | Ogihara T.,Osaka University
Current Hypertension Reviews | Year: 2010

Obesity, hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension and diabetes mellitus. Human obesity, hypertension and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to obesity. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of β2-and β3-adrenoceptor genes with sympathetic nervous system activity, obesity, hypertension and metabolic syndrome have not been fully clarified. A few studies regarding the relationships between sympathetic nervous activity and adrenoceptor polymorphisms in the same studies have been reported. Masuo et al. have observed in a series of studies in a Japanese male cohort that: 1) β2-adrenoceptor polymorphisms are associated with heightened sympathetic nerve activity, and predict the future onset of obesity and hypertension in nonobese individuals, 2) β2-adrenoceptor polymorphisms accompanied by heightened sympathetic nerve activity and abdominal obesity, predict weight loss resistance during a weight loss program, and also predict rebound weight gain, 3) β2-adrenoceptor polymorphisms are linked to blunted leptin-mediated sympathetic nerve activation, leptin-resistance and resultant obesity, 4) β2-adrenoceptor polymorphisms are related to insulin-resistance, in both nonobese and obese normotensive individuals, and 5) β3-adrenoceptor polymorphism is directly linked to obesity and hypertension, but only in obese individuals. These suggest that β2-and β3-adrenoceptor polymorphisms accompanying heightened sympathetic nerve activity play a major role in the onset and the maintenance of obesity, hypertension and insulin resistance. This article provides the current topics involving the influence of the sympathetic nervous system and β2-and β3-adrenoceptor polymorphisms in obesity, hypertension and metabolic syndrome (type 2 diabetes). © 2010 Bentham Science Publishers Ltd. Source


Masuo K.,Nucleus Network Ltd. | Masuo K.,Baker IDI Heart and Diabetes Institute | Lambert G.W.,Baker IDI Heart and Diabetes Institute | Esler M.D.,Baker IDI Heart and Diabetes Institute | And 3 more authors.
Hypertension Research | Year: 2010

Sympathetic nervous system hyperactivity is observed in patients with renal injury, renovascular hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD). Elevated sympathetic activity is of prognostic relevance in that plasma norepinephrine concentrations predict survival and the incidence of cardiovascular events in patients with ESRD, as well as future renal injury in normotensive healthy subjects with renal function in the normal range. Renal injury, CKD and ESRD are often associated with obesity, and its common sequelae hypertension and diabetes. In fact, hypertension and diabetes mellitus are the main causes of ESRD in western societies and together account for approximately more than 50% of ESRD incidence in the United States and Japan. Obesity also leads to increases in the incidence of cardiovascular diseases. Several clinical and epidemiological studies have clearly documented that heightened sympathetic nervous activity has an important role in the onset and maintenance of obesity and hypertension. Elevated sympathetic nervous activity may actually represent an important mechanism contributing to the onset and maintenance of renal injury at least in part through its concomitant adverse effects on obesity and hypertension. Understanding the contribution of sympathetic nervous hyperactivity to the onset and maintenance of renal injury might aid in the prevention and treatment of renal injury, CKD and ESRD. Very recently, renal sympathetic denervation was shown to be a potentially novel therapeutic strategy in resistant hypertension. In addition, renin-angiotensin system inhibitors are recommended as the initial therapy because of their renal protective effect, especially in hypertensive patients with type 2 diabetes or with proteinuria. The purpose of this review is to provide an overview of our current knowledge on the relationships between sympathetic nerve activity and renal function to further our understanding of the precise roles of sympathetic nerve activity in renal injury, particularly in the context of obesity and hypertension. These insights may be useful to improve prevention and treatment of renal injury in these patients. © 2010 The Japanese Society of Hypertension All rights reserved. Source


Masuo K.,Baker IDI Heart and Diabetes Institute | Masuo K.,Nucleus Network Ltd.
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2010

Obesity is an escalating global health problem and established cardiovascular risk factor for the development of cardiovascular and metabolic diseases. Leptin derived from the adipose tissue acts centrally to suppress appetite and increase energy expenditure, therefore leptin resistance is considered as an important mechanism for the onset and maintenance of obesity; Leptin analogues as well as leptin receptor blockers have been candidates for the treatment of obesity, however clinical trials in obese populations have yielded variable results. Given specific circumstances in obese subjects could optimize the beneficial actions of the hormone and minimize its deleterious effects. In this review, human recombinant leptin (pegylated polyethylene glycol recombinant human leptin (PEG-OB) and recombinant methionyl human leptin (r-metHuLeptin) is developed to control resistant and morbid obesity will be discussed. © 2010 Bentham Science Publishers Ltd. Source


Masuo K.,Nucleus Network Ltd. | Masuo K.,Baker IDI Heart and Diabetes Research Institute
Current Hypertension Reviews | Year: 2013

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2- adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in "Journal of Obesity" [1], and another of my own reviews on the relationships with hypertension in 2010 in "International journal of Hypertension" [2], with 37 articles provided by the "PubMed" with the keywords of "adrenoceptor polymorphisms, obesity, hypertension and diabetes" searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be related to the ethnicity, gender, severeity of obesity, duration of hypertension or obesity, etc (refer the "Possible confounding variable affecting the relationships" section and Table 4). Therefore, this review may not be so much different from the previous ones, but, of importance, currently most investigations have shown that the β-adrenoceptor polymorphisms accompanying sympathetic nervous activity contribute to the onset and maintenance of hypertension, diabetes and obesity. © 2013 Bentham Science Publishers. Source


Masuo K.,Nucleus Network Ltd. | Masuo K.,Baker IDI Heart and Diabetes Institute
Current Hypertension Reviews | Year: 2011

Obesity, hypertension and obesity-related hypertension are growing health problems. Several epidemiological studies have shown a high prevalence of cardiovascular complications and all cause of mortality in obesity and hypertension. Obesity and hypertension are important and independent risk factors for cardiovascular disease development. An integrated cardiovascular risk management approach involving aggressive blood pressure (BP) control should be adopted in patients at high cardiovascular risk (i.e. those with ischemic heart disease, end-organ damage, type 2 diabetes) and the use of well-tolerated antihypertensive agents with protective benefits beyond BP lowering. The identification and management of risk factors is an important part of the overall management of hypertensive patients. Given that obese patients are more predisposed to target organ damage development, stringent targets for blood pressure control have been set in clinical guidelines, including those of the Joint National Committee (JNC-7) [1], the World Health Organisation and the International Society of Hypertension (WHO/ISH) [2], the European Society of Hypertension (ESH) [3] and the Japanese Society of Hypertension (JSH-2009) [4]. Pertinently, clinical trials and real-life evidence suggest that these targets are difficult to achieve. Hypertension in obesity is characterized by stimulation of the renin-angiotensin-aldosterone system (RAAS), elevated sympathetic activity, insulin resistance and selective leptin resistance. Importantly, these characteristics, even in isolation constitute risk factors for cardiovascular disease development and progression. It is therefore imperative that pharmacological treatments should be selected based on favourable effects on these factors. Furthermore, in choosing an antihypertensive agent, effectiveness needs to be accompanied by favourable metabolic, cardioprotective, and renal protective properties. Recent pharmacogenetic studies have shown that several polymorphisms may contribute to antihypertensive effectiveness. Weight loss is recommended as the first line of treatment for hypertension associated with obesity. Indeed, lifestyle modification including a low caloric diet, reducing sedentary behaviour and exercise form the foundation of all therapy. For the subjects who are more severe obesity or inability to undertake an exercise program, bariatric surgery are recommended. Anti-obesity drugs have been developed but unfortunately some were associated with significant side effects and were recently withdrawn from the markets in the United States, Europe and Australia. Leptin administration has a theoretical basis in obesity therapy and, while it has been examined in overweight and obese human subjects and in animal models, the anti-obesity effects of leptin administration are controversial. The combination of high blood pressure with obesity, for a variety of reasons, renders the hypertension difficult to control, with patients frequently requiring two or more types of medications to achieve blood pressure goals. Many large cohort studies have compared the efficacies of antihypertensive drug classes in hypertensive patients with the metabolic syndrome, however, there are few systemic reviews of antihypertensive drug treatments for patients with obesity. Moreover the mechanisms underlying both obesity and hypertension remain to be elucidated therby making it difficult to achieve blood pressure goals. In this review I aim to provide a synthesis of the current data examining both pharmacological and nonpharmacological antihypertensive treatments in those patients with obesity-related hypertension. © 2011 Bentham Science Publishers. Source

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