No abstract

Recent studies indicate a link between carbohydrate intake and the functional state of the sympathetic nervous system. Fasting or carbohydrate restriction decreases sympathetic activity, while glucose ingestion or dietary supplementation with sucrose increases sympathetic nerve activity. To examine the potential contributions of hyperglycemia and hyperinsulinemia to sympathetic stimulation, sympathetic activity was assessed by measurement of plasma norepinephrine (NE) levels and concomitant cardiovascular indices in nonobese young men during glucose and insulin infusions using glucose clamp techniques. In the insulin infusion studies (euglycemic glucose clamp), insulin was administered at 2 mU/kg/min and 5 mU/kg/min for 2 h while blood glucose was maintained at basal levels by a variable rate of glucose infusion. In the hyperglycemic studies, blood glucose was raised 125 mg/dl above basal and maintained at that level for 2h. In response to both insulin infusions, plasma NE rose progressively over the course of the study, increasing 50% with the 2-mU infusion (from mean basal value of 240 ± 34 pg/ml to 360 ± 41 at 150 min, P < 0.001 for changes over time by analysis of variance) and 117% with the 5-mil infusion (from 254 ± 20 pg/ml to 551 ± 88 at 150 min, P < 0.001). The plasma NE response was greater with the 5-mll than with the 2-mU insulin infusion (P < 0.001), and similarly, was greater during the 2-mU insulin infusion than during a control test in which neither insulin nor glucose was infused (P < 0.001). Associated with the elevations in plasma NE In the 2-mU insulin infusion were increases in pulse rate (P < 0.05), pulse pressure (P < 0.005), and pulse rate - systolic blood pressure product (P < 0.01), and during the 5-mU insulin infusions there were increases in pulse pressure (P < 0.001), mean arterial blood pressure (P < 0.001), and pulse rate - systolic blood pressure product (P < 0.001). Plasma NE did not change during the hyperglycemic glucose clamp nor during control tests, and pulse pressure in the hyperglycemic studies (P < 0.005) was the only cardiovascular measurement increased by these two infusion protocols. The clearance of NE in three subjects was unaffected by the 2-mU insulin infusion. Thus, insulin infusion increases sympathetic nervous system activity in the absence of changes in blood glucose.

In light of the worldwide epidemic of obesity, and in recognition of hypertension as a major factor in the cardiovascular morbidity and mortality associated with obesity, The Obesity Society and The American Society of Hypertension agreed to jointly sponsor a position paper on obesity-related hypertension to be published jointly in the journals of each society. The purpose is to inform the members of both societies, as well as practicing clinicians, with a timely review of the association between obesity and high blood pressure, the risk that this association entails, and the options for rational, evidenced-based treatment. The position paper is divided into six sections plus a summary as follows: pathophysiology, epidemiology and cardiovascular risk, the metabolic syndrome, lifestyle management in prevention and treatment, pharmacologic treatment of hypertension in the obese, and the medical and surgical treatment of obesity in obese hypertensive patients. The United States is currently facing a very real obesity epidemic. The most recent National Health and Nutrition Examination Survey indicates that approximately two thirds of US adults are presently classified as overweight or obese (body mass index [BMI] !25) and one third as obese (BMI !30) (1,2). While the numbers alone are formidable, they leave unaddressed the medical costs associated with obesity and obesity-related comorbidities, not the least of which is obesity-related hypertension. Given the frequent concurrence of obesity and hypertension, it is no coincidence that as the rate of obesity continues to rise, so too does the rate of hypertension. It is estimated that at least 75% of the incidence of hypertension is related directly to obesity (1). It is essential, therefore, to develop treatment strategies for the management of obesity in order to reduce the development of obesity-related hypertension as well as to effectively manage high blood pressure (BP) in the obese.Recent publications have estimated that the annual medical burden of obesity and obesity-related diseases in the United States totaled roughly $147 billion in 2008 (1) and that projected obesity-related medical expenses will more than double by 2018, topping $344 billion, or about 21% of total healthcare spending (1). Although lifestyle changes aimed at prevention, especially in childhood, are the ultimate solution to the societal problem of obesity and its complications, the scope of illness caused by obesity demands immediate attention and therapeutic intervention in the obese population. Given the important role that obesity plays in the pathogenesis of hypertension, the leadership of both The Obesity Society and The American Society of Hypertension have commissioned this position paper for the purpose of providing the membership of both societies, as well as the community of clinicians in practice, with a current and timely summary on the relationship between weight and BP, on the cardiovascular (CV) risk imposed and on the management of obesity-related hypertension.

Thus, the evidence summarized here supports an important role for insulin and the sympathetic nervous system in the pathogenesis of obesity-related hypertension. Is it possible that insulin-mediated sympathetic stimulation contributes a pro-hypertensive effect in non-obese as well? It seems possible in young borderline hypertensives where sympathetically mediated thermogenic mechanisms are potent enough to compensate for the increased caloric intake, thereby enabling these young hypertensives to avoid obesity. This is consistent with an observation made in the original Framingham cohort that not only did obesity predict the eventual development of hypertension, but hypertension, as well, predicted the eventual development of obesity. A reasonable interpretation of these data suggests that as subjects age and the effectiveness of thermogenic mechanisms wanes, obesity might develop as a consequence of increased caloric intake no longer effectively buffered by the increased SNS activity. It is important to note that the mechanisms described here exert a pro-hypertensive effect and cannot properly be considered to 'cause' hypertension. Hypertension is rarely the consequence of a single mechanism. It is also true, as pointed out convincingly by Julius and his colleagues, that enhanced sympathetic activity, as a primary factor, can be associated with both hypertension, insulin resistance and, possibly, obesity [39]. And, finally, it should be noted that the mechanism described here is not the only mechanism linking obesity and hypertension. A rapidly emerging body of evidence indicates that leptin, the polypeptide product of the ob/ob gene secreted from adipose tissue, exerts potent central neural effects on both appetite and sympathetic activity. Leptin levels, elevated in obese humans, have the potential to increase both sympathetic activity and blood pressure [40-43]. A more comprehensive summary of the relationships between hypertension and obesity may, therefore, involve insulin and leptin, as well as the SNS, as represented in the schema presented in Figure 7. Both leptin and insulin may, therefore, be considered as compensatory mechanisms recruited to restore energy balance, with the SNS as one of the effector arms. Viewed in this way, obesity-related hypertension is inextricably linked to the metabolic economy of the obese.

A B S T R A C T Brown adipose tissue (BAT)is an important site of adaptive changes in thermogenesis in the rat. The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue. The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat. Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT. Acute exposure to 4°C increased NE turnover in IBAT 4-to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus. In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure. Alterations in feeding were also associated with changes in NE turnover in IBAT. Fasting for 2 d decreased NE turnover in IBAT (-35% from 29.2±4.2 ng NE/h to 18.9±5.9) and in heart (-52%). In animals fed a "cafeteria" diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 24.8±4.5 ng NE/h to 51.7±6.8) and heart (+66%). Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteriafed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow. Thus NE turnover techniques can be satisfactorily applied to the