Insulin Resistance,Energy Balance and Sympathetic Nervous System Activity

Insulin resistance and hyperinsulinemia are commonly associated with hypertension in the obese. The nature of this association is obscure. An hypothesis is developed that attributes obesity-related hypertension to sympathetic stimulation. The relationship between insulin and the sympathetic nervous system (SNS) has its origins in the mediation of dietary thermogenesis. Fasting suppresses while carbohydrate and fat feeding stimulate sympathetic activity. Insulin-mediated glucose metabolism within critical central neurons links dietary intake and central sympathetic outflow. The sympathetic nervous system, in turn, contributes to changes in metabolic rate that accompany alterations in dietary intake. It is hypothesized that insulin resistance is a mechanism recruited in the obese to limit further weight gain and stabilize body mass. Insulin-mediated sympathetic stimulation is one mechanism that may restore energy balance in the obese since the obese are not resistant to the stimulatory effect of insulin on the SNS. Sympathetically mediated stimulation of the heart, vasculature and kidney contributes, in genetically predisposed individuals, to the development of hypertension. Viewed in this light, obesity-related hypertension is the unfortunate by-product of an adaptive mechanism (insulin resistance) recruited to restore energy balance in the obese. Possible implications of this formulation are discussed.     

Diet-induced changes in sympathetic nervous system activity: Possible implications for obesity and hypertension

The sympathetic nervous system responds to changes in caloric intake; caloric restriction decreases and carbohydrate administration increases sympathetic nervous system activity in animals and man. Insulin may be a major link between changes in dietary intake and changes in central sympathetic outflow. Caloric restriction reduces, and carbohydrate administration increases blood pressure in spontaneously hypertensive rats, changes consistent with a primary effect of caloric intake on sympathetic nervous system activity. Stimulation of the sympathetic nervous system by overfeeding may contribute to the development and maintenance of hypertension in biologically-predisposed animals and man. The association of obesity and hypertension may reflect chronic overfeeding, although diet-induced changes in sympathetic nervous system activity may affect blood pressure in non-obese individuals as well.     

Role of Hyperinsulinemia and Insulin Resistance in Hypertension: Metabolic Syndrome Revisited

Hyperinsulinemia and insulin resistance were proposed more than 30 years ago to be important contributors to elevated blood pressure (BP) associated with obesity and the metabolic syndrome, also called syndrome X. Support for this concept initially came from clinical and population studies showing correlations among hyperinsulinemia, insulin resistance, and elevated BP in individuals with metabolic syndrome. Short-term studies in experimental animals and in humans provided additional evidence that hyperinsulinemia may evoke increases in sympathetic nervous system (SNS) activity and renal sodium retention that, if sustained, could increase BP. Although insulin infusions may increase SNS activity and modestly raise BP in rodents, chronic insulin administration does not significantly increase BP in lean or obese insulin-resistant rabbits, dogs, horses, or humans. Multiple studies in humans and experimental animals have also shown that severe insulin resistance and hyperinsulinemia may occur in the absence of elevated BP. These observations question whether insulin resistance and hyperinsulinemia are major factors linking obesity/metabolic syndrome with hypertension. Other mechanisms, such as physical compression of the kidneys, activation of the renin-angiotensin-aldosterone system, hyperleptinemia, stimulation of the brain melanocortin system, and SNS activation, appear to play a more critical role in initiating hypertension in obese subjects with metabolic syndrome. However, the metabolic effects of insulin resistance, including hyperglycemia and dyslipidemia, appear to interact synergistically with increased BP to cause vascular and kidney injury that can exacerbate the hypertension and associated injury to the kidneys and cardiovascular system.     

Caloric restriction lowers blood pressure in the spontaneously hypertensive rat

In the spontaneously hypertensive rat (SHR), caloric restriction without sodium restriction is associated with reduced blood pressure. Four days of fasting lowered blood pressure 19% while 4 days of eating 50% of ad lib intake reduced blood pressure 10%. Similar dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto—WKY). These data are consistent with the hypothesis that caloric restriction lowers sympathetic activity.     

Obesity, hypertension, and sympathetic nervous system activity

Several epidemiologic studies have shown that obesity represents an independent risk factor for the development of cardiovascular diseases, including hypertension, myocardial ischemic disease, and cardiac arrhythmias. One of the most appealing concepts in obesity-related hypertension is that a specific etiology can be identified. There is now substantial evidence that human obesity is characterized by abnormalities in sympathetic cardiovascular control. The application of sensitive techniques to assess sympathetic nervous system (SNS) activity in humans, including catecholamine levels, norepinephrine (NE) spillover techniques, and microneurography have furthered this concept. Catecholamine levels in obesity have been conflicting, with high, normal, and low levels reported. However, studies examining weight loss have found that the fall in blood pressure (BP) was highly correlated with reductions in plasma NE. Examination of NE spillover in obesity has shown regional overactivity in the kidneys. High renal SNS activity could lead to sodium retention and abnormal glomerular hemodynamics that could raise BP. Microneurography, which determines muscle sympathetic outflow, has shown consistent elevation in obesity, but no difference between normotensive and hypertensive obesity. However, the hyperinsulinemia of obesity may act in concert with the SNS to elevate BP, as the combination of the two seems to produce vascular constriction. Leptin also has several cardiovascular actions that may contribute to BP regulation. Epidemiologic studies also found that SNS activity predicts hypertension in obese subjects.     

Responses of serum insulin and blood pressure to cold and handgrip in obese patients.

A close correlation between body weight and blood pressure has been frequently observed in both clinical and epidemiological studies. The aim of this clinical trial was to evaluate whether, in obese patients, there is any relationship between blood pressure, at rest or during sympathetic stimulation, and blood glucose and serum insulin, both while fasting and during an oral glucose challenge. Twenty obese patients (age 26-65 years, body weight 97 +/- 16 kg, 11 normotensive and 9 hypertensive) entered the study. After a 4-week run-in period on an isocaloric diet with normal intake of sodium, blood pressure and heart rate were measured at rest and during sympathetic stimulation induced by cold and isometric testing. Responses of glucose and insulin to a standardized 75 g oral glucose tolerance test were also evaluated. The responses of glucose and insulin to glucose challenge were not statistically different in normotensive and hypertensive obese patients. Levels of insulin in the serum in the serum in the fasting state and during glucose load were significantly correlated with the response of blood pressure to cold and isometric exercise, but not to blood pressure at rest. The response of heart rate to cold was closely related to insulin only in the subgroup of normotensives. The present findings support the hypothesis that the sympathetic nervous system, which influences secretion of insulin and regulation of blood pressure, is involved in the pathophysiology of the association of obesity and hypertension.     

Relation of obesity and diet to sympathetic nervous system activity

The hypothesis that dietary intake and obesity stimulate the sympathetic nervous system was investigated in a cross-sectional study of 572 men aged 43-85 years from the Normative Aging Study. Habitus was represented by body mass index, as a measure of overall adiposity, and by the ratio of abdomen-to-hip circumference (abdomen/hip ratio), as a measure of centripetal fat distribution. Sympathetic activity was assessed by measurement of 24-hour urinary norepinephrine excretion. Increased body mass index and total caloric intake were independently associated with increased 24-hour urinary norepinephrine excretion (p = 0.0001 and p = 0.0055, respectively). In addition, mean urinary norepinephrine excretion was higher in subjects classified as either hyperglycemic (serum fasting glucose greater than or equal to 113 mg/dl) and hyperinsulinemic (serum fasting insulin greater than or equal to 19 microIU/ml) (p = 0.0023) or in subjects classified as either hyperglycemic or hyperinsulinemic (p = 0.0063) than the mean urinary norepinephrine excretion in normal subjects. These relations were demonstrated to be independent of age, smoking status, and physical activity. Our results are consistent with the hypothesis that insulin mediates sympathetic stimulation in response to dietary intake and increases sympathetic nervous system activity in the obese.     

Ethnic differences in insulinemia and sympathetic tone as links between obesity and blood pressure

Hyperinsulinemia and increased sympathetic nervous system (SNS) activity are thought to be pathophysiological links between obesity and hypertension. In the present study, we examined the relation among heart rate (HR), blood pressure (BP), and percent body fat (hydrodensitometry or DEXA), fasting plasma insulin concentration, and muscle sympathetic nerve activity (MSNA, microneurography) in male, normotensive whites (n=42) and Pima Indians (n=77). Pima Indians have a high prevalence of obesity and hyperinsulinemia but a relatively low prevalence of hypertension. Compared with whites, Pima Indian men had a higher percent body fat (28% versus 21%) and higher fasting insulin concentrations (210 versus 132 pmol/L) but lower MSNA (27 versus 33 bursts/min) (all P<0.001). In both ethnic groups, HR and BP were positively related to percent body fat and MSNA, and both were significant independent determinants of HR and BP in multiple regression analyses. However, MSNA was positively related to percent body fat and the fasting insulin concentration in whites (r=0.60 and r=0.47, both P<0.01) but not in Pima Indians (r=0.15 and r=0.03, NS) (P<0.01 for ethnic differences in the slope of the regression lines). These results confirm the physiological importance of the SNS in normal BP regulation but indicate that the roles of hyperinsulinemia and increased SNS activity as mediators for the relation between obesity and hypertension can differ between different ethnic groups. The lack of an increase in SNS activity with increasing adiposity and insulinemia in Pima Indians may contribute to the low prevalence of hypertension in this population.     

Insulin Sensitivity in the Pathogenesis of Hypertension and Hypertensive Complications

Epidemiologic and clinical studies suggest an association between hyperinsulinemia (and insulin resistance) and hypertension. This relationship is not present in secondary forms of hypertension and may persist despite adequate antihypertensive therapy. Normotensive offspring of hypertensive parents are also, as a group, insulin resistant and hyperinsulinemic. The association of hyperinsulinemia (and insulin resistance) with hypertension is more marked in the obese but present in lean hypertensives as well. Physiological mechanisms by which insulin might increase blood pressure include sympathetic nervous system stimulation and enhancement of renal sodium reabsorption. Evidence exists linking both of these mechanisms to hypertension. Insulin is also independently associated with myocardial infarction and microalbuminuria, two long term complications of high blood pressure. Experimentally induced decreases in insulin resistance and hyperinsulinemia, furthermore, have been associated with decreased blood pressure. In summary, the     

Secondary hypertension: obesity and the metabolic syndrome

The epidemic of obesity in the United States and around the world is intensifying in severity and scope and has been implicated as an underlying mechanism in systemic hypertension. Obese hypertensive individuals characteristically exhibit volume congestion, relative elevation in heart rate, and high cardiac output with concomitant activation of the renin-angiotensin-aldosterone system. When the metabolic syndrome is present, insulin resistance and hyperinsulinemia may contribute to hypertension through diverse mechanisms. Blood pressure can be lowered when weight control measures are successful, using, for example, caloric restriction, aerobic exercise, weight loss drugs, or bariatric surgery. A major clinical challenge resides in converting short-term weight reduction into a sustained benefit. Pharmacotherapy for the obese hypertensive patient may require multiple agents, with an optimal regimen consisting of inhibitors of the renin-angiotensin-aldosterone system, thiazide diuretics, beta-blockers, and calcium channel blockers if needed to attain contemporary blood pressure treatment goals.     

Hyperinsulinism, heart rate variability and circadian variation of arterial pressure in obese hypertensive patients]

AIMS: During insulin resistance, sympathetic nerve activity is increased. However insulin resistance is a common feature of obesity and essential hypertension, it is unclear if chronic hyperinsulinemia per se contributes to sympathetic overactivation. The purpose of our study was to explore++ the relationships between chronic hyperinsulinemia and heart rate variability (HRV), a non-intensive tool to assess autonomic function, in obese and hypertensive subjects. METHODS: 24 hours Holter ECG for HRV time and frequency domain analysis was performed in 77 patients, mean age 53 +/- 10 years, 52 men and 25 women, free of diabetes, without beta-blockers, divided in four groups according to three parameters, body mass index (BMI > 27 kg/m2 in man and > 25 kg/m2 in woman defined obesity), arterial pressure and insulinemia (fasting insulinemia > 25 mUI/L defined hyperinsulinemia): 27 patients obese, hypertensive, with hyperinsulinemia; 28 patients obese, hypertensive, without hyperinsulinemia; 12 patients non obese, hypertensive, without hyperinsulinemia; 10 patients obese, normotensive, without hyperinsulinemia. RESULTS: In comparison with the three other groups, patients with hyperinsulinemia showed a significant decrease (p < 0.05) of SDNN and the power of total spectrum (0.01-1 Hz) band, which are indexes of global HRV, and a significant decrease (p < 0.005) of SD and the normalized power of the low frequency (0.04-0.15 Hz) band, both indexes reflecting sympathetic modulation of HRV. In contrast, no significant difference was observed between the four groups for indexes of HRV reflecting parasympathetic tone. These relations were independent of mean RR. Fasting insulinemia was significantly (p < 0.0001) related with HRV in time domain (SDNN; r = -0.43; SD: r = -0.49) and spectral domain (total spectrum: r = -0.49; low frequency: r = -0.52). CONCLUSION: Chronic hyperinsulinemia appears to be an important determinant of HRV, particularly for the indexes reflecting sympathetic influence, independent of obesity and hypertension.     

Obesity and hypertension

Substantial evidence from epidemiological data supports a link between obesity and hypertension. However, the relationship between the two disorders is not straightforward and most likely represents an interaction of demographic, genetic, hormonal, renal, and hemodynamic factors. Age, race, and sex also modulate the strength of the association between obesity and hypertension. Hyperinsulinemia, which is characteristic of obesity, can contribute to the probability of developing hypertension by activating the sympathetic nervous system (SNS) and by causing sodium retention. The pressor effect of insulin in obesity may be further enhanced by the observation that its vasodilator action can be blunted in obese subjects. Preliminary data have shown that leptin, whose levels are increased in most obese individuals, can contribute to hypertension in obesity through its effects on insulin, SNS, and sodium excretion. The kidney may also have a role in the pathophysiology of hypertension in obesity. Abnormal renal sodium handling coupled with structural changes in the kidney of an obese patient can raise blood pressure. In addition, obesity is associated with distinct cardiovascular hemodynamic alterations and development of eccentric myocardial hypertrophy. Most of these obesity-associated abnormalities, as well as hypertension itself, can be reversed by weight loss. Furthermore, weight loss can prevent, or at least delay, the development of hypertension in patients with high-normal blood pressure. Weight reduction should be the first-line treatment in every obese hypertensive patient. However, the majority of patients will need pharmacologic intervention in conjunction with weight loss. Selection of antihypertensive agents in the overweight patient should take into account the mechanisms leading to hypertension and the metabolic abnormalities that characterize the obese patient.     

Neural mechanisms in human obesity-related hypertension.

OBJECTIVE: Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder. DESIGN AND METHODS: Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure. RESULTS: In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese individuals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese individuals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese individuals. CONCLUSIONS: The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys; the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese individuals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese individuals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese individuals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.     

Relationship between vasosympathetic activity and insulin resistance in normotensive and mildly hypertensive obese patients

Several studies have well demonstrated that obesity is associated with changes in cardiovascular vagosympathetic activity. The aim of the present work was to evaluate this activity in normotensive and in mildly hypertensive obese patients, and to correlate this activity with clinical and biological indexes of insulin resistance. Heart rate (HR) and systolic blood pressure (sBP) were examined by spectral analysis in 70 normotensive obese patients (group 1), 32 mildly hypertensive obese patients (group 2), and 21 controls. The high frequency peak of HR variations at a controlled breathing rate (vagal activity) was significantly reduced in both groups (p < 0.001). The mid frequency peak of sBP in the standing position (sympathetic activity) was similar in both groups and in the control group. In groups 1 and 2, the high frequency peak correlated negatively with age (p = 0.005 and 0.034 respectively). In group 1, the mid frequency peak correlated positively with fat mass, fasting plasma insulin and triglyceride levels, and insulin resistance index (p < or = 0.03). In group 2, the mid frequency peak correlated positively with fasting insulin and insulin resistance index (p = 0.006 and 0.007 respectively). This study shows that, in obese patients: 1. cardiac vagal activity is reduced in normotensive and mildly hypertensive subjects; 2. vascular sympathetic activity is unchanged in means but may be increased as a consequence of adiposity, hyperinsulinemia and insulin resistance, and this increase is likely to be involved in the increase of blood pressure.     

Relationships of Chronic Hyperinsulinemia,Heart Rate Variability,and Circadian Variation of Blood Pressure in Obese Hypertensive Subjects

Background: During insulin resistance, sympathetic nerve activity is increased. However insulin resistance is a common feature of obesity and essential hypertension, it is unclear if chronic hyperinsulinemia per se contributes to sympathetic overactivation. The purpose of our study was to explore the relationship between hyperinsulinemia and heart rate variability (HRV), a noninvasive tool to assess autonomic function, in obese and hypertensive subjects. Methods: 24-hour Holter ECG for HRV time and frequency domain analysis was performed in 77 patients: mean age 53 ± 10 years; 52 men and 25 women; free of diabetes; without beta-blockers. The patient were divided into four groups according to three parameters, body mass index (BMI > 27 kg/m² in the men and > 25 kg/m² in the women defined obesity), arterial pressure, and insulinemia (fasting insulinemia > 25 mUI/L defined hyperinsulinemia). Twenty-seven patients were obese, hypertensive, with hyperinsulinemia; 28 patients obese, hypertensive, without hyperinsulinemia; 12 patients nonobese, hypertensive, without hyperinsulinemia; 10 patients obese, normotensive, without hyperinsulinemia. Results: In comparison with the three other groups, patients with hyperinsulinemia showed a significant decrease (P < 0.05) of SDNN and the power of total spectrum (0.01–1 Hz) band, which are indexes of global HRV, and a significant decrease (P < 0.005) of SD and the normalized power of the low frequency (0.04–0.15 Hz) band, both indexes reflecting sympathetic modulation of HRV. In contrast, no significant difference was observed among the four groups for indexes of HRV reflecting parasympathetic tone. These relations were independent of mean R-R. Fasting insulinemia was significantly (P < 0.0001) related with HRV in time domain (SDNN: r =?0.43; SD: r =-0.49) and spectral domain (total spectrum: r =?0.49; low frequency: r =?0.52). Conclusion: Chronic hyperinsulinemia appears to be an important determinant of HRV, particularly for the indexes reflecting sympathetic influence, independent of obesity and hypertension. A.N.E. 1999;4(3):316–324     

Effect of obesity and weight reduction in hypertension

Obesity is known to be associated with diabetes, hypertension and hyperlipidemia in the majority of the patients. There could be inaccuracy in measuring the blood pressure in obesity, therefore a cuff of sufficient size is important in blood pressure measurement. All parameters of obesity have been found to have a correlation with hypertension and it has been suggested that change in weight would cause a change in blood pressure. A weight reduction of 12 kg results in a blood pressure fall of 21/13 mm Hg. Such changes in blood pressures have been noted in untreated hypertensives. A few studies have negated the role of change in weight to have any influence on hypertension. Obesity causes a higher cardiac output and higher blood volume leading to hypertension. There may be increased intracellular sodium and reduced sodium-potassium-ATPase activity in obesity which causes increased sodium loading in hypertension. Abnormalities related to the insulin-carbohydrate metabolism and the renin-angiotensin aldosteron system have also been demonstrated in obese patients. Weight reduction also causes reduced dietary salt intake and diminished sympathetic activity. The benefits of weight reduction appear to be directly related to the amount of weight lost.     

The effect of diet or exercise on plasma norepinephrine kinetics in moderately obese young men

An increase in sympathetic nervous system (SNS) activity in the obese has been described by some but not all investigators. It is possible that an increase in SNS tone may play a role in the predisposition to atherosclerotic cardiovascular disease noted in the obese. The effect of dietary weight loss or exercise training on resting SNS activity in moderately obese subjects has not been extensively studied and the results of previous studies are conflicting. Therefore, we prospectively evaluated resting SNS activity in healthy moderately obese subjects randomized to either a three month dietary weight loss (n = 13) or endurance exercise training (n = 18). All subjects were weight stabilized on a constant composition diet for 10 days prior to study both before and after the interventions. Although both groups lost weight, weight loss was greater in the diet group (-13.6 +/- 6.7 vs -2.3 +/- 3.4 kg, P less than 0.001). The composition of weight loss was also different with 32 percent of total weight loss as fat free mass (FFM) in the dieters compared to no significant change in FFM in the exercisers. The caloric requirement for weight stabilization declined after the diet but increased following exercise training (-247 vs + 202 kcal/day, P less than 0.001). No significant changes in blood pressure occurred in either group, and neither group had a significant change in resting plasma norepinephrine concentration. Plasma epinephrine concentrations were also unchanged. However, SNS activity as reflected by arterialized plasma NE kinetics revealed that NE appearance rate declined by 17 percent after dietary weight loss (P less than 0.01), but was not significantly changed after exercise training. These results suggest that dietary weight loss is more effective than exercise training in reducing overall resting SNS activity in normotensive subjects. Since exercise training is known to reduce the SNS response to a given submaximal workload, a combination of diet plus exercise might be the most effective way to reduce overall SNS activity and its possible role in the premature atherosclerosis associated with obesity.     

Resting metabolic rate and substrate use in obesity hypertension

There is substantial evidence that obesity is a prime risk factor for the development of hypertension. Although hyperinsulinemia and an increased activity of the sympathetic nervous system have been implicated in the pathogenesis of "obesity hypertension," their effects on energy metabolism have not been studied thus far. In the present study, we therefore examined resting metabolic rate (RMR) and basal substrate oxidation in subjects with obesity and obesity-related hypertension. A total of 166 subjects were characterized for RMR and basal substrate use through indirect calorimetry. Blood pressure was measured at rest and with 24-hour ambulatory monitoring. Blood samples were collected for the measurement of plasma catecholamines, leptin, and the insulin response to an oral glucose load. In our study population, 116 subjects were defined as hypertensive and 91 were defined as obese. Hypertensive patients under beta-adrenergic blockade (n=42) had a significantly lower RMR than did patients without beta-blockade (P<0. 05) and were therefore excluded from further analyses. Univariate regression analysis revealed a significant relationship between RMR and body fat mass, as well as body fat-free mass, in both groups. Compared with obese normotensive control subjects (n=27), obese hypertensives (n=43) had a 9% higher RMR (P<0.05), higher plasma catecholamine (P<0.05) and leptin (P<0.05) levels, and an increased insulin response to oral glucose (P<0.01). Together, these findings are compatible with the idea that chronic neurogenic and metabolic adaptations related to obesity may play a role in the development of obesity hypertension in susceptible individuals.     

Pathophysiogical role of leptin in lifestyle-related diseases. Studies with transgenic skinny mice overexpressing leptin

Leptin is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure. Plasma leptin concentrations are elevated in obese subjects, suggesting its pathophysiological role in obesity-related lifestyle-related diseases. We have recently succeeded in the generation of transgenic skinny mice overexpressing leptin. They exhibit increased glucose metabolism and insulin sensitivity accompanied by a significant increase in insulin signaling for glucose utilization in the skeletal muscle and liver. They also show blood pressure elevation through the sympathetic activation. Introduction of the lethal yellow agouti (A(y)) allele into transgenic skinny mice results in late-onset obesity and diabetes with blood pressure elevation similar to those found in nontransgenic agouti mice (A(y)/+ mice). After caloric restriction, blood pressure elevation is reversed but insulin resistance still remains in A(y)/+ mice in parallel with a reduction of plasma leptin concentrations. By contrast, blood pressure elevation is sustained but insulin resistance is reversed in transgenic mice overexpressing leptin with the A(y) allele (Tg/+:A(y)/+ mice), which remain hyperleptinemic. Collectively, our data suggest the pathophysiologic and therapeutic implication of leptin in obesity-related insulin resistance and hypertension.     

Sympathoadrenal activity in human obesity: heterogeneity of findings since 1980.

Alterations in sympathetic nervous system (SNS) activity are widely believed to contribute to the pathophysiology of the obese state. Disagreement, however, exists as to whether the predominant sympathetic abnormality is a decrease in neuronal activity (leading to diminished sympathetically-mediated energy expenditure and weight gain) or an increase (leading to hypertension). Findings summarized from over 40 separate studies support both hypotheses as well as the alternative thesis that SNS activity does not differ in obese humans compared to lean controls. Another abnormality being noted with increasing frequency in human obesity is reduced adrenaline (Ad) levels in plasma, both at rest or in response to a stimulus such as physical activity. Whether diminished adrenal medullary function is a cause or consequence of the obese state and whether the adrenal medulla plays any role in the regulation of energy metabolism on a daily basis are not known at the present time. Thus, while depressed SNS activity may be a sufficient explanation for the development of obesity, it is not a necessary condition. Suppressed adrenal medullary function may also contribute to this disorder.