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Obesity hypertension
AJH
2002; 15:50S–52S
Obesity Hypertension Albert P. Rocchini The association between obesity and hypertension is well recognized. However, the exact mechanisms whereby obesity causes hypertension are complex and multifactorial. The current article summarizes some of the known mechanisms responsible for obesity hypertension. Am J Hy-
T
he association between obesity and hypertension has been recognized since the early 1900s. However, the exact mechanism whereby obesity causes hypertension is still unknown. Obesity hypertension is complex and multifactorial. Ample human and animal data link obesity hypertension to fluid retention. We1 have demonstrated that obese adolescents have a renal function relationship (plot of urinary sodium excretion as a function of arterial pressure) that has a shallower slope than nonobese adolescents. We also observed that the renal function relationship normalizes after weight loss. The relationship between urinary sodium excretion and mean arterial pressure is known to be altered by intrinsic and extrinsic factors that affect the ability of the kidney to excrete sodium. Some of the factors that could produce alterations in the renal function curves in obese individuals are insulin resistance, structural changes in the kidney, altered vascular function and structure, activation of the renin-angiotensin-aldosterone system, activation of the sympathetic nervous system, and alterations in the hypothalamic-pituitary-adrenal axis (Fig. 1).
Insulin Resistance Insulin resistance or hyperinsulinemia can result in chronic sodium retention. Insulin can enhance renal sodium retention both directly, through its effects on renal tubules,2 and indirectly, through stimulation of the sympathetic nervous system and through augmenting angiotensin II-mediated aldosterone secretion.3 We and other investigators have documented both in obese adolescents and obese dogs that there is a direct relationship between insulin and sodium sensitivity of blood pressure (BP).1,4,5 However, in contrast to these and other reports linking hyperinsulinemia to hypertension, certain other studies Received October 15, 2001. Accepted October 16, 2001. From the Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan. This study was supported in part by grants 1RO1 1-IL 52205, 0895-7061/02/$22.00 PII S0895-7061(01)02299-3
pertens 2002;15:50S–52S © 2002 American Journal of Hypertension, Ltd. Key Words: Insulin resistance, sympathetic nervous system, vascular reactivity. have been unable to establish such relationships.6 On the basis of available data in the literature it appears that selective insulin resistance, not just hyperinsulinemia, is a more likely metabolic link between obesity and hypertension. The term selective insulin resistance implies that although insulin may have an impaired ability to cause whole body glucose uptake in an individual or an animal, some of the other physiologic actions of insulin may be preserved. With respect to hypertension, one of the important actions of insulin is its ability to induce sodium retention. We have shown that obese adolescents have selective insulin resistance, in that they are resistant to the ability of insulin to stimulate glucose uptake, yet are still sensitive to the renal sodium-retaining effect of insulin.7 Another mechanism that may link insulin resistance to salt sensitivity in obesity is an alteration in insulin receptor structure or function. Reduced sensitivity to insulin is believed due to a prereceptor or receptor defect. In this type of resistance, high concentrations of insulin overcome the defect and evoke a maximum insulin stimulation of the tissue. Alternatively, reduced responsiveness to insulin is associated with a reduced maximum insulin stimulation of the tissue and is believed to be due to a defect that is distal to the insulin receptor complex. Experimental studies provide some insights. We have demonstrated that weight gain is associated with both a reduced maximum insulinstimulated glucose uptake and a shift of the dose–response curve to the right in the dog; thus, weight gain results in both a reduced sensitivity and responsiveness to insulin.8 In addition, there is evidence that dietary salt content alters insulin receptor function in the rat.9 Sechi9 found that an increase in dietary salt content decreases insulin receptor number and mRNA levels in the kidney of normal WistarKyoto (WKY) and Sprague-Dawley rats. However, when rats are insulin resistant, this salt-mediated decrease in HL-18575, 2R01-HL-35743, 2P60 AM 20572, and 2P01H1L18575-24 from the National Institutes of Health. Address correspondence and reprint requests to Dr. Albert P Rocchini, Pediatric Cardiology, C.S. Mott Children’s Hospital, University of Michigan Health Systems, Box 0204, Ann Arbor, MI 48109-0204. © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–February 2002–VOL. 15, NO. 2, PART 2
OBESITY HYPERTENSION
51S
FIG. 1. A schematic outline of factors that contribute to the pathogenesis of obesity hypertension.
insulin receptor number is lost.9 Sechi reported that when control Sprague-Dawley rats are fed a high salt diet, renal insulin receptor number and mRNA levels decrease; however, when fructose is added to the high salt diet, the rats become insulin resistant and hypertensive without change in renal insulin receptor number and mRNA. If similar changes also occur in obese humans, this abnormality might contribute to sodium retention and hypertension.
Structural Changes in the Kidney Structural changes in the kidneys of obese individuals can cause fluid retention. The kidneys from obese subjects are tightly encapsulated with fatty tissue, and fat penetrates the renal hilum into the sinuses surrounding the medulla.10 The fat accumulation results in an elevated interstitial fluid hydrostatic pressure (19 mm Hg in obese dogs compared with 9 to 10 mm Hg in lean dogs). The elevated interstitial pressure reduces medullary blood flow and causes tubular compression, thus, slowing tubular flow rate and increasing fraction tubular reabsorption.10
Altered Vascular Structure and Function Another way that obesity can cause hypertension and sodium retention is through alteration in vascular structure and function. Vascular abnormalities exist in obese individuals. In obese adolescents, Rocchini et al11 demonstrated that ischemic exercise results in a decreased maximal forearm blood flow and an increased minimum vascular resistance. These studies demonstrated that the abnormal vascular responses to ischemic exercise directly correlate with fasting insulin and whole body glucose uptake, and that both the vascular and metabolic abnormalities improve with weight loss.11 In normal nonobese
volunteers, insulin induces peripheral arterial vasodilation. However, Baron et al12 demonstrated that insulin-resistant individuals exhibit blunted insulin-mediated vasodilation and impaired endothelium-dependent vasodilation.
Renin-AngotensinAldosterone System Obesity could cause sodium retention and hypertension through alteration in the renin-angiotensin-aldosterone system. The renin-angiotensin-aldosterone system is an important determinant of efferent glomerular arteriolar tone and tubular sodium reabsorption. Enhanced activity of the renin-angiotensin system has been reported in obese humans and dogs.3,13 In addition, obesity is associated with elevated aldosterone levels and an altered relation between angiotensin II and aldosterone.
Sympathetic Nervous System Obesity could also cause sodium retention and hypertension through stimulation of the sympathetic nervous system. Landsberg and Krieger14 have suggested that in obese individuals the sympathetic nervous system is chronically activated in an attempt to prevent further weight gain and that obesity-related hypertension is a by-product of the overactive sympathetic nervous system. Preliminary studies by Hall et al15 have suggested that 7 days of combined ␣- and -adrenergic blockade reduced arterial pressure to a much greater extent in obese than normal dogs. These investigators also demonstrated that renal denervation prevents both the hypertension and sodium retention associated with obesity.16 Finally, we17 have shown that clonidine can prevent the hypertension, sodium retention, and insulin resistance associated with feeding dogs a high fat diet.
52S
OBESITY HYPERTENSION
HypothalamicPituitary-Adrenal Axis The final way that obesity could cause sodium retention and hypertension is through alterations in the hypothalamic-pituitary-adrenal axis. The similarities between Cushing’s syndrome and the metabolic abnormalities associated with obesity hypertension has lead Bjorntorp and Rosmond18 to speculate that hypercortisolemia is involved in the pathogenesis of obesity hypertension. Their hypothesis also explains the pathophysiology behind the observation, originally made by Jean Vague,19 that the cardiovascular and metabolic consequences of obesity were greatest in individuals whose fat distribution pattern favored the upper body segments. Rosmond and others20 also have demonstrated that a restriction fragment length polymorphism of the glucocorticoid receptor gene is associated with poorly controlled hypothalamic-pituitaryadrenal axis function, as well as abdominal obesity, insulin resistance, and hypertension.
Summary In summary, conclusive data suggest that obesity, especially upper body fat distribution, is an independent risk factor for the development of hypertension. There is general agreement that obesity hypertension is caused by excessive fluid retention. However, controversy exists as to what factors are mechanistically responsible for the fluid retention. Ample data suggest that selective insulin resistance and obesity hypertension are related. Other hormonal systems (renin-angiotensin-aldosterone, sympathetic nervous system, and hypothalamic-pituitary-adrenal axis) have also been identified to relate to obesity, hypertension, and insulin resistance. Further studies are necessary not only to clarify the origin of defects in insulin action that are responsible for the development of insulin resistance, but also to more precisely define the exact role that insulin resistance and the regulatory abnormalities in these other hormone systems play in BP homeostasis.
References 1.
2.
Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989;321: 580 –585. DeFronzo RA, Cooke CR, Andres R, Fabona GR, Davis PJ: The
AJH–February 2002–VOL. 15, NO. 2, PART 2
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4.
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14. 15.
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18. 19.
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effect of insulin on renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest 1975;55:845–855. Rocchini AP, Moorehead C, DeRemer S, Goodfriend TL, Ball DL: Hyperinsulinemia and the aldosterone and pressor responses to angiotensin II. Hypertension 1990;15:861–866. Hall JE, Granger JP, Hester RL, Montani JP: Mechanisms of sodium balance in hypertension: role of pressure natriuresis. J Hypertens 1986;4(suppl 4):S57–S65. Rocchini AP, Moorehead C, Wentz E, Deremer S: Obesity-induced hypertension in the dog. Hypertension 1987;9(suppl III):III64 – III68. Hall JE, Brands MW, Kivlighn SD, Mizelle IL, Hidebrandt DA, Gaillard CA: Chronic hyperinsulinemia and blood pressure: interaction with catecholamines? Hypertension 1990;15:519 –527. Rocchini AP, Katch V, Kveselis D, Moorehead C, Martin M, Lampman R, Gregory M: Insulin and renal retention in obese adolescents. Hypertension 1989;14:367–374. Rocchini A, Marker P, Cervenka T: Time course of insulin resistance associated with weight gain in the dog: relationship to the development of hypertension. Am J Physiol 1996;272:E147–E154. Sechi LA: Mechanisms of insulin resistance in rat models of hypertension and their relationships with salt sensitivity. J Hypertens 1999;17:1229 –1237. Hall JE, Brands MW, Henegar JR, Shek EW: Abnormal kidney function as a cause and a consequence of obesity hypertension. Clin Exp Pharmacol Physiol 1998;25:58 –64. Rocchini AP, Moorehead C, Katch V, Key J, Finta KM: Forearm resistance vessel abnormalities and insulin resistance in obese adolescents. Hypertension 1992;19:615–620. Baron AD, Steinberg HO, Chaker H: Insulin mediated skeletal muscle vasodilation contributed to both insulin sensitivity and responsiveness in lean humans. J Clin Invest 1995;96:786 –792. Tuck MI, Sowers J, Dornfield L, Kledzik G, Maxwell M: The effect of weight reduction on blood pressure plasma renin activity and plasma aldosterone level in obese patients. N Engl J Med 1981;304: 930 –933. Landsberg L, Krieger DR: Obesity, metabolism and the sympathetic nervous system. Am J Hypertens 1989;2:125S–132S. Hall JE, Van Vliet BN, Gamty CA, Connell RD, Brands MW: Role of increased adrenergic activity in obesity-induced hypertension. Circulation 1992;86(suppl I):I. Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, Granger JP: Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension 1995;25(part 2):893–897. Rocchini AP, Mao HZ, Babu K, Marker P, Rocchini AJ: Clonidine prevents insulin resistance and hypertension in obese dogs. Hypertension 1999;33(part II):548 –553. Bjorntorp P, Rosmond R: Neuroendocrine abnormalities in visceral obesity. Intern J Obesity Rel Metab Dis 2000;24(suppl 2):S80 –S85. Vague J: The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20 –34. Rosmond R, Chagnon YC, Holm G, Changon M, Perusse L, Lindell K, Carlsson B, Bouchard C, Bjorntorp P: A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis. Obesity Research 2000;8:211–218.
2002; 15:50S–52S
Obesity Hypertension Albert P. Rocchini The association between obesity and hypertension is well recognized. However, the exact mechanisms whereby obesity causes hypertension are complex and multifactorial. The current article summarizes some of the known mechanisms responsible for obesity hypertension. Am J Hy-
T
he association between obesity and hypertension has been recognized since the early 1900s. However, the exact mechanism whereby obesity causes hypertension is still unknown. Obesity hypertension is complex and multifactorial. Ample human and animal data link obesity hypertension to fluid retention. We1 have demonstrated that obese adolescents have a renal function relationship (plot of urinary sodium excretion as a function of arterial pressure) that has a shallower slope than nonobese adolescents. We also observed that the renal function relationship normalizes after weight loss. The relationship between urinary sodium excretion and mean arterial pressure is known to be altered by intrinsic and extrinsic factors that affect the ability of the kidney to excrete sodium. Some of the factors that could produce alterations in the renal function curves in obese individuals are insulin resistance, structural changes in the kidney, altered vascular function and structure, activation of the renin-angiotensin-aldosterone system, activation of the sympathetic nervous system, and alterations in the hypothalamic-pituitary-adrenal axis (Fig. 1).
Insulin Resistance Insulin resistance or hyperinsulinemia can result in chronic sodium retention. Insulin can enhance renal sodium retention both directly, through its effects on renal tubules,2 and indirectly, through stimulation of the sympathetic nervous system and through augmenting angiotensin II-mediated aldosterone secretion.3 We and other investigators have documented both in obese adolescents and obese dogs that there is a direct relationship between insulin and sodium sensitivity of blood pressure (BP).1,4,5 However, in contrast to these and other reports linking hyperinsulinemia to hypertension, certain other studies Received October 15, 2001. Accepted October 16, 2001. From the Division of Pediatric Cardiology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan. This study was supported in part by grants 1RO1 1-IL 52205, 0895-7061/02/$22.00 PII S0895-7061(01)02299-3
pertens 2002;15:50S–52S © 2002 American Journal of Hypertension, Ltd. Key Words: Insulin resistance, sympathetic nervous system, vascular reactivity. have been unable to establish such relationships.6 On the basis of available data in the literature it appears that selective insulin resistance, not just hyperinsulinemia, is a more likely metabolic link between obesity and hypertension. The term selective insulin resistance implies that although insulin may have an impaired ability to cause whole body glucose uptake in an individual or an animal, some of the other physiologic actions of insulin may be preserved. With respect to hypertension, one of the important actions of insulin is its ability to induce sodium retention. We have shown that obese adolescents have selective insulin resistance, in that they are resistant to the ability of insulin to stimulate glucose uptake, yet are still sensitive to the renal sodium-retaining effect of insulin.7 Another mechanism that may link insulin resistance to salt sensitivity in obesity is an alteration in insulin receptor structure or function. Reduced sensitivity to insulin is believed due to a prereceptor or receptor defect. In this type of resistance, high concentrations of insulin overcome the defect and evoke a maximum insulin stimulation of the tissue. Alternatively, reduced responsiveness to insulin is associated with a reduced maximum insulin stimulation of the tissue and is believed to be due to a defect that is distal to the insulin receptor complex. Experimental studies provide some insights. We have demonstrated that weight gain is associated with both a reduced maximum insulinstimulated glucose uptake and a shift of the dose–response curve to the right in the dog; thus, weight gain results in both a reduced sensitivity and responsiveness to insulin.8 In addition, there is evidence that dietary salt content alters insulin receptor function in the rat.9 Sechi9 found that an increase in dietary salt content decreases insulin receptor number and mRNA levels in the kidney of normal WistarKyoto (WKY) and Sprague-Dawley rats. However, when rats are insulin resistant, this salt-mediated decrease in HL-18575, 2R01-HL-35743, 2P60 AM 20572, and 2P01H1L18575-24 from the National Institutes of Health. Address correspondence and reprint requests to Dr. Albert P Rocchini, Pediatric Cardiology, C.S. Mott Children’s Hospital, University of Michigan Health Systems, Box 0204, Ann Arbor, MI 48109-0204. © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–February 2002–VOL. 15, NO. 2, PART 2
OBESITY HYPERTENSION
51S
FIG. 1. A schematic outline of factors that contribute to the pathogenesis of obesity hypertension.
insulin receptor number is lost.9 Sechi reported that when control Sprague-Dawley rats are fed a high salt diet, renal insulin receptor number and mRNA levels decrease; however, when fructose is added to the high salt diet, the rats become insulin resistant and hypertensive without change in renal insulin receptor number and mRNA. If similar changes also occur in obese humans, this abnormality might contribute to sodium retention and hypertension.
Structural Changes in the Kidney Structural changes in the kidneys of obese individuals can cause fluid retention. The kidneys from obese subjects are tightly encapsulated with fatty tissue, and fat penetrates the renal hilum into the sinuses surrounding the medulla.10 The fat accumulation results in an elevated interstitial fluid hydrostatic pressure (19 mm Hg in obese dogs compared with 9 to 10 mm Hg in lean dogs). The elevated interstitial pressure reduces medullary blood flow and causes tubular compression, thus, slowing tubular flow rate and increasing fraction tubular reabsorption.10
Altered Vascular Structure and Function Another way that obesity can cause hypertension and sodium retention is through alteration in vascular structure and function. Vascular abnormalities exist in obese individuals. In obese adolescents, Rocchini et al11 demonstrated that ischemic exercise results in a decreased maximal forearm blood flow and an increased minimum vascular resistance. These studies demonstrated that the abnormal vascular responses to ischemic exercise directly correlate with fasting insulin and whole body glucose uptake, and that both the vascular and metabolic abnormalities improve with weight loss.11 In normal nonobese
volunteers, insulin induces peripheral arterial vasodilation. However, Baron et al12 demonstrated that insulin-resistant individuals exhibit blunted insulin-mediated vasodilation and impaired endothelium-dependent vasodilation.
Renin-AngotensinAldosterone System Obesity could cause sodium retention and hypertension through alteration in the renin-angiotensin-aldosterone system. The renin-angiotensin-aldosterone system is an important determinant of efferent glomerular arteriolar tone and tubular sodium reabsorption. Enhanced activity of the renin-angiotensin system has been reported in obese humans and dogs.3,13 In addition, obesity is associated with elevated aldosterone levels and an altered relation between angiotensin II and aldosterone.
Sympathetic Nervous System Obesity could also cause sodium retention and hypertension through stimulation of the sympathetic nervous system. Landsberg and Krieger14 have suggested that in obese individuals the sympathetic nervous system is chronically activated in an attempt to prevent further weight gain and that obesity-related hypertension is a by-product of the overactive sympathetic nervous system. Preliminary studies by Hall et al15 have suggested that 7 days of combined ␣- and -adrenergic blockade reduced arterial pressure to a much greater extent in obese than normal dogs. These investigators also demonstrated that renal denervation prevents both the hypertension and sodium retention associated with obesity.16 Finally, we17 have shown that clonidine can prevent the hypertension, sodium retention, and insulin resistance associated with feeding dogs a high fat diet.
52S
OBESITY HYPERTENSION
HypothalamicPituitary-Adrenal Axis The final way that obesity could cause sodium retention and hypertension is through alterations in the hypothalamic-pituitary-adrenal axis. The similarities between Cushing’s syndrome and the metabolic abnormalities associated with obesity hypertension has lead Bjorntorp and Rosmond18 to speculate that hypercortisolemia is involved in the pathogenesis of obesity hypertension. Their hypothesis also explains the pathophysiology behind the observation, originally made by Jean Vague,19 that the cardiovascular and metabolic consequences of obesity were greatest in individuals whose fat distribution pattern favored the upper body segments. Rosmond and others20 also have demonstrated that a restriction fragment length polymorphism of the glucocorticoid receptor gene is associated with poorly controlled hypothalamic-pituitaryadrenal axis function, as well as abdominal obesity, insulin resistance, and hypertension.
Summary In summary, conclusive data suggest that obesity, especially upper body fat distribution, is an independent risk factor for the development of hypertension. There is general agreement that obesity hypertension is caused by excessive fluid retention. However, controversy exists as to what factors are mechanistically responsible for the fluid retention. Ample data suggest that selective insulin resistance and obesity hypertension are related. Other hormonal systems (renin-angiotensin-aldosterone, sympathetic nervous system, and hypothalamic-pituitary-adrenal axis) have also been identified to relate to obesity, hypertension, and insulin resistance. Further studies are necessary not only to clarify the origin of defects in insulin action that are responsible for the development of insulin resistance, but also to more precisely define the exact role that insulin resistance and the regulatory abnormalities in these other hormone systems play in BP homeostasis.
References 1.
2.
Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M: The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989;321: 580 –585. DeFronzo RA, Cooke CR, Andres R, Fabona GR, Davis PJ: The
AJH–February 2002–VOL. 15, NO. 2, PART 2
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14. 15.
16.
17.
18. 19.
20.
effect of insulin on renal handling of sodium, potassium, calcium and phosphate in man. J Clin Invest 1975;55:845–855. Rocchini AP, Moorehead C, DeRemer S, Goodfriend TL, Ball DL: Hyperinsulinemia and the aldosterone and pressor responses to angiotensin II. Hypertension 1990;15:861–866. Hall JE, Granger JP, Hester RL, Montani JP: Mechanisms of sodium balance in hypertension: role of pressure natriuresis. J Hypertens 1986;4(suppl 4):S57–S65. Rocchini AP, Moorehead C, Wentz E, Deremer S: Obesity-induced hypertension in the dog. Hypertension 1987;9(suppl III):III64 – III68. Hall JE, Brands MW, Kivlighn SD, Mizelle IL, Hidebrandt DA, Gaillard CA: Chronic hyperinsulinemia and blood pressure: interaction with catecholamines? Hypertension 1990;15:519 –527. Rocchini AP, Katch V, Kveselis D, Moorehead C, Martin M, Lampman R, Gregory M: Insulin and renal retention in obese adolescents. Hypertension 1989;14:367–374. Rocchini A, Marker P, Cervenka T: Time course of insulin resistance associated with weight gain in the dog: relationship to the development of hypertension. Am J Physiol 1996;272:E147–E154. Sechi LA: Mechanisms of insulin resistance in rat models of hypertension and their relationships with salt sensitivity. J Hypertens 1999;17:1229 –1237. Hall JE, Brands MW, Henegar JR, Shek EW: Abnormal kidney function as a cause and a consequence of obesity hypertension. Clin Exp Pharmacol Physiol 1998;25:58 –64. Rocchini AP, Moorehead C, Katch V, Key J, Finta KM: Forearm resistance vessel abnormalities and insulin resistance in obese adolescents. Hypertension 1992;19:615–620. Baron AD, Steinberg HO, Chaker H: Insulin mediated skeletal muscle vasodilation contributed to both insulin sensitivity and responsiveness in lean humans. J Clin Invest 1995;96:786 –792. Tuck MI, Sowers J, Dornfield L, Kledzik G, Maxwell M: The effect of weight reduction on blood pressure plasma renin activity and plasma aldosterone level in obese patients. N Engl J Med 1981;304: 930 –933. Landsberg L, Krieger DR: Obesity, metabolism and the sympathetic nervous system. Am J Hypertens 1989;2:125S–132S. Hall JE, Van Vliet BN, Gamty CA, Connell RD, Brands MW: Role of increased adrenergic activity in obesity-induced hypertension. Circulation 1992;86(suppl I):I. Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, Granger JP: Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension 1995;25(part 2):893–897. Rocchini AP, Mao HZ, Babu K, Marker P, Rocchini AJ: Clonidine prevents insulin resistance and hypertension in obese dogs. Hypertension 1999;33(part II):548 –553. Bjorntorp P, Rosmond R: Neuroendocrine abnormalities in visceral obesity. Intern J Obesity Rel Metab Dis 2000;24(suppl 2):S80 –S85. Vague J: The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20 –34. Rosmond R, Chagnon YC, Holm G, Changon M, Perusse L, Lindell K, Carlsson B, Bouchard C, Bjorntorp P: A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis. Obesity Research 2000;8:211–218.