No abstract

Oxidative stress plays a pathogenic role in hypertension, particularly the one associated with diabetes and obesity. Here, we test the hypothesis that renal dopamine D1 receptor dysfunction in obese Zucker rats is caused by oxidative stress. One group each from lean and obese Zucker rats received tempol, a superoxide dismutase mimetic in drinking water for 2 weeks. Obese animals were hypertensive, hyperglycemic, and hyperinsulinemic, exhibited renal oxidative stress, and increased protein kinase C activity. Also, there was hyperphosphorylation of D1 receptor, defective receptor-G-protein coupling, blunted dopamine-induced Na ؉ -K ؉ -ATPase inhibition, and diminished natriuretic response to D1 receptor agonist, SKF-38393. However, obese animals had elevated levels of plasma nitric oxide and urinary cGMP. In addition, L-N-nitroarginine and sodium nitroprusside showed similar effect on blood pressure in lean and obese rats. In obese animals, tempol reduced blood pressure, blood glucose, insulin, renal oxidative stress, and protein kinase C activity. Tempol also decreased D1 receptor phosphorylation and restored receptor G-protein coupling. Dopamine inhibited Na ؉ -K ؉ -ATPase activity, and SKF-38393 elicited a natriuretic response in tempol-treated obese rats. Thus in obese Zucker rats, tempol ameliorates oxidative stress and improves insulin sensitivity. Consequently, hyperphosphorylation of D1 receptor is reduced, leading to restoration of receptor-G-protein coupling and the natriuretic response to SKF-38393. Diabetes 54: 2219 -2226, 2005

Abstract-This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin. Twenty-to 22-week-old male wild-type (WT) C57BL/6J and obese MC4R (Ϫ/Ϫ) mice (Nϭ5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions. After a 3-day stable control period, leptin was infused (2 g/kg per minute IV) for 7 days in WT, obese ad libitum-fed MC4R (Ϫ/Ϫ), and nonobese pair-fed MC4R (Ϫ/Ϫ) mice. WT mice receiving vehicle for 7 days served as controls. MC4 (Ϫ/Ϫ) mice were 30% heavier and had 4-and 11-fold increases in plasma insulin and leptin levels, respectively, compared with WT mice. Despite obesity, MAP and heart rate tended to be lower in MC4R (Ϫ/Ϫ) mice compared with WT mice. Chronic leptin infusion in the different groups increased plasma leptin levels to 45 to 65 ng/mL. Seven-day leptin infusion in WT mice increased MAP by 12Ϯ3 mm Hg despite a 35% reduction in food intake and an 8% reduction in body weight. Leptin did not alter plasma glucose but reduced plasma insulin in WT mice (5.9Ϯ1.0 versus 3.0Ϯ0.5 U/mL). These cardiovascular and metabolic actions of leptin were abolished in obese and nonobese MC4R (Ϫ/Ϫ) mice. These data suggest that MC4R deficiency, and not obesity-induced leptin resistance, abolished the cardiovascular and metabolic actions of leptin in obese MC4R (Ϫ/Ϫ) mice. Thus, a functional MC4R is essential for the chronic cardiovascular and metabolic actions of leptin. (Hypertension. 2006;48:58-64.)Key Words: hypertension Ⅲ arterial pressure Ⅲ heart rate Ⅲ insulin Ⅲ insulin resistance Ⅲ obesity Ⅲ hypothalamus Ⅲ sympathetic nervous system L eptin, a 167-amino-acid peptide released from adipocytes, acts on the central nervous system (CNS) to suppress appetite and increase energy expenditure by increasing sympathetic nervous system (SNS) activity to thermogenic tissues, such as the brown adipose tissue. 1,2 Leptin also increases sympathetic activity to nonthermogenic organs, such as the kidneys and adrenal glands. 2 Moreover, chronic leptin infusion in rats increases arterial pressure, and this effect can be inhibited by combined ␣-and ␤-adrenergic receptor blockade, suggesting a role for the SNS in the pressor actions of leptin. 3 Neuroanatomical and functional studies indicate an important role for the hypothalamic pro-opiomelanocortin (POMC) neurons in mediating some of the actions of leptin. POMC neurons are principal sites of leptin receptor expression, and leptin increases POMC neuronal firing and POMC protein expression. 4,5 Conditional POMC neuron-specific leptin receptor deletion in mice leads to a modest increase in body weight. 6 One of the byproducts of hypothalamic POMC post-translational processing, ␣-melanocyte-stimulating hormone (␣-MSH), is considered to be an important mediator of some of the action of leptin to reduce food intake. ␣-MSH binds the hypothalamic melanocortin 3/4 receptors (MC3/4R) to e...

These findings suggest that the increased morbidity to sepsis in obesity may result from exaggerated microvascular inflammatory and thrombogenic responses that include the activation of endothelial cells with subsequent expression of adhesion molecules, such as P-selectin.

Despite considerable progress in understanding the pathophysiology of obesity, there are still no specific guidelines for the treatment of obesity hypertension other than weight reduction. Special considerations for obese hypertensive patients, in addition to controlling blood pressure, are correcting the metabolic abnormalities and protecting the kidneys from injury. This remains an important area for further research, especially in view of the current 'epidemic' of obesity in most industrialized countries.

Abstract-The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (Ϫ/Ϫ) and heterozygous (ϩ/Ϫ) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (nϭ5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (Ϫ/Ϫ) mice were severely obese compared with MC4R (ϩ/Ϫ) and WT mice (body weight 48Ϯ1.5 versus 31Ϯ0.6 and 30Ϯ0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (Ϫ/Ϫ) 110Ϯ3 mm Hg; MC4R (ϩ/Ϫ) 109Ϯ2 mm Hg; WT 114Ϯ2 mm Hg), and HR in MC4R (Ϫ/Ϫ) was lower than in WT (604Ϯ5 versus 645Ϯ9 bpm; PϽ0.05) but not different from MC4R (ϩ/Ϫ) (625Ϯ13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (Ϫ/Ϫ) compared with MC4R (ϩ/Ϫ) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (Ϫ/Ϫ) than in MC4R (ϩ/Ϫ) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (Ϫ/Ϫ) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities. Key Words: obesity Ⅲ insulin resistance Ⅲ hypertension, sodium-dependent Ⅲ arterial pressure Ⅲ renin-angiotensin system E vidence from epidemiological, clinical, and experimental studies has consistently demonstrated that obesity is a major cause of essential hypertension. 1-3 Previous studies show that ␣/␤-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain in diet-induced obese animal models, indicating that increased sympathetic nervous system (SNS) activation is an important cause of obesity-induced hypertension. 3,4 However, the mechanisms that link SNS activation to the development of hypertension in obesity are still unclear.One potential mechanism that could link obesity, SNS activation, and hypertension is the hypothalamic proopiomelanocortin (POMC) pathway. Several studies have indicated that the hypothalamic melanocortin system, acting through the melanocortin-3 receptor (MC3R) and MC4R, is a major regulator of energy balance. ␣-Melanocyte-stimulating hormone (␣-MSH), the proteolytic byproduct of the POMC peptide, activates the hypothalamic MC3/4R to suppress appetite and to increase energy expenditure. 5 Recent studies suggest that the hypothalamic melanocortin system may also be important in cardiovascular regulation. For example, acute intracerebroventricular injections of ␣-MSH increase SNS activity to the kidneys, 6 and chronic activation of MC3/4...

Excess weight gain is a major cause of increased blood pressure in most patients with essential hypertension, and also greatly increases the risk for renal disease. Obesity raises blood pressure by increasing renal tubular reabsorption, impairing pressure natriuresis, causing volume expansion due to activation of the sympathetic nervous system and renin-angiotensin system, and by physical compression of the kidneys, especially when visceral obesity is present. The mechanisms of sympathetic nervous system activation in obesity may be due, in part, to hyperleptinemia that stimulates the hypothalamic pro-opiomelanocortin pathway. With prolonged obesity, there may be a gradual loss of nephron function that worsens with time and exacerbates hypertension. Weight reduction is an essential first step in the management of obesity hypertension and renal disease. Special considerations for the obese patient, in addition to adequately controlling the blood pressure, include correction of the metabolic abnormalities and protection of the kidneys from further injury.

This study examined the importance of direct central nervous system (CNS) actions and increased adrenergic activity in mediating the chronic antidiabetic and cardiovascular actions of leptin. Insulin-deficient rats (streptozotocin, 50 mg/kg) were used to examine the effects of leptin on glucose homeostasis independent of changes in insulin. Male Sprague-Dawley rats were instrumented with arterial and venous catheters and intracerebroventricular cannula for 24-h/day blood pressure (BP) and heart rate (HR) monitoring and intravenous and intracerebroventricular infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, intravenous or intracerebroventricular, completely restored to control values plasma glucose levels (384 Ϯ 58 to 102 Ϯ 28 and 307 Ϯ 38 to 65 Ϯ 7 mg/dl, respectively), food intake, BP, and HR (304 Ϯ 8 to 364 Ϯ 7 and 317 Ϯ 13 to 423 Ϯ 9 bpm, respectively). Combined blockade of ␣1-, ␤1-, and ␤2-adrenergic receptors attenuated the rise in HR by 30 to 50% but had no effect on the antidiabetic and dietary actions of leptin. Blockade of ␤ 3-adrenergic receptors did not attenuate the chronic cardiovascular or metabolic effects of leptin. These data demonstrate that leptin, via its direct actions in the CNS, has powerful antidiabetic actions in insulin-deficient rats independent of increased peripheral ␣ 1, ␤1, ␤2, and ␤3-adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via ␣ 1-and ␤1/␤2-adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation. glucose; insulin; blood pressure; food intake; diabetes; sympathetic activity; central nervous system; heart rate; kidney; appetite LEPTIN, AN ADIPOCYTE-DERIVED peptide, regulates body weight and body fat mass by reducing appetite and increasing energy expenditure (10,11,28). Emerging evidence, however, indicates that leptin also has important antidiabetic and cardiovascular effects. For example, leptin administration enhances insulin-stimulated glucose uptake in peripheral tissues and decreases plasma insulin levels in normal rats (2,4,29,34) and improves insulin sensitivity in humans and mice with lipodystrophy characterized by severe insulin resistance (24, 30). Improved insulin sensitivity enhances insulin-mediated suppression of glucose output by the liver and increases glucose uptake by tissues such as skeletal muscle and fat. The overall effect is to reduce plasma glucose and/or the plasma level of insulin required to maintain euglycemia.Leptin may also have important effects on glucose homeostasis that are independent of insulin. For example, leptin injections in insulin-deficient diabetic animals restored plasma glucose levels to normal levels even though plasma insulin levels were nearly undetectable (5). Although the powerful effects of leptin on glucose regulation have been clearly demonstrated, the mechanisms...