Sympathetic Activity In Obesity Research Articles

Sympathetic activity in obesity: a brief review of methods and supportive data.

The increase in the prevalence of obesity and the concomitant rise in obesity-related illness have led to substantial pressure on health care systems throughout the world. While the combination of reduced exercise, increased sedentary time, poor diet, and genetic predisposition is undoubtedly pivotal in generating obesity and increasing disease risk, a large body of work indicates that the sympathetic nervous system (SNS) contributes to obesity-related disease development and progression. In obesity, sympathetic nervous activity is regionalized, with activity in some outflows being particularly sensitive to the obese state, whereas other outflows, or responses to stimuli, may be blunted, thereby making the assessment of sympathetic nervous activation in the clinical setting difficult. Isotope dilution methods and direct nerve recording techniques have been developed and utilized in clinical research, demonstrating that in obesity there is preferential activation of the muscle vasoconstrictor and renal sympathetic outflows. With weight loss, sympathetic activity is reduced. Importantly, sympathetic nervous activity is associated with end-organ dysfunction and changes in sympathetic activation that accompany weight loss are often reflected in an improvement of end-organ function. Whether targeting the SNS directly improves obesity-related illness remains unknown, but merits further attention.

Sex differences in sympathetic activity in obesity and its related hypertension.

The prevalence of obesity is rapidly increasing in the United States, particularly among women. Approximately 60-70% of hypertension in adults may be directly attributed to obesity. In addition, maternal obesity is a major risk factor for hypertensive disorders during pregnancy. The underlying mechanisms for the association between obesity and cardiovascular risk are multifactorial, but activation of the sympathetic nervous system is one significant contributing factor. This brief review summarizes the current knowledge on sex differences in sympathetic activity in obesity and its related hypertension, with a focus on studies in humans. Evidence suggests that abdominal visceral fat, rather than subcutaneous fat, is related to augmented sympathetic activity regardless of sex. Race/ethnicity may affect the relationship between obesity and sympathetic activity. Obesity-related hypertension has an important neurogenic component, which is characterized by sympathetic overactivity. However, sex may influence the association between hypertension and sympathetic overactivity in obese people. Finally, both body weight and sympathetic overactivity seem to be involved in the development of gestational hypertensive disorders in women. Chronic hyperinsulinemia due to insulin resistance, high plasma levels of leptin, and/or obstructive sleep apnea may be responsible for sympathetic overactivity in obesity-related hypertension.

Leptin‐induced neuroinflammatory effects in the hypothalamic neurons: role of Sirt1 and FoxO1

Accumulated evidence indicates that central nervous system signaling pathways may contribute to the etiology and pathogenesis of obesity‐induced hypertension. Hypothalamic leptin‐mediated signaling may contribute to the exaggerated sympathoexcitation in obesity. Leptin can influence food intake, energy expenditure and sympathetic nerve activity via hypothalamic pro‐opiomelanocortin (POMC) neurons in the arcuate nucleus (ARCN) of hypothalamus. The aim of the study was to determine the effects of leptin on the neuroinflammation‐mediated high sympathetic nerve activity in obesity. We used hypothalamic neuronal cell mHypoA‐POMC (CLU500) and microglial cell (SIM‐A9) to observe pro‐inflammatory and anti‐inflammatory cytokines levels after 24 hours leptin treatment. We found that leptin incubation increased the levels of pro‐inflammatory cytokines interleukin 6 (IL‐6), interleukin 1β (IL‐1β), and tumor necrosis factor alpha (TNFα) in both POMC and microglial cells. Leptin treatment also reduced the level of lipoxin A4, a potent anti‐inflammatory bioactive lipid formed from arachidonic acid in both cells. Knockdown nutrient‐sensing enzyme sirtuin 1 (Sirt1) by siRNASirt1 significantly attenuated the levels of leptin‐induced pro‐inflammatory cytokines in the POMC and microglial cells. On the contrary, knockdown transcription factor forkhead box protein O1 (FoxO1) by siRNAFoxO1 significantly enhanced leptin‐induced pro‐inflammatory cytokines. Further, in vivo study, we found significant increased protein expressions of IL‐6, IL‐1β and TNFα in the ARCN in 12 weeks high fat induced obese rats. siRNASirt1 reduced leptin‐mediated renal sympathetic nerve activity in obese rats. The study suggests that enhanced leptin‐mediated sympathetic activation in obesity may via hypothalamic neuroinflammatory pathway. We propose Sirt1 and FoxO1 in hypothalamus are key regulators of leptin signaling pathway contributed to the over sympathetic activation in obesity.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Role of the Autonomic Nervous System in the Pathophysiology of Obesity.

Obesity is reaching epidemic proportions globally and represents a major cause of comorbidities, mostly related to cardiovascular disease. The autonomic nervous system (ANS) dysfunction has a two-way relationship with obesity. Indeed, alterations of the ANS might be involved in the pathogenesis of obesity, acting on different pathways. On the other hand, the excess weight induces ANS dysfunction, which may be involved in the haemodynamic and metabolic alterations that increase the cardiovascular risk of obese individuals, i.e., hypertension, insulin resistance and dyslipidemia. This article will review current evidence about the role of the ANS in short-term and long-term regulation of energy homeostasis. Furthermore, an increased sympathetic activity has been demonstrated in obese patients, particularly in the muscle vasculature and in the kidneys, possibily contributing to increased cardiovascular risk. Selective leptin resistance, obstructive sleep apnea syndrome, hyperinsulinemia and low ghrelin levels are possible mechanisms underlying sympathetic activation in obesity. Weight loss is able to reverse metabolic and autonomic alterations associated with obesity. Given the crucial role of autonomic dysfunction in the pathophysiology of obesity and its cardiovascular complications, vagal nerve modulation and sympathetic inhibition may serve as therapeutic targets in this condition.

Editorial: New Translational Insights on Metabolic Syndrome: Obesity, Hypertension, Diabetes and Beyond.

Editorial: New Translational Insights on Metabolic Syndrome: Obesity, Hypertension, Diabetes and Beyond.

Obesity-Induced Hypertension: Brain Signaling Pathways.

Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension.

Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways.

Although salt is a major environmental factor in the development of hypertension, the degree of salt sensitivity varies widely among individuals. The mechanisms responsible for this variation remain to be elucidated. Recent studies have revealed the involvement of two important signaling pathways in renal tubules that play key roles in electrolyte balance and the maintenance of normal blood pressure: the β2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no-lysine kinase (WNK)4-Na(+)-Cl(-) cotransporter pathway, which is active in distal convoluted tubule (DCT)1, and the Ras-related C3 botulinum toxin substrate (Rac)1-mineralocorticoid receptor (MR) pathway, which is active in DCT2, connecting tubules, and collecting ducts. β2-Adrenergic stimulation due to increased renal sympathetic activity in obesity- and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter. This results in the suppression of WNK4 transcription followed by the activation of Na(+)-Cl(-) cotransporters in the DCT and elevated Na(+) retention and blood pressure upon salt loading. Rac1 activates MRs, even in the absence of ligand binding, with this activity increased in the presence of ligand. In salt-sensitive animals, Rac1 activation due to salt loading activates MRs in DCT2, connecting tubules, and collecting ducts. Thus, GRs and MRs are independently involved in two pathways responsible for renal Na(+) handling and salt-sensitive hypertension. These findings suggest novel therapeutic targets and may lead to the development of diagnostic tools to determine salt sensitivity in hypertensive patients.

The brain melanocortin system, sympathetic control, and obesity hypertension.

Excess weight gain is the most significant, preventable cause of increased blood pressure (BP) in patients with primary (essential) hypertension and increases the risk for cardiovascular and renal diseases. In this review, we discuss the role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension. In addition, we highlight potential mechanisms by which the brain melanocortin system modulates metabolic and cardiovascular functions.

Role of leptin and central nervous system melanocortins in obesity hypertension

Obesity is a major worldwide health problem. Excess weight gain is the most significant preventable cause of increased blood pressure (BP) in patients with essential hypertension and increases the risk for cardiovascular and renal diseases. Our goal is to review the mechanisms that link obesity with hypertension, with special emphasis on the role of leptin and the brain melanocortin system in driving sympathetic activation in obesity. Despite increased interest in obesity as a major risk for developing hypertension, the precise mechanisms linking excess weight gain with increases in BP are still elusive. Current evidence suggests that increased sympathetic nervous system (SNS) activity contributes to impaired renal-pressure natriuresis and sodium retention in obesity. Recent findings indicate that the adipocyte-derived hormone, leptin, activates brain centers that regulate SNS activity through a melanocortin-system-dependent pathway. The interaction of leptin and the brain melanocortin system represents an important area of research to further our understanding of the mechanisms leading to sympathetic activation in obesity. Sympathetic overactivity is an important link between excess weight gain and increased BP. Hormones and cytokines secreted by the adipose tissue that interact with neural pathways (e.g. melanocortin system) appear to play a key role in contributing to sympathetic activation in obesity and represent potential new targets for therapies.

Sympathetic Activation in Obesity

The hypothesis that human obesity is associated with a state of adrenergic overdrive dates back to ≈50 years ago, when a group of American investigators noted that sympathetic function was indeed altered in the obese subject.1 Since then, many studies have attempted to investigate whether and to what extent sympathetic activation is a hallmark of the autonomic profile of the obese state. The results, which have also been included in a meta-analysis,2 although suggestive for a hyperadrenergic state, did not permit any definite conclusion on this issue to be drawn. Several factors may account for these inconclusive results. First, the data collected were mainly based on the biochemical assay of plasma norepinephrine or its urinary metabolites, that is, an approach known to have a limited reproducibility and sensitivity in detecting the adrenergic abnormalities characterizing a physiological or a pathophysiological state.3 Furthermore, plasma norepinephrine concentration relies on a variety of biological processes taking place both at a synaptic and at a postsynaptic level, such as the reuptake of the neurotransmitter by the adrenergic nerve terminals and the tissue clearance process of norepinephrine, as well as its functional role as a cotransmitter with epinephrine.3 These complex steps make hard to establish whether and to what extent an elevation in circulating levels of norepinephrine (or its urinary metabolites) mirrors a true increase in central adrenergic outflow or whether it rather reflects an impairment of the physiological processes mentioned above taking place at a peripheral neural level. More stringent evidence on the adrenergic overdrive characterizing the obese state …

Exposure to a High-Fat Diet Alters Leptin Sensitivity and Elevates Renal Sympathetic Nerve Activity and Arterial Pressure in Rabbits

The activation of the sympathetic nervous system through the central actions of the adipokine leptin has been suggested as a major mechanism by which obesity contributes to the development of hypertension. However, direct evidence for elevated sympathetic activity in obesity has been limited to muscle. The present study examined the renal sympathetic nerve activity and cardiovascular effects of a high-fat diet (HFD), as well as the changes in the sensitivity to intracerebroventricular leptin. New Zealand white rabbits fed a 13.5% HFD for 4 weeks showed modest weight gain but a 2- to 3-fold greater accumulation of visceral fat compared with control rabbits. Mean arterial pressure, heart rate, and plasma norepinephrine concentration increased by 8%, 26%, and 87%, respectively (P<0.05), after 3 weeks of HFD. Renal sympathetic nerve activity was 48% higher (P<0.05) in HFD compared with control diet rabbits and was correlated to plasma leptin (r=0.87; P<0.01). Intracerebroventricular leptin administration (5 to 100 microg) increased mean arterial pressure similarly in both groups, but renal sympathetic nerve activity increased more in HFD-fed rabbits. By contrast, intracerebroventricular leptin produced less neurons expressing c-Fos in HFD compared with control rabbits in regions important for appetite and sympathetic actions of leptin (arcuate: -54%, paraventricular: -69%, and dorsomedial hypothalamus: -65%). These results suggest that visceral fat accumulation through consumption of a HFD leads to marked sympathetic activation, which is related to increased responsiveness to central sympathoexcitatory effects of leptin. The paradoxical reduction in hypothalamic neuronal activation by leptin suggests a marked "selective leptin resistance" in these animals.

Mechanisms mediating renal sympathetic activation to leptin in obesity

Leptin plays a critical role in the control of energy homeostasis. The sympathetic cardiovascular actions of leptin have emerged as a potential link between obesity and hypertension. We previously demonstrated that in mice, modest obesity induced by 10 wk of a high-fat diet is associated with preservation of leptin ability to increase renal sympathetic nerve activity (SNA) despite the resistance to the metabolic effects of leptin. Here, we examined whether selective leptin resistance exists in mice with late-stage diet-induced obesity (DIO) produced by 20 wk of a high-fat diet. The decrease in food intake and body weight induced by intraperitoneal or intracerebroventricular injection of leptin was significantly attenuated in the DIO mice. Regional SNA responses to intravenous leptin were also attenuated in DIO mice. In contrast, intracerebroventricularly administered leptin caused contrasting effects on regional SNA in DIO mice. Renal SNA response to intracerebroventricular leptin was preserved, whereas lumbar and brown adipose tissue SNA responses were attenuated. Intact renal SNA response to leptin combined with the increased cerebrospinal fluid leptin levels in DIO mice represents a potential mechanism for the adverse cardiovascular consequences of obesity. Lastly, we examined the role of phosphoinositol-3 kinase (PI3K) and melanocortin receptors (MCR) in mediating the preserved renal SNA response to leptin in obesity. Presence of PI3K inhibitor (LY294002) or MC3/4R antagonist (SHU9119) significantly attenuated the renal SNA response to leptin in DIO and agouti obese mice. Our results demonstrate the importance of PI3K and melanocortin receptors in the transduction of leptin-induced renal sympathetic activation in obesity.

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …

Is obstructive sleep apnea the cause of sympathetic nervous activation in human obesity?

based on findings in experimental models of obesity, the sympathetic nervous system has commonly been assumed to have a determining role in obesity development through its influence on the regulation of energy expenditure. An earlier hypothesis was that sympathetic nervous activity was low in

Factors that influence the risk of hypertension in obese individuals.

Obesity, which has reached epidemic prevalence, is now recognized as an independent risk factor for increasing blood pressure. The complex mechanisms of obesity-related hypertension are unclear, but several studies have provided evidence of a hypertensive shift in pressure natriuresis. Excess sympathetic outflow to the kidneys and changes in renal structure and function may both affect the renal pressure relationship. Other factors that may contribute to altered natriuresis include hyperinsulinemia, hyperleptinemia and activation of the renin-angiotensin system. Disruption of the renal alpha2 adrenoceptors or leptin receptor implicated in natriuresis control may also be an additive risk for the increase in tubular reabsorption in obesity hypertension. Recent advances have highlighted the importance of two adipocyte-derived hormones - leptin and angiotensinogen - in obesity hypertension. Leptin has direct central effects that increase sympathetic outflow to the kidney and the new concept of selective leptin resistance, suggests the maintenance of leptin-induced sympathetic activation in obesity, despite resistance to leptin metabolic effects. On the other hand, a recent study showed that angiotensinogen produced in the adipocyte is also relevant to blood pressure control. The article reviews the factors implicated in the disruption of blood pressure control in obesity. Further investigation on the time course of the disease would reveal the relative importance of each of the factors that influence the risk of hypertension in obese individuals.

1850 Insulin levels, sleep apnea and sympathetic activity in obesity

1850 Insulin levels, sleep apnea and sympathetic activity in obesity

The sympathetic system and hypertension

Measurement of regional sympathetic activity in lean essential hypertension patients using electrophysiologic (sympathetic nerve recording) and neurochemical (measurement of norepinephrine spillover) techniques demonstrates activation of sympathetic outflow to the heart, kidneys, and skeletal muscle vasculature in younger (< 45 years) patients. The increase in sympathetic activity is a mechanism for both initiating and sustaining the blood pressure elevation. Sympathetic nervous activation also confers specific cardiovascular risk. Stimulation of the sympathetic nerves to the heart promotes the development of left ventricular hypertrophy and contributes to the genesis of ventricular arrhythmias and sudden death. Sympathetically mediated vasoconstriction in skeletal muscle vascular beds reduces the uptake of glucose by muscle, and is thus a basis for insulin resistance and consequent hyperinsulinemia. Understanding the neural pathophysiology of obesity-related hypertension has been more difficult. In normotensive obesity, renal sympathetic tone is doubled, but cardiac norepinephrine spillover (a measure of sympathetic activity in the heart) is only 50% of normal. In obesity-related hypertension, there is a comparable elevation of renal norepinephrine spillover, but without suppression of cardiac sympathetics, as here cardiac norepinephrine spillover is more than double that of normotensive obese and 25% higher than in healthy volunteers. Increased renal sympathetic activity in obesity may be a necessary cause for the development of hypertension (predisposing to hypertension development), but apparently is not a sufficient cause. The discriminating feature of the obese who develop hypertension is the absence of the presumably adaptive suppression of cardiac sympathetic outflow seen in the normotensive obese. The sympathetic nervous system has moved towards center stage in cardiovascular medicine. The importance of sympathetic activation in heart failure progression and mortality and in the generation of ventricular arrhythmias is now well established. In essential hypertension also, although the mechanism differs somewhat between the lean and obese, the sympathetic nervous system is a key factor in the genesis of the disorder, and additionally promotes the development of complications. Through their central inhibition of sympathetic nervous activity, I 1 agents such as rilmenidine powerfully reduce sympathetic nervous activity in essential hypertension patients, lowering blood pressure, and carrying the potential for specific cardiovascular protection.

Sympathetic nervous system activation in essential hypertension, cardiac failure and psychosomatic heart disease.

Regional sympathetic activity can be studied in humans using electrophysiological methods measuring sympathetic nerve firing rates and neurochemical techniques providing quantification of noradrenaline spillover to plasma from sympathetic nerves in individual organs. Essential hypertension: Such measurements in patients with essential hypertension disclose activation of the sympathetic outflows to skeletal muscle blood vessels, the heart and kidneys, particularly in younger patients. This sympathetic activation, in addition to underpinning the blood pressure elevation, most likely also contributes to left ventricular hypertrophy, and to the commonly associated metabolic abnormalities of insulin resistance and hyperlipidaemia. Antihypertensive drugs, such as moxonidine, which act primarily by inhibiting the sympathetic nervous system, should have additional clinical benefits beyond those attributable to blood pressure reduction, in protecting against hypertensive complications. Obesity-related hypertension: Understanding the neural pathophysiology of hypertension in the obese has been difficult. In normotensive obesity, renal sympathetic tone is doubled, but cardiac noradrenaline spillover (a measure of sympathetic activity in the heart) is only 50% of normal. In obesity-related hypertension, there is a comparable elevation of renal noradrenaline spillover, but without suppression of cardiac sympathetics (cardiac sympathetic activity being more than double that of normotensive obese and 25% higher than in healthy volunteers). Increased renal sympathetic activity in obesity may be a 'necessary' cause for the development of hypertension (and predisposes to hypertension development), but apparently is not a 'sufficient' cause. The discriminating feature of the obese who develop hypertension is the absence of the adaptive suppression of cardiac sympathetic tone seen in the normotensive obese. Heart failure: In cardiac failure, the sympathetic nerves of the heart are preferentially stimulated. Noradrenaline release from the failing heart at rest in untreated patients is increased as much as 50-fold, similar to the level seen in the healthy heart during near-maximal exercise. Activation of the cardiac sympathetic outflow provides adrenergic support to the failing myocardium, but at a cost of arrhythmia development and progressive myocardial deterioration. Psychosomatic heart disease: No more than 50% of clinical coronary heart disease is explicable in terms of classical cardiac risk factors. There is gathering evidence that psychological abnormalities, particularly depressive illness, anxiety states, including panic disorder and mental stress, are involved here, 'triggering' clinical cardiovascular events, and possibly also contributing to atherosclerosis development. The mechanisms of increased cardiac risk attributable to mental stress and psychiatric illness are not entirely clear, but activation of the sympathetic nervous system seems to be of prime importance.

Neural mechanisms in human obesity-related hypertension.

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. 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. 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. 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.

Cardiovascular consequences of obesity: role of leptin.

1. Several mechanisms have been implicated in the association between obesity and hypertension, including salt-sensitivity, insulin resistance and sympathetic activation. Obese animals and humans exhibit exaggerated blood pressure responses to increases in salt intake. 2. Although insulin resistance is common in obesity, it is clear that abnormal insulin action is not the sole or sufficient cause of hypertension in obesity. Obesity is associated with increased activity of the sympathetic nervous system. Sympathetic blockade has been reported to attenuate sodium retention and hypertension in experimental models of obesity. 3. The mediators responsible for salt sensitivity, insulin resistance and sympathetic activation in obesity remain unclear. 4. The novel protein hormone leptin is produced almost exclusively by adipose tissue and acts in the central nervous system through a specific receptor and multiple neuropeptide pathways to decrease appetite and increase energy expenditure. 5. Increasing evidence suggests that leptin may have wider actions influencing autonomic, cardiovascular, renal and endocrine function. We have shown that leptin increases sympathetic nerve activity to kidney, hindlimb and adrenal gland, in addition to brown adipose tissue. 6. Despite this sympathoexcitatory action, acute systemic administration of leptin does not acutely increase arterial pressure or heart rate in anaesthetized animals. This may reflect opposing antihypertensive actions of leptin. For example, leptin increases renal sodium and water excretion, apparently through a direct tubular action. In addition, leptin increases systemic insulin sensitivity, even in the absence of weight loss. 7. In conclusion, leptin may act as a mediator linking body adiposity with changes in insulin action, sympathetic neural outflow and renal sodium excretion. Alterations in leptin generation or action may, in part, underlie the sympathetic, endocrine and renal consequences of obesity.