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Symposium Report |
1 Baker Heart Research Institute, Melbourne, Australia
Abstract
Earlier ideas that sympathetic nervous system activity is low in human obesity, contributing to weight gain through absence of sympathetically mediated thermogenesis, can now be discounted. The application of sympathetic nerve recording techniques and isotope dilution methodology quantifying neurotransmitter release from sympathetic nerves has established that the sympathetic outflows to the kidneys and skeletal muscle vasculature are activated in obese humans. The cause remains unclear. The adipocyte hormone, leptin, stimulates the sympathetic nervous system in rodents, but whether this applies in humans is uncertain. Cross-sectional studies suggest a quantitative link exists between regional sympathetic nervous tone (most notably in the kidneys) and rates of leptin release, but definitive studies documenting that leptin administration activates the human sympathetic nervous system have not been done. What might be the clinical implications of these new findings? The demonstration that the suppressed sympathetic tone characterizing many experimental models of obesity does not exist in human obesity weakens the case for the use of ß3-adrenergic agonists as thermogenic agents to facilitate weight loss. Although the neurogenic character of obesity-related hypertension is now established, whether antiadrenergic antihypertensive drugs are the preferred agents for blood pressure reduction has not been adequately tested. Multiple site central venous sampling, disclosing release of leptin into the internal jugular veins, led to the demonstration that the leptin gene is also expressed in the brain, in addition to adipocytes. Brain resistance to leptin has been inferred in human obesity, given that overweight is accompanied by high plasma leptin levels. The fact that the genes for leptin and its receptors are normally expressed in the brain in human obesity, and that release of leptin from the brain is actually increased, argues against this. Brain leptin release has the potential to override the peripheral, adipocyte leptin system.
(Received 20 June 2005;
accepted after revision 29 July 2005; first published online 16 August 2005)
Corresponding author Nina Eikelis, Baker Heart Research Institute, PO Box 6492 St. Kilda Road Central, Melbourne, Vic 8003, Australia. Email: nina.eikelis{at}baker.edu.au
Obesity, a major nutritional disorder in the industrialized and ‘industrializing’ world, is considered to be a disorder of energy balance. Obesity is associated with increased risk of hypertension, heart disease and diabetes. The public perception that obesity is largely due to lack of will power and gluttony, though widely held, is unsatisfactory. Twin and adoption studies, as well as models of obesity in experimental animals now indicate that obesity results from an interaction of both genetic and environmental factors. A world-wide trend towards positive energy balance, consequent on reduced energy expenditure through lowering of levels of physical work and on increased dietary caloric intake, is expressed in individuals as weight gain to greater or lesser extents depending on genetic predisposition.
While these underlying genetic influences in human obesity remain essentially unknown, alterations in the autonomic nervous system have been suggested to be of importance. Based on findings in animal models of obesity, the sympathoadrenal system has commonly been assumed to have a determining role in obesity development, through its influence on regulation of energy expenditure. An earlier hypothesis was that sympathetic underactivity, by reducing thermogenesis, might lead to weight gain in obesity, with some experimental observations supporting this view. One example was provided by surgical lesioning of the ventromedial hypothalamus in rodents, in which obesity was due to increased appetite, but also to lowered sympathetic activity and obesity (Bray, 1986).
More recent clinical data, based on sympathetic nerve recording (microneurography) and isotope dilution-derived measurements of norepinephrine release to plasma, indicates that human obesity is accompanied by activation of the sympathetic nervous system rather than its suppression (Vaz et al. 1997; Grassi et al. 1998), thereby supporting the hypotheses attributable to Landsberg (Landsberg & Young, 1978), which envisaged sympathetic activation as an adaptive response to overeating, helping to stabilize body weight but contributing to complications of obesity such as hypertension. A large body of literature reviewed by and Young & Macdonald (1992) addressed this issue of whether sympathetic nervous system activity is changed in obesity. The studies reviewed used the methods of an earlier era, plasma and urinary norepinephrine measurements, now known to be of limited validity (Esler et al. 1990), which perhaps explains why at the time of that review (Young & Macdonald, 1992) the consensus view was that sympathetic nervous and adrenal medullary activity is commonly reduced in human obesity.
Mutations in the ob/ob gene in the mouse result in obesity and diabetes, a syndrome resembling human obesity. The cloning of the ob/ob gene indicated that it encodes a hormone, called leptin, that is expressed primarily in adipose tissue (Zhang et al. 1994), and at lower levels in placenta (Masuzaki et al. 1997), stomach (Bado et al. 1998), the brain (Esler et al. 1998; Morash et al. 1999; Eikelis et al. 2004) and the heart (Purdham et al. 2004). Early studies suggested that leptin might be an afferent signal in a negative feedback loop registering the size of the adipose mass. The plasma levels of leptin are highly correlated with fat mass and body weight. Leptin levels are increased in obese humans (Jequier, 2002). This increase in plasma leptin levels in human obesity suggests that the obesity may be the result of leptin resistance, an issue we will return to later in this review.
Sympathetic nervous system activity in human obesity
Clinical measurements of rates of sympathetic nerve firing by clinical neurography (Grassi & Esler, 1999) and of norepinephrine release from sympathetic nerves to plasma (Vaz et al. 1997) provide the most secure methods for assessing regional sympathetic nervous function in humans (Grassi & Esler, 1999). Clinical microneurography can record nerve firing rates in subcutaneous sympathetic nerves distributed to skin and skeletal muscles. Microneurography, however, does not give access to the sympathetic nerves of internal organs, which may be more relevant to thermogenesis and to obesity complications. The activity of sympathetic nerves innervating internal organs such as the kidneys and heart can be estimated, however, by measuring norepinephrine spillover using isotope dilution methodology and sampling of blood from the venous drainages of interest, using a central venous catheter (Esler et al. 1990; Grassi & Esler, 1999).
Our published work (Vaz et al. 1997; Rumantir et al. 1999; Eikelis et al. 2004) and that of others (Narkiewicz et al. 1998; Mark et al. 1999; Purdham et al. 2004) indicates that human obesity is accompanied by activation of the sympathetic nervous system. In human obesity, the whole body norepinephrine spillover rate, which is an indication of an overall sympathetic activity, is typically normal (Vaz et al. 1997; Rumantir et al. 1999; Purdham et al. 2004). In contrast, we find that renal norepinephrine spillover, indicative of renal sympathetic activity, is approximately doubled, while cardiac sympathetic activity is reduced (Fig. 1) (Vaz et al. 1997; Rumantir et al. 1999; Purdham et al. 2004). This renal sympathetic activation appears to be a primary pathophysiological mechanism of obesity-related hypertension; that is, the hypertension is ‘neurogenic’. Even when not accompanied by the elevation in blood pressure, human obesity is characterized by sympathetic nervous activation. The higher renal and lower cardiac sympathetic nerve activity in overweight people represents a differentiation of CNS sympathetic outflow, with increased traffic in the renal sympathetic nerves and reduced cardiac sympathetic nerve firing (Fig. 2).
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Leptin kinetics in human obesity
We have tested the question of whether the hyperleptinemia of human obesity drives the sympathetic nervous activation. It is well established that plasma leptin concentrations correlate directly with the level of human adiposity. The increase in plasma leptin concentration in obesity could potentially be due to an increase in leptin synthesis, a decrease in leptin clearance or both. A number of previous studies have determined leptin plasma kinetics directly (Klein et al. 1996; Jensen et al. 1999). It is generally believed that endogenous leptin production rate is increased with increasing adiposity (Klein et al. 1996). On the other hand, there is a debate as to whether leptin elimination from plasma is affected in obesity.
Renal clearance of leptin
The role of the kidney in leptin plasma clearance in humans has been evaluated by measuring leptin levels in arterial and renal venous plasma from healthy humans and patients with varying degrees of renal insufficiency (Esler et al. 1998; Sharma & Considine, 1998). Our own observations showed a net mean extraction of leptin from plasma of 17% in passage through the kidneys (Esler et al. 1998). Sharma & Considine (1998) reported a 12% decrease of leptin across the renal circulation in healthy subjects, and that in patients with moderate renal insufficiency, leptin clearance by the kidney is markedly reduced. In experimental studies, reduced leptin clearance was noted in rats that had undergone bilateral nephrectomy (Cumin et al. 1996). Hence, in both humans and rodents, it appears that the kidney is the major site of leptin clearance.
We calculated leptin extraction across the kidneys in human obesity. Renal clearance was calculated from the fractional extraction of leptin across the kidneys, utilizing renal vein catheterization and renal plasma flow measurements. Renal extraction of leptin was calculated as the product of arterial leptin plasma concentration and renal leptin plasma clearance. Renal plasma flow was determined by measuring the plasma clearance of para-aminohippurate (Eikelis et al. 2004). Renal clearance of leptin in overweight men was similar to that in age-matched lean men, indicating that the elevated plasma leptin concentration derives entirely from increased rates of release of leptin to plasma (Eikelis et al. 2004).
Our results are in line with the previous report by Klein et al. (1996) who reported that the rate of leptin clearance from plasma and plasma leptin half-life was unrelated to adiposity. On the other hand, a recent study by Wong et al. (2004) found that leptin elimination tends to be slower with increased adiposity. The later study, however, used peripheral vein sampling for the measurements of serum leptin levels after leptin administration. The discrepancy between the results perhaps reflect the differences in the methodologies used, as well as the subject population. On balance, a combination of greater leptin production per unit of body fat and increased production from expanded total body fat mass, rather than alterations in leptin clearance, seem to account for the increase in plasma leptin concentrations observed in obesity.
Leptin receptor messenger RNA is highly expressed in the kidney, suggesting that leptin transport across the kidney is an important step for tissue uptake and catabolism. Leptin receptor mRNA is also expressed in the lung, the splanchnic bed (liver, spleen, and small intestine) and skeletal muscle (Jensen et al. 1999). An importance of nonrenal tissues in leptin metabolism, however, has not been established. The study by Jensen et al. (1999) aimed to evaluate the importance of nonrenal beds in leptin clearance. While the results of that study confirmed the importance of kidney in leptin clearance, no evidence was found for material pulmonary or splanchnic leptin uptake.
Regional release of leptin to plasma
We used simultaneous arterio-venous blood sampling to test for leptin release to plasma from individual organs, specifically the brain, heart, liver and forearm (Fig. 3) (Esler et al. 1998; Eikelis et al. 2004). Central venous catheterization and measurement of regional plasma flows was performed using our well-established techniques (Esler et al. 1990). Surprisingly there was no leptin overflow into the coronary sinus of the heart despite our previous observation of leptin expression in the human myocardium (Wiesner et al. 2000; Eikelis et al. 2004). Even more unexpected was our finding that there was no net release of leptin into the hepatic vein (Eikelis et al. 2004), it being thought that there would be substantial leptin release from omental adipose tissue. It is possible that leptin released from omental adipose tissue might have been cleared from plasma during passage through the liver. On the other hand, the concentration of leptin was higher in internal jugular venous than arterial plasma in healthy people (Esler et al. 1998; Wiesner et al. 1999; Eikelis et al. 2004).
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Alternative explanations for the observed step-up in trans-cerebral plasma leptin concentration other than lepin release from the brain, such as addition of leptin to jugular venous drainage by brain-associated adipocytes, are unlikely. The proportion of plasma leptin deriving from brain leptin release into the jugular veins was surprisingly large (Eikelis et al. 2004) (Fig. 3). At steady-state, whole-body leptin production was taken to equal the renal extraction of leptin (Fig. 3). Based on this value for whole-body leptin secretion, with subtraction of regional leptin fluxes across the brain, heart and hepatomesenteric circulation, a maximum value for adipocyte-derived leptin release to plasma was estimated (Fig. 3) (Eikelis et al. 2004). This figure relies on the assumption that inputs to plasma from the lungs, skeletal muscle and the urogenital system are small and can be discounted, which appears to be true (Esler et al. 1998; Jensen et al. 1999).
Links between whole-body leptin secretion and sympathetic nervous activity
Leptin and the sympathoadrenal system appear to be intimately linked. It has been suggested that there may be a two-way interaction between leptin and the sympathetic nervous system, perhaps constituting a regulatory feedback loop, with leptin acting within the hypothalamus to cause activation of central sympathetic outflow and stimulation of adrenal medullary release of epinephrine (Elmquist et al. 1998b), and conversely, with the sympathetic nervous system inhibiting leptin release from white adipose tissue (Trayhurn et al. 1998). Our own findings in humans, however, do not support the proposition that the sympathetic nervous system inhibits leptin release (Eikelis et al. 2003).
While increases in sympathetic outflow to the kidneys, adipose tissue and skeletal muscles following leptin administration have been well documented in animals (Dunbar et al. 1997; Matsumura et al. 2000), the effect of leptin infusions in humans has not been definitively studied to date. When we evaluated whether an association might exist between regional sympathetic activity and the whole-body leptin secretion rate, we found that of measures of sympathoadrenal function tested, only total and renal norepinephrine spillover rates correlated with leptin secretion rate (Fig. 4) (Eikelis et al. 2004). This suggests but certainly does not prove that hyperleptinemia may be the prime mover underlying the sympathetic nervous activation present in human obesity, and particularly in the sympathetic outflow to the kidneys. The whole-body leptin secretion rate was unrelated to cardiac norepinephrine spillover or to the secretion of adrenaline.
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While leptin is released primarily from adipose tissue, there has been a recent shift of opinion which recognizes that leptin is also expressed in other sites. We used simultaneous arterial and internal jugular venous blood sampling to test whether uptake of leptin by the brain might be reduced in human obesity, and provide a basis for leptin resistance (Esler et al. 1998). As mentioned above, we found that the concentration of leptin was actually higher in internal jugular venous than arterial plasma (Fig. 5) (Esler et al. 1998; Wiesner et al. 1999; Eikelis et al. 2004), suggesting that leptin is released from the brain to plasma. The sampling from the internal jugular vein was performed high up at the base of the brain to exclude the possibility of sampling facial venous drainage. The proportion of leptin derived from the brain was surprisingly high (40%). We demonstrated that leptin release from the brain is influenced by gender, being higher in women and adiposity (Wiesner et al. 1999; Eikelis et al. 2004). The notion that leptin resistance in human obesity is associated with a failure of leptin to enter the brain now seems untenable, given this evidence of leptin production by the brain itself (Table 1).
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Brain leptin resistance
While injections of leptin were found to rapidly induce weight loss in ob/ob mice (Halaas et al. 1995), earlier enthusiasm that leptin or a synthetic leptin agonist might have value as an antiobesity drug has waned. Typical obese humans and animals are hyperleptinemic and resistant to exogenous leptin administration. Clinical trials utilizing parenteral administration of leptin in human obesity have been unsuccessful. The concept that leptin resistance exists in obesity is almost as old as the discovery of leptin itself. The observation that in humans plasma leptin levels and body weight are closely linked suggested that perhaps leptin may lose its anorexic effects as its plasma concentration rises (Maffei et al. 1995). It has proven easy to induce leptin resistance experimentally. An early study demonstrated experimentally that substantially more leptin needed to be administered to diet-induced obese mice to cause significant feeding inhibition and loss of body weight than was required for a comparable effect in their lean, standard chow-fed counterparts (Campfield et al. 1995). In this regard it may well be that in experimental obesity brain leptin resistance is selective, such that the effects of leptin on appetite and thermogenesis are inhibited, while the effects on sympathetic activity, including that in the kidneys is preserved (Mark et al. 1999). This issue of selective resistance to leptin is discussed in an accompanying paper in this symposium (Haynes, 2005).
Since several obese leptin-resistance animal models respond better to central as opposed to peripheral leptin administration, it has been suggested that leptin resistance resides at the level of the blood–brain barrier. In other words, the inability of leptin to reach its target in the hypothalamus has been seen as the cause of leptin resistance. The biological processes hypothesized to underly leptin resistance include greater leptin binding to blood-borne proteins (one of which is the soluble leptin receptor), diminished transport of leptin into the brain, lowered brain leptin receptor expression levels, and reductions in leptin-receptor second messenger responsiveness (Ahima & Flier, 2000). Plasma protein binding of leptin actually decreases with increasing obesity, rendering this possibility unlikely (Houseknecht et al. 1996). Several studies have now documented relatively reduced levels of CSF leptin in obese humans (Schwartz et al. 1996). Furthermore, there are two reports of decreased blood–brain capillary leptin transport in rat models of obesity (Matsumura et al. 2000; Banks & Farrell, 2003).
When we examined leptin uptake by the brain directly by simultaneously measuring leptin concentrations in arterial and internal jugular venous plasma we found a net efflux of leptin from the brain (Wiesner et al. 1999; Eikelis et al. 2004). Even more surprising was the observation that leptin release was greater in overweight than lean men. Furthermore, we have also demonstrated the presence of leptin protein in human cadaver hypothalami, at levels which are undiminished in obesity, although whether this is derived primarily from CNS leptin production or from leptin uptake from plasma is uncertain. We have also been able to detect leptin expression in the human hypothalamus (Fig. 6) (our unpublished observations).
One suggested mechanism of leptin resistance is the presence of leptin receptor defects, of several possible types. Some isoforms of the leptin receptor are spliced abnormally and do not result in appropriate signal transduction. Splicing abnormalities can also produce lowered levels of functional receptors. In fa/fa Zucker rats there is a missense mutation in the leptin receptor (Phillips et al. 1996). This mutation causes obesity, despite the fact that the expression of the leptin gene is significantly augmented. We have been unable to show that reduced leptin receptor expression in human hypothalami accompanies obesity, across a wide range of body mass index (BMI) values (Fig. 6).
Several mutations in the human leptin receptor gene that result in a truncated receptor unable to activate the signal transduction pathway have been described (Lahlou et al. 2000). These mutations result in early onset obesity, and do suggest an importance of leptin in body weight regulation in humans. Such mutations in the leptin receptor gene, however, are very rare (Lahlou et al. 2000), and contribute very little to the current obesity ‘epidemic’.
Since most cases of human obesity are not associated with low plasma leptin levels or mutated leptin receptors, a defect could, perhaps, lie in the signalling cascade. Recently SOCS-3 (suppressor of cytokine signalling 3) has been demonstrated to play a role in leptin resistance (Bjorbaek et al. 1999). SOCS proteins are negative regulators of the JAK/STAT signalling pathways. It has been shown experimentally that injection of leptin stimulates the production of SOCS-3. The signalling cascade induced by leptin binding to its receptor is blocked due to SOCS-3 binding to leptin. It has been demonstrated that older rats are less sensitive to leptin administration and have an increased SOCS-3 expression compared to younger rats (Wang et al. 1996).
In summary, although several biological mechanisms have been suggested to underly leptin resistance, the existence of brain leptin resistance in human remains conjectural.
Implications for therapy
This delineating of the neural pathophysiology of human obesity has direct relevance to existing and planned drug therapies for obesity, and for the high blood pressure which often accompanies obesity.
Drug treatment of obesity
Long-term success rates in the control of obesity in the clinic are low, no better than 10%. The mainstays of nonpharmacological treatment, dietary modification with calorie restriction, and implementation of an exercise program often fail to achieve or to maintain weight loss, so that antiobesity drugs are often prescribed. Two drug classes are currently widely used, the intestinal lipase inhibitor class, which reduce fat digestion and absorption, and the centrally acting mixed norepinephrine/serotonin reuptake blockers, exemplified by sibutramine. Sibutramine acts primarily as an appetite suppressant, not as a sympathetic activating, thermogenic drug, as was thought initially.
There has been a long-held expectation that drugs of the ß3-adrenergic agonist class, through stimulation of thermogenesis, would prove to be valuable weight loss agents. This high expectation was based in part on the belief that sympathetic nervous system activity was low in human obesity, and that administration of a ß3-adrenergic agonist would ‘correct’ this. As it is now clear that human obesity is not characterized by sympathetic nervous underactivity, the logic underpinning the development of this drug class is weakened.
High hopes were also held at first for leptin, or leptin agonists. A large trial of injectable leptin failed to cause weight loss (Bell-Anderson & Bryson, 2004), perhaps attributable to ‘leptin resistance’, or to failure of leptin to have the primary role in control of adipose tissue mass in humans which would have been anticipated from studies in rodents.
Drug treatment of obesity-related hypertension
Might the findings we describe on the neural pathophysiology of obesity-related hypertension have any implications for its rational treatment? Given that sympathetic activation in obese hypertensive patients seems to contribute directly to the blood pressure elevation, is it appropriate to specifically recommend antihypertensive drugs which inhibit the sympathetic nervous system? Although this has not been established formally, using this criterion, ß-adrenergic receptor blocking drugs and drugs of the imidazoline class, which inhibit central sympathetic outflow, might perhaps be preferred antihypertensive drugs.
There are, however, additional considerations beyond specific targeting of sympathetic mediation of the hypertension. One is whether these antiadrenergic drugs impair insulin sensitivity, an important consideration in the hypertensive obese. A second is whether they are antithermogenic, and contribute to weight gain. In terms of influence on insulin sensitivity, of the three antiadrenergic drug classes the imidazolines are preferred. Imidazolines increase insulin sensitivity (Haenni & Lithell, 1999), by inhibiting sympathetic outflow to skeletal muscle blood vessels, and increasing skeletal muscle blood flow and glucose delivery to skeletal muscle, the latter being an important determinant of insulin sensitivity (Julius et al. 1992). Conversely, ß-adrenergic blockade reduces skeletal muscle blood flow and increases insulin resistance.
An antithermogenic effect is evident with ß-adrenergic blockers, which on average cause rather small (perhaps 1–2 kg) but measurable weight gain in long-term antihypertensive drug trials. Weight gain is not seen with the centrally acting imidazoline agents (Sharma et al. 2004) despite their very substantial suppression of the sympathetic nervous system (Esler et al. 2004). This is probably due to their reduction of postprandial insulin responses (Haenni & Lithell, 1999), which favours weight loss.
The ‘tailoring’ of antihypertensive therapy to pathophysiology, however, cannot be the primary therapeutic principle in hypertension, in part because knowledge of both hypertension pathophysiology and the precise mechanisms of drug action remains imperfect. Further, overriding clinical considerations commonly apply in the choice of initial therapy, such as the presence of coexisting illnesses carrying particular pharmaceutical recommendations. Whether obesity-related hypertension has a specific sensitivity to antiadrenergic drugs, in fact, has not been adequately investigated. Despite these caveats, the two nonpharmacological measures most commonly applied in the treatment of obesity-related hypertension, dietary calorie restriction and an exercise program are known to suppress sympathetic nervous system activity (O'Dea et al. 1982; Meredith et al. 1991).
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Acknowledgements
This work was supported through funding of a PhD scholarship, Australian Postgraduate Award, (to N.E.) and by a Centre of Clinical Excellence Grant to the Baker Heart Research Institute from the National Health and Medical Research Council of Australia.
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50% lower (P < 0.1). BMI, body mass index in kg m–2.
