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Symposium Report |
1 Howard Florey Institute2 Department of Physiology, University of Melbourne, Victoria 3010, Australia 3 Department of Physiology, Monash University, Victoria 3800, Australia
Abstract
Leptin, a peptide hormone normally associated with body weight homeostasis, is implicated in the generation of obesity-induced hypertension. Administration of leptin increases sympathetic nerve activity and blood pressure; however, the neural circuity involved in this pressor effect is not clearly defined. In this review we describe experiments in which pseudorabies virus was injected into the heart, kidney and the vasculature within skeletal muscle to reveal the distribution of neurones in the hypothalamus that project to these cardiovascular tissues. This distribution is compared to the well-documented distribution of leptin receptors. Finally we discuss microinjection studies designed to examine the effect of leptin, in these regions, on sympathetic nerve discharge and arterial blood pressure. Leptin injected directly into the ventromedial hypothalamus, arcuate nucleus and lateral hypothalamic area (particularly the perifornical area) increased lumbar sympathetic nerve activity. In addition, microinjection into the ventromedial hypothalamus and parvocellular paraventricular nucleus increased blood pressure. Our results demonstrate a discrete set of hypothalamic pathways that may underlie the involvement of leptin in obesity-induced hypertension.
(Received 6 July 2005;
accepted after revision 29 July 2005; first published online 16 August 2005)
Corresponding author A. Allen: Department of Physiology, University of Melbourne, Victoria 3010, Australia. Email: a.allen{at}unimelb.edu.au
The obese (ob) gene product, leptin, is a 16-kDa peptide hormone produced predominantly by white adipocytes that regulates appetite and energy expenditure through its actions on receptors in the central nervous system. Leptin has also been shown to play a role in blood pressure regulation. Studies in humans have shown that a positive correlation exists between circulating levels of leptin and blood pressure, where hypertensive subjects were found to have higher levels of serum leptin than their normotensive counterparts (Agata et al. 1997; Hirose et al. 1998; Suter et al. 1998). Increases in plasma leptin levels are also strongly associated with increases in body weight due to the elevation of body fat mass which enhances the expression of the leptin gene in adipose tissue (Maffei et al. 1995; Considine et al. 1996). Hence, leptin has been postulated to play a primary role in obesity hypertension.
In animal models, the over-expression of leptin, as seen in the transgenic skinny mouse, is associated with a sympathetically mediated hypertension (Ogawa et al. 1999; Aizawa-Abe et al. 2000). In contrast, obese (ob/ob) mice that do not produce leptin (Zhang et al. 1994) exhibit diminished sympathetic nerve activity (Young & Landsberg, 1983) and have significantly lower mean arterial pressure than their lean counterparts (Mark et al. 1999), supporting a correlation with leptin per se rather than being overweight. The role of leptin in cardiovascular control is further highlighted by experiments showing that chronic or acute leptin administration increases blood pressure, heart rate and sympathetic nerve discharge (SND) in normal (Collins et al. 1996; Dunbar et al. 1997; Haynes et al. 1997; Shek et al. 1998) and fasted (Casto et al. 1998) rats. While the underlying aetiology of the action of leptin on blood pressure is unclear, the final common pathways seem to involve the sympathetic nervous system.
Human obesity is characterized by a marked sympathetic activation (Grassi et al. 1998; Rumantir et al. 1999). Plasma noradrenaline (norepinephrine) concentration is higher in obese subjects compared with their non-obese counterparts (Sowers et al. 1982; Tuck et al. 1983; Maxwell et al. 1994). Weight gain in humans increases the activity of the sympathetic nervous system and decreases parasympathetic nervous system activity and the converse is observed with weight loss (Aronne et al. 1995). This activation of the sympathetic outflow is preferentially directed to certain vascular beds, including the kidneys (Rumantir et al. 1999; Esler et al. 2001), skeletal muscle (Grassi et al. 1995; Jones et al. 1997) and heart (Rumantir et al. 1999).
Thus, a considerable body of evidence from humans and experimental animals points to an association between obesity, leptin, sympathetic overactivity and hypertension. However, to date, the regions of the central nervous system responsible for the sympatho-excitatory effect of leptin have not been systematically studied.
Distribution of leptin receptors in hypothalamus
The distribution of the leptin receptor (ObR) located primarily in the hypothalamus has been described using immunohistochemistry (Hakansson et al. 1998; Shioda et al. 1998) and in situ hybridization histochemistry (Elmquist et al. 1998) in the rat, and has been found to closely parallel that described in humans (Couce et al. 1997).
It is becoming increasingly evident that the distribution of leptin receptor subtype b (ObRb) defined in many studies using antisera raised against C terminal epitopes of the peptide (e.g. Hakansson et al. 1998), is slightly at odds with that arising from descriptions of ObRb mRNA (e.g. Elmquist et al. 1998). These differences are primarily related to the immunocytochemical labelling of ObRb in the magnocellular paraventricular and supraoptic nuclei, sites that do not express ObRb mRNA. Such discrepancies are sometimes cited as a reason to call into question the nature of the entire distribution of ObR as identified with antisera raised against the receptor. We have recently sought to test the validity of the immunocytochemical labelling of ObRb using a commercial antibody (Ob-R (m-18), sc-1834, Santa Cruz Biotechnology, CA, USA) which has been used extensively in studies of the hypothalamus (e.g. Horvath et al. 1999; Ellacort et al. 2002). This was applied to hypothalamic sections of mice with a large DNA deletion resulting in a complete lack of all isoforms of the ObR (Leprdb-rlpy, The Jackson Laboratory, Bar Harbour, ME, USA). Using this antibody, pericellular labelling was present in neurones throughout the hypothalamus in regions thought to contain the receptor on the basis of previous imunocytochemical evidence (Fig. 1). This is despite clear evidence that the receptor was not present in these mice (Kim et al. 2003). These data focus attention on the growing concern about specificity of widely used antibodies raised against the ObR. However, they do not explain the tantalisingly close correspondence (with the few exceptions noted above) between distribution patterns of the putative receptor, identified with immunocytochemistry, and its mRNA using in situ hybridization histochemistry. It is the latter that is acknowledged as the most reliable indicator of ObR distribution.
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Leptin receptors in neural pathways influencing blood pressure
To define the distribution of sympathetic efferent pathways that correspond to sites expressing ObR we performed a retrograde tracing study using the transynaptic tracer, pseudorabies virus. All experimental procedures were approved by the Howard Florey Institute and Australian Animal Health Laboratories Animal Experimentation Ethics Committee and performed in accordance with the Australian National Health and Medical Research ‘Code of Practice for the Care and Use of Animals for Scientific Purposes’. Rats were obtained from the Animal Resource Centre (Canning Vale, Western Australia, Australia). For injections, male Sprague-Dawley rats (200–300 g) were anaesthetized with sodium pentobarbitone (60 mg kg–1 I.P.) and administered an analgesic (buprenorphin, 0.1 ng kg–1, I.M.) for pain relief. Detailed information regarding the neurotropic virus used in these tracing studies, the Bartha strain of pseudorabies, have been published elsewhere (Card et al. 1990, 1992). It has been used by us extensively and by many other groups as a neuroanatomical tool to map chains of synaptically connected neurones (Strack et al. 1989; Strack & Loewy, 1990; Sly et al. 1999; Oldfield et al. 2002). Microinjections of the virus were made into the left ventricular myocardium, the left kidney or the left adductor brevis (a hindlimb skeletal muscle). Rats were allowed to survive for sufficient time (3–4 days) to detect the passage of virus into hypothalamic neurones. While deeply anaesthetized with sodium pentobarbitone (Nembutal, 100 mg kg–1), rats were perfused with 4% paraformaldehyde. Brains were then processed for immunohistochemical detection of the virus (Sly et al. 1999; Oldfield et al. 2002).
The temporal and spatial distribution of viral labelling in the hypothalamus was qualitatively similar following inoculation of the three sites. Three days after inoculation of the heart, kidney or skeletal muscle, virally infected neurones first appeared in the anterior parvocellular and dorsal parvocellular parts and both the ventral and dorsal zones of the medial parvocellular PVN (Fig. 2A). At this time point, which coincided with first appearance of labelled neurones in the PVN, a small number of virally infected neurones were also detected in the LHA. Four days after inoculation, a larger number of virally infected neurones were present in the PVN and the LHA with many of the latter concentrated in the perifornical region (Fig. 2B). Virally infected neurones were also present in the retrochiasmatic nucleus at this stage. Virally infected neurones in the VMH and ARH appear late on the fourth day, always subsequent to the labelling described above.
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Blood pressure and sympathetic responses to intrahypothalamic microinjection of leptin
Sympathetic nerve activity and blood pressure have been shown to be elevated by intracerebroventricular or intravenous administration of leptin (Dunbar et al. 1997; Haynes et al. 1997; Shek et al. 1998). In order to assess whether leptin might activate receptors in specific brain regions to modulate sympathetic vasomotor activity, microinjection experiments were performed in isoflurane-anaesthetized (2–2.4% in oxygen) Sprague-Dawley rats. All experiments were approved by the Howard Florey Institute Animal Experimentation Ethics Committee. Rats were prepared for recording blood pressure and lumbar SND, as described in detail previously (Allen et al. 1993; Allen, 2001). Microinjections of recombinant murine leptin (100 ng in 100 nl) were made into the VMH, ARH, LHA and PVN. The injectate contained 1% rhodamine-labelled microsphere to enable anatomical verification of injection sites. Sites for microinjection, such as the LHA and PVN were chosen because the anatomical maps showed that these nuclei contained a high percentage of neurones in regions expressing leptin receptors that were directed to cardiovascular tissues. Similarly, microinjections of leptin were made in the VMH and the ARH on the basis that they have high concentrations of ObR and because they are likely to be modulators of SND.
Injection of leptin into the VMH produced the largest and most consistent increases in lumbar SND (mean increase, 24 ± 10%; range, 1.2–123.3%; n = 13; P < 0.05) (Figs 3A and 4). The magnitude of the lumbar SND response to leptin in different parts of the VMH appeared to vary dependent upon its subnuclear distribution. The largest increases were produced by injections into the rostral and medial parts of the VMH (Fig. 4) whilst the increases in lumbar SND became smaller as the injections of leptin moved into the caudal area of the VMH (Fig. 4). Direct injection of leptin into the ARH (mean, 11 ± 3%; range, 2.1–29.8%; n = 9; P < 0.01; Fig. 3B) and LHA (mean +8 ± 2%; range, –19 to 37%; n = 21; P < 0.01; Fig. 3C) produced more variable changes in lumbar SND. The greatest increases in lumbar SND from injection of leptin into the LHA were consistently found when microinjections were made into the perifornical region (Fig. 4). Microinjection of leptin into the PVN produced small increases in lumbar SND (Fig. 3D). In the majority of cases, injection of leptin into the VMH, ARH, LHA and PVN did not alter heart rate significantly and produced variable changes in blood pressure which were characterized by an increase in systolic blood pressure and little or no change in diastolic blood pressure, resulting in only small changes in mean arterial pressure (see Table 1). Overall our results support those reported for changes in renal SND following microinjection of leptin into the hypothalamus (Marsh et al. 2003) and also for changes in plasma catecholamine levels following microinjection into the VMH (Satoh et al. 1999).
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Lying just ventral to the VMH is the retrochiasmatic area. This region contains sympathetic premotor neurones (Swanson & Kuypers, 1980) and a low concentration of ObR (Elmquist et al. 1998). The possibility exists that injections made more ventrally into the VMH may have activated these neurones to increase lumbar SND. Given the low ObR concentration, we did not initially target this region for leptin injections. However a previous report did demonstrate that the only spinally projecting neurones that expressed the immediate early gene product Fos in response to intravenous administration of leptin were found in the lateral ARH and directly adjacent retrochiasmatic area (RCA) (Elias et al. 1998a). This would seem at odds with the data presented in the present paper where physiological changes in SND and blood pressure are elicited from areas outside the mediobasal hypothalamus. In this respect it should be remembered that the Fos response shown by Elias and colleagues is in an area (or closely adjacent to it) with a compromised blood–brain-barrier. It may be that the activation of immediate early genes in this case reflects the ready accessibility of systemically applied leptin to this region. The lack of labelling elsewhere in the hypothalamus may be the result of a retarded or slower transfer of leptin via the saturable transport system for leptin shown to exist in areas protected by the blood–brain-barrier.
The role of the ARH in relation to blood pressure regulation is still unclear. Leptin injected into the ARH produced a small increase in lumbar SND and had no effect on blood pressure. The variable responses produced (both positive and negative) upon leptin microinjections into the LHA and the PVN may be explained by these two nuclei possessing both pressor and depressor neurones. In previous studies, electrical stimulation of the PVN produced both increases and decreases in blood pressure and sympathetic activity (Gilbey et al. 1982; Porter & Brody, 1985; Yamashita et al. 1987) presumably because of microenvironments within the nucleus. Similarly, the LHA has also been shown to possess both pressor and depressor sites (Allen & Cechetto, 1992). In general, however, leptin was found to have a pressor effect in the hypothalamus by increasing lumbar SND and blood pressure.
While trends were established as to the impact of leptin on SND in different hypothalamic nuclei, in some cases responses of variable magnitude were produced upon injection of leptin into the same area of the hypothalamus. The variability in the size of the response, which did not appear to be related to depth of anaesthesia or the size of injection (always 100 nl), may reflect differences in the exact site of injection within the nucleus. In this respect, plots of size of response versus site of injection in some cases revealed regional differences within nuclei (Fig. 4).
We have demonstrated actions of leptin in discrete hypothalamic sites that are behind the blood–brain-barrier. However, the source of leptin that acts on these receptors under physiological conditions remains unclear. The delivery of leptin into the CNS represents a crucial step in the actions of leptin. The ARH, which contains a high level of ObR expression, has a compromised blood–brain-barrier allowing large blood-derived peptides, such as leptin, access to neuronal receptors. Support for this mode of entry playing a pivotal role in the actions of leptin is derived from lesion studies. Ablation of the circumventricular organs results in a reduction in the effect of exogenous leptin on food intake and SND (Tang-Christensen et al. 1999; Haynes, 2000). However, it is well documented that leptin also crosses the blood–brain-barrier via a saturable transport system (Banks et al. 1996, 2000; Burguera et al. 2000) involving the short form of the leptin receptor (ObRa) (Chen et al. 1996; Lee et al. 1996; Kastin et al. 1999). This mode of access is consistent with the results obtained in the present study. The suggestion that leptin enters the brain by a transport system and acts directly at sites containing ObR is also supported by the observation that peripherally administered leptin causes activation of leptin–receptor signalling pathways in regions behind the blood–brain-barrier, such as in the brainstem (Hosoi et al. 2002). However, a cautious approach to these studies must be used as activation of intracellular pathways in response to systemic administration of leptin is not necessarily evidence of direct receptor-mediated activation of a specific neuronal population. It may represent a reflex response or excitation consequent to activation of an ‘upstream’ neurone.
Conclusion
In the present studies, we have shown that leptin can activate sympathetic efferent pathways via a number of discrete regions in the mediobasal hypothalamus. These regions possess neurones projecting polysynaptically to cardiovascular tissues, such as the heart and kidney, and express ObRb mRNA. This evidence, together with a well defined active transport mechanism for leptin to cross the blood–brain-barrier, supports the prospect that blood-derived leptin can act at multiple sites throughout the hypothalamus. It is likely that these pathways form part of the neural substrate underpinning obesity-induced hypertension.
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Acknowledgements
The work from the authors' laboratories described in this manuscript, was supported by the National Health and Medical Research Council of Australia and the National Heart Foundation (Australia).
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, 3.1–10; 
, 10.1–20; 
, 20.1–50, 
, 50.1 +) with each filled symbol representing excitation and open symbols representing inhibition. PVN, paraventricular nucleus; dp, dorsal parvocellular part of the PVN; mpd, medial parvocellular part of the PVN; mpv, medial parvocellular part, ventral zone of the PVN; pml, posterior magnocellular, lateral division of the PVN; lp, lateral parvocellular part of the PVN; VMHc, ventromedial nucleus, central part; VMHdm, ventromedial nucleus, dorsomedial part; VMHvl, ventromedial nucleus, ventrolateral part; LHA, lateral hypothalamic area; RCH, retrochiasmatic area; fx, fornix; III, third ventricle; ME, median eminence; ARH, arcuate nucleus.