Leptin acts in the forebrain to differentially influence baroreflex control of lumbar, renal and splanchnic sympathetic nerve activity and heart rate

Abstract

While leptin is known to increase sympathetic nerve activity (SNA), we tested the hypothesis that leptin also enhances baroreflex control of SNA and HR. Using α-chloralose anesthetized male rats, mean arterial pressure (MAP), HR, lumbar SNA (LSNA), splanchnic SNA (SSNA), and renal SNA (RSNA) were recorded before and for 2 hr after lateral cerebroventricular (LV) leptin or aCSF administration. Baroreflex function was assessed using a four parameter sigmoidal fit of HR and SNA responses to slow ramp (3-5 min) changes in MAP, induced by iv infusion of nitroprusside and phenylephrine. Leptin (3 μg) increased (P<0.05) basal LSNA, SSNA, RSNA, HR and MAP, and the LSNA, SSNA, RSNA, and HR baroreflex maxima. Leptin also increased gain of baroreflex control of LSNA and RSNA, but not of SSNA or HR. The elevations in HR were eliminated by pretreatment with methscopalamine, to block parasympathetic nerve activity; however, after cardiac sympathetic blockade with atenolol, leptin still increased basal HR and MAP and the HR baroreflex maximum and minimum. Leptin (1.5 μg) also increased LSNA and enhanced LSNA baroreflex gain and maximum, but did not alter MAP, HR, or the HR baroreflex. LV aCSF had no effects. Finally, to test if leptin acts in the brainstem, leptin (3 μg) was infused into the 4^th ventricle; however, no significant changes were observed. In conclusion, leptin acts in the forebrain to differentially influence baroreflex control of LSNA, RSNA, SSNA and HR, with the latter action mediated via suppression of parasympathetic nerve activity.

INTRODUCTION

Clinical and experimental studies have shown that obesity is associated with hypertension, due at least in part to increases in sympathetic nerve activity (SNA).^1;2 Considerable effort has been directed toward identifying the underlying mechanisms. As recently reviewed^2;3 one potential candidate is leptin, a 16-kDa peptide hormone produced predominantly by white adipocytes. Acute leptin administration increases SNA to multiple organs, including brown adipose tissue, the hindlimb, adrenal gland, and kidney,³ and chronic leptin infusion produces hypertension.^2;3 In addition, leptin-deficient obese mice (ob/ob mice) fail to exhibit hypertension, despite massive obesity.^2;3

Another deleterious consequence of obesity is impaired sensitivity of the baroreceptor reflex.^4-6 Decreased baroreflex function has been identified as a risk factor for subsequent adverse cardiovascular events in humans with type 2 diabetes mellitus.⁷ However, the mechanism is unknown. While leptin has been considered,⁸ current information is conflicting. For example, monogenic forms of rodent obesity due to loss of leptin or to mutations of the leptin receptor exhibit decreased baroreflex gain,^9-12 suggesting that leptin enhances baroreflex function. Conversely, systemic administration of leptin was reported to be ineffective,¹³ and microinjection of leptin into the nucleus tractus solitarius (NTS) suppressed baroreflex control of heart rate (HR).¹⁴ Therefore, one aim of the present experiments was to further investigate if leptin influences baroreflex function. Given the well-established sympathoexcitatory effects of leptin, we hypothesized that leptin would also enhance the SNA responses to decreases in arterial pressure (i.e. baroreflex gain). A key feature of these experiments is that we compared the effects of leptin on baroreflex control of lumbar SNA (LSNA), renal SNA (RSNA), as well as splanchnic SNA (SSNA). In addition, to test if leptin influences baroreflex control of HR via changes in the activity of the sympathetic nervous system or the parasympathetic nervous system, experiments were performed to determine if the effects of leptin on the HR baroreflex were eliminated by systemic pretreatment with drugs that blocked cholinergic (methscopolamine) or beta-adrenergic (atenolol) receptors.

Leptin has been shown to increase SNA following selective microinjection into several hypothalamic nuclei^15-19 and into the NTS.^14;20 Therefore, in order to activate these multiple sites concurrently, leptin was infused via a lateral cerebral ventricle (LV). In addition, to begin to identify the sites at which leptin acts to modify baroreflex function, we compared the effects of leptin infusion via the LV, which will activate receptors in both the hypothalamus and NTS, versus the fourth ventricle (4V), to target brainstem leptin receptors.

METHODS

Animals

Forty male (320-450g) Sprague Dawley rats (Charles River Laboratories, Inc) were used for these experiments. All of the rats were acclimated for at least 1 week before experimentation in a room with a 12-hour:12-hour light/dark cycle, with food (LabDiet 5001, Richmond, IN, USA) and water provided ad libitum. All procedures were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and approved by the Institutional (Oregon Health & Science University) Animal Care and Use Committee.

Surgery

Under isoflurane anesthesia, a tracheal tube, femoral arterial and venous catheters, and a recording electrode around the lumbar, splanchnic or renal sympathetic nerve were implanted (see Supplement for details). After preparing the rat for icv infusions, a loading dose of α-chloralose (50 mg kg⁻¹; Sigma) was administered intravenously (iv) over 30 min, while isoflurane was slowly withdrawn, and this was followed by a continuous infusion of α-chloralose (25 mg kg⁻¹ h⁻¹) for the duration of the experiment. Throughout the experiment, artificial ventilation with 100% oxygen was maintained, and respiratory rate and tidal volume were adjusted to maintain expired CO₂ at 3.5-4.5%. Anesthetic depth was regularly confirmed by the lack of a pressor or withdrawal response to a foot or tail pinch. After completion of surgery and the α-chloralose loading dose, rats were allowed to stabilize for at least 60 min before experimentation.

Baroreflex function

Pulsatile and mean arterial pressures, HR and SNA were continuously recorded, and baroreflex function was assessed as previously described²¹ (see Supplement for details).Briefly, complete baroreflex curves were constructed by fitting a sigmoidal curve to the changes in HR and SNA induced by slow changes in AP following iv infusion of nitroprusside and phenylephrine. Absolute values of baroreflex gain (BRG) and the mean±SEM of other sigmoidal parameters (baroreflex maxima, minima, and midpoint) are depicted in the figures.

Intracerebroventricular infusions

With a flat skull and using bregma and the dorsal surface of the dura as zero, single-barreled glass pipettes drawn to a small tip were used for both LV and 4V infusions. Coordinates for positioning the LV cannulae were as follows (mm from bregma): 1.0 caudal, 1.4 lateral, and 4.2 dorsal. A pipette was placed into the 4V using the following coordinates (mm): 2.0 caudal to the interaural line, on the midline, and 7.3 ventral to the skull surface. Leptin (R&D Systems) was dissolved in artificial cerebrospinal fluid (aCSF) containing (in mM): 128 NaCl, 2.6 KCl, 1.3 CaCl₂, 0.9 MgCl₂, 20 NaHCO₃, 1.3 Na₂HPO₄ and 2.0 dextrose, pH 7.4. Correct pipette placement was confirmed at the end of the experiment by infusing ~ 100 nL of 2.5% Alcian blue in 0.5 mM/L of sodium acetate via the same pipette, removing the brain, and verifying the presence of dye in the cerebroventricles.

Experimental Protocols

After stabilization, basal baroreflex function was established by producing at least two baroreflex curves, 30 min apart, with similar gains; the final control curve was used for data analysis. Protocol 1: After reestablishment of basal values, LSNA and HR BRG were measured 1 and 2 hr after LV injection of a dose of leptin that has been shown to inhibit food intake when administered in conscious rats^22;23 (3 μg in 3 μL, followed by 5 μg/hr, n=5), a lower leptin dose (1.5 μg in 1.5 μL, followed by 5 μg/hr, n=5) or the aCSF vehicle (0.6 μL/min, n=5). In separate groups of rats, SSNA (n=6) or RSNA (n= 5) and HR BRG were measured after LV injection of the higher leptin dose. The HR and MAP results from the 3 groups of rats receiving the higher leptin dose were combined (n=16). Protocol 2: After establishing basal baroreflex function, either methscopolamine (1 mg/kg, n=4) or atenelol (2mg/kg hr, n=5) was administered iv, at doses previously documented to block cardiac parasympathetic and sympathetic contributions, respectively.²⁴ Thirty min later, baroreflex curves were generated to assess the effects of the blockade alone. Then, leptin was administered icv (3 μg followed by 5 μg/hr), and baroreflex function was reassessed after 1 and 2 hr. Protocol 3: After control measurements, LSNA and HR BRG were measured 1 and 2 hr after leptin (3 μg, followed by 5 μg/hr, n=5) administration into the 4V. In each protocol, basal data were taken as the average of the 30 sec period prior to each BRG measurement.

Statistical Analysis

All data are presented as means ± SEM. Between-group differences were evaluated using one- or two-way ANOVA for repeated measures and the post hoc Newman–Keuls test. P values<0.05 were considered statistically significant.

RESULTS

LV leptin administration increases gain of baroreflex control of LSNA and RSNA, but not of SSNA or HR

LV leptin (3 μg) administration increased basal LSNA and RSNA after 1 and 2 hr; the lower dose of leptin (1.5 μg) increased LSNA only at 2 hr (Figures 1, 2). In contrast, basal SSNA was not significantly elevated until 2 hr after 3 μg leptin (Figure 2). MAP and HR also increased 2 hr following leptin (3 μg) injection; however, 1.5 μg leptin did not significantly alter MAP or HR (Table 1). Basal values were not significantly changed during icv infusion of aCSF (Figure 1 and Table 1).

Figure 1. Effects of LV leptin or aCSF on baseline LSNA.

LV leptin (3 μg, n=5, top) increased basal LSNA at 1 and 2 hr, whereas the lower dose (1.5 μg, n=5) increased basal LSNA only at 2 hr (middle). aCSF (n=5) had no effects on LSNA. *P<0.05 vs CON; †P<0.05 vs aCSF at the same time.

Figure 2. Effects of LV leptin on baseline RSNA and SSNA.

LV leptin (3 μg) increased basal RSNA (n=5, top) at 1 and 2 hr, whereas SSNA (n=6, bottom) was increased only at 2 hr. *P<0.05 vs CON.

Table 1.

Effect of LV leptin and aCSF on basal MAP and HR

Variable	Control	Leptin 1 hr	Leptin 2 hr
3 μg leptin (n = 16) ‡
MAP (mmHg)	103 ± 4	106 ± 4	118 ± 5*†
HR (bpm)	328 ± 14	357 ± 16	388 ± 19*†
1.5 μg leptin (n = 5)
MAP (mmHg)	105 ± 4	102 ± 2	99 ± 2
HR (bpm)	345 ± 22	342 ± 16	355 ± 19
aCSF (n = 5)
MAP (mmHg)	102 ± 7	98 ± 7	98 ± 14
HR (bpm)	342 ± 9	355 ± 9	360 ± 5

^*P<0.05 vs Control

^†P<0.05 vs aCSF, same time.

^‡The MAP and HR results were combined from the separate sets of rats used for studies of LSNA, SSNA, and RSNA. These data were not different between groups (2 way repeated measures ANOVA, insignificant group and interaction).

Baroreflex control of LSNA, SSNA, RSNA, and HR were differentially altered by icv leptin. Leptin increased LSNA (3 and 1.5 μg doses) and RSNA BRG (Figures 3, 4); the LSNA and RSNA reflex maximum and range were also elevated (Figures 3, 4 and Supplement, Tables S1 and S2; see Figure 1S for representative experiment). On the other hand, while the SSNA maximum was elevated 1 and 2 hr after leptin, BRG was not significantly increased (Figure 4 and Supplement, Table S3). Similarly, the higher dose of leptin increased the HR reflex maximum, and BP₅₀ after 2 hr (Supplement, Table S4), without significantly altering HR BRG (Figure 5). Leptin increased the baroreflex minimum of LSNA and HR (Figures 3 and 5; Supplemental Tables S1 and S4), but not of RSNA and SSNA (Figure 4 and Supplemental Tables S2 and S3).

Figure 3. Effects of LV leptin or aCSF on baroreflex control of LSNA.

Both doses of LV leptin (1.5 and 3 μg) increased baroreflex gain, as well as the LSNA baroreflex maximum. In contrast, aCSF (n=5) had no effects on the baroreflex. *P<0.05 vs CON; †P<0.05 vs aCSF at the same time.

Figure 4. Effects of leptin on baroreflex control of RSNA and SSNA.

Leptin (LV, 3 μg) increased the RSNA (n=5; top) baroreflex maximum and gain (insert) after 1 and 2 hr. Leptin also increased the SSNA (n=6; bottom) baroreflex maximum at 1 and 2 hr, and the BP₅₀ at 2 hr (n=6, *P <0.05); however, the SSNA baroreflex gain and minimum were unchanged (top, insert). *P<0.05 vs CON.

Figure 5. Effects of LV leptin or aCSF on baroreflex control of HR.

While neither the lower dose of leptin (n=5) nor aCSF (n=5) influenced the HR baroreflex, the higher dose of leptin (top) increased the HR baroreflex maximum and minimum (n=16) without altering gain. *P<0.05 vs CON. †P<0.05 vs aCSF at the same time.

Methscopolamine blocks the effect of leptin to increase HR and alter baroreflex control of HR

Methscopolamine increased basal HR, without altering MAP; maximum and minimum baroreflex HR were increased and HR BRG was reduced (Table 2 and Figure 6). More importantly, following methscopolamine, leptin failed to alter basal MAP, HR, or influence baroreflex control of HR (Figure 6 and Supplement, Table S5). To determine if the failure of leptin to increase HR was due to a maximal elevation following methscopolamine, the β-agonist, isoproterenol (1 μg/kg) was injected iv after methscopolamine administration and 2 hr of leptin infusion. Notably, isoproterenol increased HR from 409±19 to 495±23 bpm, a value higher than the baroreflex HR maximum (446±2 bpm; P<0.05, n=3).

Table 2.

Effects of methscopolamine and atenolol on MAP and HR, before and after icv leptin (3 μg)

Variable	Control	Methscopolamine	Leptin 1 hr	Leptin 2 hr
MAP (mmHg)	118 ± 5	118 ± 4	117 ± 8	109 ± 7
HR (bpm)	355 ± 13	403 ± 4*	409 ± 8*	411 ± 7*
	Control	Atenelol	Leptin 1 hr	Leptin 2 hr
MAP (mmHg)	113 ± 5	92 ± 2*	102 ± 5*	106 ± 5†
HR (bpm)	351 ± 13	318 ± 8*	326 ± 6*	348 ± 13†

^*P<0.05 vs Control

^†P<0.05 vs atenolol.

Figure 6. Effects of leptin on the HR baroreflex were blocked by methscopolamine, but not atenolol.

Top. Methscopolamine (1mg/kg, i.v., n=4, solid gray line and circles) elevated the HR baroreflex curve, increased the HR maximum and minimum (P<0.05), but reduced the HR gain (insert, *P<0.05). However, following methscopolamine, leptin did not affect the baroreflex control of HR (dashed and dotted lines). Bottom. Atenolol (2mg/kg·hour, i.v., n=5, solid gray line and circles) depressed the HR baroreflex curve and reduced the HR maximum (P < 0.05). Following atenolol, leptin increased the HR maximum and minimum and reduced the HR gain (insert, P < 0.05). *P<0.05 vs CON; †P<0.05 vs atenolol.

Atenolol reduced basal MAP and HR and decreased the baroreflex HR maximum and the HR range (Figure 6, Table 2, and Supplement, Table S5). Following atenolol, 2 hr of leptin infusion increased basal MAP and HR and elevated the baroreflex HR maximum and minimum (Figure 6 and Supplement, Table S5). Interestingly, HR gain was reduced 2 hr after initiating the leptin infusion (Figure 6) in atenolol-treated rats.

4V leptin does not alter basal or baroreflex control of LSNA, HR and MAP

In sharp contrast to the potent effects of leptin administered via the LV, basal MAP, HR and LSNA, as well as BRG and baroreflex parameters, were not altered during 4V leptin infusion (Figure 7 and Supplement, Table S6).

Figure 7. Effects of 4V leptin (3 μg) on basal LSNA and baroreflex control of LSNA and HR.

No significant changes in basal LSNA or in baroreflex control of LSNA and HR were observed following 4V leptin (3μg) infusion.

DISCUSSION

The major goal of this study was to test the hypothesis that leptin acts centrally to enhance baroreflex control of SNA and HR and, if so, to begin to investigate the mechanisms. The important new findings are: 1) leptin increases SSNA (as well as LSNA, RSNA, HR and MAP, as previously reported¹⁹); 2) central leptin exerts differential effects on baroreflex control of LSNA, SSNA and HR; 3) the ability of leptin to increase HR and its baroreflex regulation is eliminated by pretreatment with methscopolamine, to block the parasympathetic nervous system, but not by pretreatment with atenolol, to block cardiac sympathetic effects; and 4) these actions of leptin are not observed when leptin is infused via the 4V. Collectively, these data indicate that central leptin acts in the forebrain to influence baroreflex control of SNA and HR, with the latter action mediated via suppression of cardiac parasympathetic tone.

Previous studies have demonstrated that intravenous or central leptin administration increases LSNA, RSNA, HR, and MAP;^19;25;26 our results confirm this work. A new finding, however, is that leptin also acts centrally to increase SSNA. Dunbar et al²⁶ reported that icv leptin decreases splanchnic blood flow, which contributes to its pressor effect. The increase in SSNA that we observed suggests that the sympathetic nervous system likely mediates this action. Plasma leptin levels increase after a meal.²⁷ Therefore, the central action of leptin to increase SSNA may help to maintain arterial pressure at a time when the splanchnic circulation is dilating to accept and distribute absorbed nutrients. In addition, in parallel to the actions of insulin,²⁸ meal-induced increases in leptin may contribute to enhanced baroreflex control of LSNA.

Monogenetic impairment of the actions of leptin, due either to loss of leptin or mutations of the leptin receptor, depresses the baroreflex,^9-12 suggesting that leptin may support or enhance baroreflex function. However, these rodent models exhibit obesity, and diet-induced obesity also decreases baroreflex control of HR^4;5;24 and, in one human study, SNA,²⁹ confounding this suggestion. The present study demonstrates that exogenous leptin administration differentially influences baroreflex function. Increases in baroreflex gain were observed for LSNA and RSNA, but not for SSNA or HR. However, leptin increased the baroreflex maximum and range of LSNA, RSNA, SSNA, and HR, as well as the baroreflex minimum of LSNA and HR. Previously, iv leptin was shown to increase the range and maximum of baroreflex control of RSNA in mice, without enhancing gain.¹³ Different species or routes of leptin administration may explain these divergent results.

The mechanism by which leptin differentially alters baroreflex control of various autonomic efferents was not identified, but may arise from actions of leptin at different brain sites, or within a site on distinct neurons. In support of this supposition, previous studies have demonstrated that leptin acts differentially to increase SNA at several hypothalamic sites containing leptin receptors.^16;18;19 We found that leptin increases the baroreflex minimum for LSNA and HR (but not for SSNA or RSNA; see also¹³); therefore, leptin can increase LSNA and HR even when baroreflex suppression is maximal at high pressures, suggesting that the neurocircuitry that mediates the increases in LSNA and HR is at least in part independent of, or distal to, brain baroreflex pathways. However, the finding that leptin also increases LSNA baroreflex gain suggests an additional interaction with baroreflex pathways. Thus, the brain neurons that initiate the effects of leptin on baroreflex control of different sympathetic nerves may also project to multiple sites in the brainstem and/or spinal cord.

Obesity mutes leptin’s effect to increase SNA to brown adipose tissue and LSNA, yet leptin-induced increases in RSNA are preserved or enhanced.^30;31 Since leptin increases gain of baroreflex control of LSNA, brain resistance to leptin could explain in part the decrease in muscle SNA baroreflex gain reported in obese humans compared to after weight loss.²⁹ On the other hand, because leptin does not influence SSNA baroreflex gain, its loss likely does not likely contribute to the decreased SSNA gain observed in Zucker rats.¹⁰ Indeed, Schreihofer et al¹⁰ came to the same conclusion, since they found that SSNA baroreflex gain is not impaired in juvenile Zucker rats, but only in older Zucker rats that exhibit considerable obesity.

While the ability of leptin to increase HR has been noted before,^14;18;32 the mechanism has not been directly investigated. Nevertheless, previous work has provided indirect evidence that leptin may suppress parasympathetic control of the heart. First, Arnold et al¹⁴ reported that NTS microinjection of leptin decreased spontaneous baroreflex sensitivity and the reflex bradycardia following bolus iv injections of phenylephrine, each of which reflect primarily cardiovagal activity. Second, correlations between leptin and indices of cardiac parasympathetic activity have been noted in humans.³³ Using a pharmacological approach, we directly tested this hypothesis. Administration of methscopolamine to block the parasympathetic nervous system completely prevented the ability of leptin to elevate HR and right-shift the baroreflex curve. This was not due to a HR ceiling effect, since after methscopolamine and leptin treatment, iv injection of the β-adrenergic agonist, isopreteronol, to mimic cardiac sympathoexcitation, increased HR even higher. Interestingly, methscopolamine also prevented the pressor response to LV leptin. Methscopolamine does not cross the blood-brain barrier, but it can exhibit some cholinergic nicotinic blocking activity.³⁴ Therefore, one explanation for this finding is that methscolpolamine inhibited ganglionic transmission. In support, we have found that iv methscopolamine decreases SNA and arterial pressure when administered after leptin infusion (Li, Shi, and Brooks, unpublished observations). On the other hand, in rats in which cardiac sympathetic activity was blocked with atenolol, leptin increased HR, MAP and right-shifted the baroreflex curve. Collectively, these data suggest that leptin increases HR at any given MAP by suppressing parasympathetic control of the heart. One of the hallmarks of obesity in humans and experimental animals is suppression of cardiac parasympathetic activity^4;24;35 in association with elevated leptin levels. Therefore, we speculate that leptin may contribute to impaired vagal activity during obesity. Interestingly, after atenolol, leptin infusion also markedly decreased baroreflex gain. Thus, leptin may also suppress the response of the parasympathetic nervous system to changes in arterial pressure, at least when cardiac sympathetic activity is also reduced. In humans, obesity can reduce sympathetic activity to the heart;¹ therefore, leptin may also contribute to the impaired cardiac baroreflex sensitivity that is observed.

Leptin has been shown to increase SNA and HR following microinjection into several hypothalamic nuclei (arcuate nucleus, dorsal medial hypothalamus, lateral hypothalamus, and ventromedial hypothalamus)^18;19;36 as well as the NTS.^14;20 However, as we previously found with insulin,³⁷ leptin infusion into the 4V, to restrict its actions to the hindbrain, was ineffective. The variance of our study with previous work may be explained by a failure of sufficient leptin to reach its active sites in the NTS, since at least in one report,²⁰ larger doses were used. Regardless of the explanation, our studies show that leptin can act in the forebrain to increase SSNA and influence baroreflex control of LSNA, RSNA, SSNA, and HR. As discussed, in view of the variable effects on baroreflex control of SNA and HR that were observed, more than one site may be involved.

While the results of this study clearly demonstrate a differential effect of leptin on baroreflex function, there are several limitations that must be considered. First, the experiments were performed in anesthetized rats. While we acknowledge that it will be important to repeat these experiments in conscious animals, it is noteworthy that α-chloralose was chosen as the anesthetic, because baroreflex function is relatively preserved. Indeed, the values of LSNA baroreflex gain measured in the present study are essentially identical to values obtained in conscious rats.^38;39 Second, the concentrations of leptin achieved in the CSF were certainly supraphysiological. However, high doses are required to establish a significant diffusion gradient, since as a large peptide only limited amounts of leptin penetrate brain from the CSF and only very slowly.⁴⁰ The fact that the stimulatory effects of leptin on LSNA in the present study were related more to the initial bolus dose than to the total infused amount supports this contention. Importantly, in rats, iv infusion of doses that increase plasma leptin within the physiological-pathophysiological range increase SNA similarly to the present study,²⁵ strongly suggesting that such levels of plasma leptin would also enhance baroreflex control. Third, the short-term effects of leptin that we observed may underestimate the potency of long-term elevations. In support, in agreement with previous work,^16;25 we found that the SNA responses to LV leptin are slowly developing and may not have peaked within our two hr study period. Moreover, chronic intracerebroventricular infusion of significantly lower doses of leptin are sufficient to elevate arterial pressure and suppress food intake.⁴¹

Perspectives

In both humans and animals, elevations in plasma leptin occur soon after beginning a high fat diet and accruing excess adiposity, in association with activation of the sympathetic nervous system.^42-44 Thus, the hypothesis that increased leptin contributes to obesity-induced sympathoexcitation has received considerable attention.^2;3 Another hallmark of obesity is depressed basal parasympathetic nerve activity and impaired HR baroreflex function, which also rapidly develops.^4-6;24;35;44 The present results suggest that leptin may also contribute to these cardiovascular consequences. On the other hand, in obese humans, baroreflex control of muscle SNA has been reported to be depressed^29;45 or preserved.^46;47 Therefore, if leptin is involved in SNA baroreflex impairment, then the factor(s) that reduce brain sensitivity to leptin’s action to enhance BRG must vary among individuals. Future experiments are required to identify the factors that modify sensitivity of the brain to leptin and to determine whether and how the impact of these factors varies among obese individuals.

NOVELTY AND SIGNIFICANCE.

What is new?

• Leptin acts in the brain to increase SSNA.

• Leptin increases LSNA and RSNA baroreflex gain (but not gain of baroreflex control of SSNA or HR) and increases LSNA, SSNA, RSNA, and HR baroreflex maxima and range.

• Leptin increases HR via suppression of parasympathetic nerve activity.

• Leptin exerts these effects via an action in the forebrain.

What is relevant?

• Obesity increases leptin. Therefore, leptin may contribute to the suppression of basal and baroreflex-mediated changes in parasympathetic nerve activity commonly observed in obese individuals and identified as a risk factor for adverse cardiovascular events.

• After a meal, like insulin, increases in leptin may contribute to enhanced LSNA baroreflex gain and may counteract splanchnic vasodilation via increases in SSNA.

Summary

Leptin acts in the forebrain to differentially influence baroreflex control of LSNA, SSNA, RSNA, and HR, with the latter action mediated via suppression of parasympathetic nerve activity