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Leptin Is Released from the Human Brain: Influence of Adiposity and Gender¹

Baker Medical Research Institute and the Alfred Baker Medical Unit (G.W., M.V., D.K., G.J., G.L., D.W., M.E.), Alfred Hospital, Melbourne 8008; and the School of Human Nutrition and Public Health, Deakin University (G.C.), Geelong 3217, Australia; and the Department of Kinesiology and Applied Physiology, University of Colorado (D.S.), Boulder, Colorado 80509

Address all correspondence and requests for reprints to: Dr. Glen Wiesner, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail: glen{at}baker.edu.au

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Leptin, a 16-kDa circulating protein primarily derived from adipocytes, is an important factor in the regulation of appetite and energy expenditure. Using simultaneous arterio-venous blood sampling, several organs were assessed with regard to their individual roles in leptin metabolism in healthy male and female subjects constituting a range of body mass indices. Plasma leptin levels were unchanged after passage through the hepatosplanchnic and forearm circulations. In contrast, concentrations in the renal vein were consistently lower than those in the renal artery (-15%; P < 0.005), indicating net extraction, whereas the brain was observed to be a net leptin releaser. Concentrations in the internal jugular vein were significantly higher than arterial levels in lean females (change, 3.0 ± 1.2 ng/mL; P < 0.02) and in obese males (body mass index, >28 kg/m²), but not lean (change, 2.3 ± 2.3 vs. 0.1 ± 0.1 ng/mL, respectively; P < 0.05), indicating a probable influence of both gender and adiposity on brain leptin release. An attempt to grossly localize the site of brain release by using cerebral venous scans to distinguish between jugular venous drainage from cortical and subcortical brain areas revealed no region-specific secretion. These data raise the possibility that the brain is a nonadipose source of leptin. In addition, the higher level of brain release observed in females may contribute to the well documented gender differences in overall plasma leptin levels.

	Introduction

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LEPTIN, a 16-kDa peptide that circulates in plasma, is thought to be part of a feedback loop that regulates fat mass by decreasing food intake and increasing energy expenditure (1, 2, 3). Leptin is secreted principally by adipocytes, with circulating levels influenced by the degree of adiposity, gender, acute changes in energy balance (independent of changes in adiposity), and various hormones, such as insulin and glucocorticoids (4).

Prior studies have shown that plasma leptin levels strongly correlate with the amount of body fat and with body mass index (BMI) (5, 6). Initial suggestions that human obesity may be due to inadequate plasma leptin levels or leptin (ob) gene expression were discounted when it was found that ob expression and plasma leptin levels were instead proportionally greater in the obese than in their leaner counterparts (6, 7). Indeed, it is now generally thought that human obesity is a state of relative leptin resistance, with reduced leptin transport into the brain a possible causal mechanism (8, 9).

Simultaneous sampling of arterial and venous blood across a range of organs is a useful tool for examining regional flux, and hence identifying organs that release leptin to or remove leptin from plasma. Using this method, in a preliminary study we investigated in men the brain’s capacity to extract leptin from plasma to test whether this is reduced in obesity, as might be predicted by the leptin resistance model. Surprisingly, our initial findings indicated a net efflux of leptin from the brain, particularly in obese men (10). We now extend those initial observations to the influence of gender and attempt to establish the source of cerebrally released leptin.

	Subjects and Methods

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Subjects

A total of 59 subjects underwent central venous catheterization and plasma leptin sampling, yielding simultaneous arterio-venous blood samples from between 1–4 different organs. The age, gender, and BMI characteristics for these 59 subjects are given in Table 1. The operational definition of obesity was presence of a BMI greater than 28 kg/m². Subjects were healthy lean and obese (but otherwise healthy) volunteers who underwent a comprehensive medical examination before experimental testing. None were diabetic or hypertensive. All were unmedicated at the time of the study. The study was performed with the written informed consent of the volunteers and the approval of the Alfred Hospital ethics review committee.

After an overnight fast, all subjects received a standardized light breakfast (350 kCal). It is our experience that consumption of a light meal reduces the chance of vasovagal syncope during placement of central venous catheters. All subjects abstained from caffeinated beverages and cigarettes for a minimum of 12 h before testing. The study was performed with the subjects supine and at rest. A 21-gauge cannula was introduced percutaneously under local anesthesia into the brachial or radial artery of either arm for blood sampling. In the same arm, an 8.5 French gauge introducer sheath was inserted percutaneously into the median antecubital vein. Venous catheterization was then performed via this sheath in up to four different sites by maneuvering this single central catheter under direct fluoroscopic control (11, 12, 13). Correct positioning of the catheter was verified by using 2 mL radiopaque contrast medium (Omnipaque, Winthrop Pharmaceuticals, Ermington, Australia). The internal jugular venous catheter was positioned high up toward the base of the skull to avoid sampling blood from the tissues of the face.

The central venous catheter was used to sample venous blood emanating from the various organs studied. Regional blood flow was determined by thermodilution (brain), indicator dilution (kidneys, gut and liver), or plethysmography (forearm) (11, 12). Plasma samples were stored at -80 C until assayed. Plasma leptin levels were assessed by RIA (Linco Research, Inc., St. Charles, MO), with an intraassay coefficient of variation of less than 10% and a sensitivity of 0.5 ng/mL.

Cerebral venous scans

Using a radionuclide cerebral venous sinus scan (13, 14), we established the pattern of venous blood flow in 11 lean females. Specifically, we determined which internal jugular vein drained predominantly cortical brain regions (i.e. the major or dominant jugular vein) and, conversely, which drained largely subcortical regions (the minor or nondominant jugular vein; Fig. 1a). It was also possible for scans to indicate anastomoses at the confluence of the sinuses, in which case both jugular veins carried an indeterminate mixture of cortically and subcortically derived blood (termed nonlateralizing cerebral drainage). Venous scans were performed using erythrocytes labeled with technetium-99m, as first described by Callahan et al. (14). Imaging was then performed using single photon emission computed tomography (13).

View larger version (49K): [in this window] [in a new window]   Figure 1. Comparisons of cortical and subcortical leptin flux, as identified by corresponding cerebral venous sinus dynamic scans, in lean women. a, Examples of internal jugular vein blood flow types and their representative scans. RD, Right dominant; LD, left dominant; NL, nonlateralizing; C, cortical drainage; SC, subcortical drainage. b, Cortical vs. subcortical venous-arterial leptin concentration differences (nanograms per mL). c, Cortical vs. subcortical plasma leptin overflow (nanograms per min).

Data are expressed as the mean ± SEM. Wilcoxon signed rank tests were used for paired analysis of organ-specific arterial and venous plasma leptin measurements. Mann-Whitney U tests were used to compare changes in transcerebral plasma leptin concentrations between groups. Student’s t tests were used to compare the morphometric variables, i.e. age and BMI, between groups. Simple linear regression was performed for correlations relating age and BMI to plasma leptin levels. The significance level was set at P < 0.05.

Regional leptin flux was calculated as the product of the venous-arterial plasma difference and plasma flow. The proportional contribution of brain leptin overflow to the circulating pool was calculated by assuming that renal clearance is the predominant plasma clearance mechanism (10, 15) and that at steady state the total leptin production is approximately equal to leptin removal by the kidneys. An order of magnitude estimate of renal leptin removal was derived by applying our previously published (10) value for renal leptin clearance (mean, 145 mL/min). Hence, renal leptin removal (nanograms per min) = arterial concentration (nanograms per mL) x 145 mL/min. The cerebral contribution was then calculated as a fraction of the estimated total leptin plasma appearance rate.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Arterial plasma leptin concentrations ranged from 1.0–23.3 ng/mL for males (6.3 ± 0.7 ng/mL) and from 3.1–30.9 ng/mL for females (13.4 ± 2.1 ng/mL). Plasma leptin levels for the various subgroups are given in Table 1. Plasma leptin concentrations were elevated in obese males compared to those in lean males. Lean females also displayed elevated plasma leptin levels compared to lean males. Gender-specific correlations revealed strong associations between BMI and plasma leptin (r = 0.86 and 0.79 for females and males, respectively).

Leptin flux across various organs

Figure 2 shows relative leptin arterio-venous plasma concentration changes across the organs studied. Plasma leptin levels were elevated by an average 15% in passage through the brain, equating to a mean veno-arterial concentration increase of 1.4 ± 0.6 ng/mL (P < 0.01). In contrast, plasma leptin concentrations were reduced by 15% in transit through the kidneys, which equated to a mean absolute reduction of 2.0 ± 0.7 ng/mL (P < 0.005).

View larger version (31K): [in this window] [in a new window]   Figure 2. Leptin venous-arterial plasma concentration gradients across various organs. Venous concentrations are represented as a percentage of corresponding arterial values. Sample sizes for each organ are: brain, 22 males and 12 females; gut and liver, 11 males; kidneys, 13 males; and forearm, 13 males. *, P < 0.01; **, P < 0.005.

Transcerebral leptin flux and obesity

The relationship between the magnitude of brain leptin spillover to BMI in males (who represented a wide range of BMI) is presented in Fig. 3. Leptin spillovers were higher in the obese male group (BMI, >28 kg/m²) than in the lean males (451 ± 391 vs. 26 ± 21 ng/min; P < 0.05). Proportional jugular venous leptin concentration increases were 36% and 3% for the obese and lean subjects, respectively.

View larger version (19K): [in this window] [in a new window]   Figure 3. Relationship of unilateral brain leptin overflow (into jugular venous plasma) to BMI in males (n = 22). Only in obese men (BMI, >28 kg/m2) was cerebral leptin overflow evident.

Gender-specific analysis of transcerebral leptin concentration flux revealed a striking sexual difference (Fig. 4). Subjects for this comparison were restricted to lean males (n = 16; BMIm 23.6 ± 0.5 kg/m²) and lean females (n = 12; BMI, 22.2 ± 0.7 kg/m²), representing a similar range of BMI. Leptin release by the brain was significant in the lean females only (change, 3.0 ± 1.2¹ vs. 0.1 ± 0.1 ng/mL, females and males respectively; ¹, P < 0.02). For females, this concentration gradient represented a mean 22% increase.

View larger version (17K): [in this window] [in a new window]   Figure 4. Comparison of unilateral transcerebral plasma leptin concentration differences (right or left internal jugular vein) in lean males (18 observations in 16 males) and females (15 observations in 12 females). Venous-arterial concentration differences were 0.1 ± 0.1 and 3.0 ± 1.2 ng/mL for males and females, respectively. *, P < 0.02.

The radionuclide cerebral venous scans allowed determination of the dominant (largely cortical draining) and nondominant (largely subcortical draining) jugular veins in 10 lean female subjects (Fig. 1). Leptin measurements associated with scans exhibiting nonlateralizing (mixed drainage) venous flows were omitted. Comparisons of subcortical and cortical flux revealed no significant regionalization of leptin secretion, with venoarterial plasma concentration differences of 4.9 ± 2.6 and 3.1 ± 1.4 ng/mL, respectively (Fig. 1b), giving mean leptin overflows of 2020 and 1840 ng/min (Fig. 1c).

Cerebral contribution to leptin pool

Given the lack of regionalization, mean unilateral jugular leptin overflow was doubled to estimate the net cerebral release rate, and the relative contribution to the whole body leptin appearance rate was then calculated. Using the median value (to counter skewness), the proportional contribution was 13% in lean men and 41% in lean females. The scatter of values in obese males made any estimate of proportional contribution unreliable.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In agreement with other reports, arterial plasma leptin levels were found to positively correlate with the degree of adiposity, in this case measured as the BMI (5, 6), and to be higher in females for any given BMI (16, 17). Although females typically possess a greater proportion of body fat per BMI, the large differences observed are unlikely to be completely accounted for by correcting for differences in fat mass (16, 17). Indeed, the mechanism and significance of this sexual difference in systemic leptin levels remain unclear, although sex hormone differences (16, 18) and gender fat patterning and adipose expression differences (7, 19) have both been implicated.

The major findings of this study were those of extraction of plasma leptin by the kidney and release of leptin by the brain in females and obese men. Regarding renal extraction of leptin, our results agree with finding that the kidneys are a major route of disposal of leptin (15). More novel was the finding that the brain releases leptin in obese males and females. Estimates of proportional contribution by the brain to the circulating plasma leptin pool indicate a surprisingly large contribution, particularly in females.

Several possibilities exist that might explain the efflux of leptin from the brain. One is that the increased jugular venous concentrations are simply due to cerebral release of peripherally synthesized leptin after prior central nervous system uptake. Leptin injected into the ventricular space of the brain has been shown to be slowly released to the bloodstream via cerebrospinal fluid (CSF) reabsorption (20). Heightened cerebral release in females and obese men could result from either enhanced cerebral uptake of leptin (more available for removal) or from a reduced capacity of the leptin that enters the CSF to penetrate and bind to target sites, resulting in more leptin being freely available for efflux from the brain. However, enhanced cerebral uptake of leptin in obesity is unlikely, given the model of leptin resistance, which suggests that access of leptin across the blood-brain barrier is reduced. Furthermore, there is no evidence for enhanced cerebral uptake of leptin in females, as CSF leptin levels are identical to those in males despite higher serum concentrations (21).

Another possibility to explain the efflux of leptin from the brain is that the brain actually produces leptin. With a few notable exceptions, leptin has essentially been viewed as an exclusively adipose-derived product (7, 22, 23); such reports found no evidence for leptin expression in the human brain. Examples of leptin derived from nonadipose sources do exist, including production by the human placenta (24), by human mammary epithelial cells (25), by skeletal muscle after induction by glucosamine (26), and in rat stomach (27). In addition, other instances are known where the brain contributes to circulating hormones largely derived from other sources, examples being the immunoregulators interleukin-6 and tumor necrosis factor- (28) and catecholamines (29). Lending some weight to the possibility that the brain produces leptin is the magnitude of secretion observed, particularly in women. Taking into account the proportional contribution the brain makes to circulating leptin levels in women (40%), there exists a potential mechanism contributing to the elevated systemic levels characteristic of females.

Alternative explanations for the observed step-up in the plasma leptin concentration in passage through the cerebral circulation, such as contamination of the jugular venous drainage by leptin from brain-associated adipocytes, and modification of the extent to which leptin is bound to plasma proteins (30), are unlikely. Internal jugular venous catheterization and blood sampling were performed high up at the base of the brain, excluding the possibility of sampling leptin derived from facial sources. Negligible amounts of adipose tissue are in close association with the brain, being largely limited to minor intracranial adipose bodies present in the cavernous sinus (31).

The possibility that the brain produces leptin has implications for the prevailing idea of leptin resistance in obesity. It has been proposed that the primary flaw in obesity may be a reduced capacity for leptin to cross the blood-brain barrier (which excludes leptin by nature of its size), with a consequently reduced effect in the hypothalamus (8, 9). The production of leptin by the brain seemingly contradicts this idea of inaccessibility to the hypothalamus, making the idea of leptin resistance untenable. However, these seemingly opposing views can be reconciled, if the presumption is made that brain-derived leptin is directly released to plasma and does not exert a paracrine effect at the hypothalamic level.

Our attempts to locate the site of brain leptin production and release by distinguishing between internal jugular venous blood emanating from cortical and subcortical regions was of limited success. Although constrained by small sample size, no regional specific production was obvious, as indicated by the similar degrees of net leptin flux obtained for both broad anatomical divisions. Considering the central role the hypothalamus plays in weight and feeding regulation (32), it might have been expected that there would be predominantly hypothalamic release, and hence greater leptin overflow from the subcortical field of drainage, but our results do not support this.

In conclusion, leptin in plasma is cleared by the kidneys and released in part by the brain. The level of cerebral leptin release to plasma is greater in females and may contribute to the sexual differences in overall plasma leptin concentrations. Obesity in men was also associated with increased leptin release. No regionalization of brain leptin secretion was observed using jugular venous drainage as an identifier of blood emanating from regions broadly categorized as cortical and subcortical. More specific topographic techniques, involving tissue analysis of leptin expression and content in different brain regions from experimental animals and human cadavers, will be required to verify and accurately localize any sites of brain leptin production.

	Footnotes

 
¹ This work was supported by a National Health and Medical Research Council of Australia Institute grant to the Baker Medical Research Institute, and NIH Grant AG-06537 from the NIA.

² Current address: Department of Physiology, St. John’s Medical College, Bangalore 560034, India.

Received November 20, 1998.

Revised March 4, 1999.

Accepted April 1, 1999.

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