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Department of Neurological Surgery (B.V.Z., S.J., W.M., S.S., S.V.), University of Southern California School of Medicine, Los Angeles, California 90033; Amgen, Inc. (C.F.L.), Thousand Oaks, California 91320
Address all correspondence and requests for reprints to: Berislav V. Zlokovic, M.D., 2025 Zonal Avenue RMR 506, Los Angeles, California 90033. E-mail: zlokovic{at}hsc.usc.edu
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Introduction |
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Recent studies indicate that leptin may have widespread actions in the central nervous system (CNS) (16, 17). The primary site of its action is thought to involve hypothalamic nuclei associated with the control of feeding and energy expenditure (18, 19). The receptors for leptin were also found in thalamic and amygdaloid nuclei and cortical neurons (19, 20). Little is known about leptin entry into the CNS. The blood-cerebrospinal fluid (CSF) barrier at the choroid plexus and the blood-brain barrier (BBB) at the cerebral endothelium are two major controlling sites for the entry of proteins into the brain (21, 22, 23, 24). Relative contributions of these two CNS transport pathways in maintaining leptin CNS homeostasis, and its access to the hypothalamic and/or other CNS targets are not known. Low uptake of leptin across the murine BBB (25) and restricted transport into the CSF in humans (26) have been reported.
It has been speculated that leptin receptors in the choroid plexus (27, 28, 29, 30) and at the BBB (31, 32, 33) may serve to transport leptin in the CNS. Recent work in transfected cells, however, indicated that all known leptin receptor isoforms are linked to intracellular signaling, but none to the transcytosis across the blood-CSF barrier and/or across the BBB (34, 35, 36). Thus, the physiological significance of potential CNS/CSF transport pathways and the mechanisms involved in leptin transport at different CNS homeostatic sites remain unclear. The present study used an in situ brain perfusion model (21) to determine simultaneously the rates of leptin transport across the blood-CSF barrier, into the hypothalamus and at the BBB, and to define the kinetic properties of putative leptin transporters and/or receptors at the luminal side of the BBB and the basolateral side of the choroid plexus epithelium. This technique has been used extensively in CNS/CSF transport studies of several peptides and proteins (21, 22, 37).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In situ brain perfusion technique
An established in situ brain/choroid plexus perfusion
technique was used for the measurement of leptin uptake in lean, normal
rats (21). This method allows direct measurements of leptin CNS/CSF
uptake under conditions where arterial inflow was controlled and the
concentration of leptin in the perfusate clamped. Briefly, the rats
were anesthetized (Nembutal, 50 mg/kg ip) and the right common carotid
artery isolated and connected to an extracorporeal perfusion circuit.
The perfusion medium consisted of 20% sheep red blood cells (oxygen
carrier) suspended in mock plasma containing 48 g/liter dextran (FW 70
000). Radiolabeled leptin (125I-leptin,
Amersham Pharmacia Biotech, specific activity
87–275 cpm/pg; three different batches were used) was introduced in
the perfusion medium at a constant tracer concentration via
a slow-drive syringe at a rate of 0.2 ml/min. The rate of perfusion
fluid was between 4 and 4.5 ml/min. The cerebrovascular tracer
99Tc-Albumin (Medi-Physics, IL, Technetium Tc99m
HSA Multidose Kit) was introduced simultaneously. Physiological
parameters (e.g. perfusion arterial pressure, acid base
status, cerebral perfusion flow etc.) were kept within the range found
in the anesthetized rat.
The first study examined the time-dependent uptake of radio-iodinated
leptin into different CNS regions using a single batch of leptin tracer
for all experiments with a final concentration in the arterial inflow
of 0.52 ± 0.09 ng/ml of 125I-leptin, more
than 97% intact by acid precipitation (TCA) and HPLC analysis. At
predetermined times ranging from 1 to 20 min rats were killed by
decapitation and the CNS tissues collected for radioactivity analysis
in a Beckman Coulter, Inc. 
4000 Counter. The
following samples were prepared from the ipsilateral perfused
hemisphere: choroid plexus and CSF from the lateral ventricle,
hypothalamus, and different BBB regions (e.g. parietal
cortex, caudate nucleus, hippocampus). The choroid plexuses were
harvested from the lateral ventricles, and the wet weights of the
choroid plexus samples were between 1.9 and 2.2 mg. The wet weight of
the choroid plexus was determined immediately after the isolation using
preweighted vials. The weights of the CSF samples from the lateral
ventricles were between 2.1 and 2.5 mg. The CSF was sampled from the
lateral ventricle by stereotactic puncture through a window in the
skull using a 10 µl Hamilton syringe. The area dissected as
hypothalamus was its ventromedial part with a standardized weight
between 18 and 24 mg. This area consisted of nervous tissue, previously
shown to be largely inside the BBB, but contained also the median
eminence, a region that is not protected by the BBB (22). The weights
of the parietal cortex, caudate nucleus and hippocampus samples varied
between 20 and 38 mg.
All plasma and CNS tissue samples were TCA-precipitated (see below) and counted simultaneously. Each time point included three to six animals per point, and each experiment/per time point was performed on the same day.
In separate experiments, unlabeled leptin at different concentrations ranging from 0.6 to 300 ng/ml was introduced into the arterial inflow simultaneously with 125I-leptin for either 1 min for measurements in the choroid plexus, CSF, and hypothalamus, or for 10 min for uptake studies at the BBB regions outside the hypothalamus. In these experiments concentration-dependent uptake of leptin was determined, and each concentration point included three to six animals per point. Leptin tracer was from two different batches of similar specific activity, and its final concentration in the arterial inflow was 0.15 ng/ml of 125I-leptin, more than 97% intact as determined by TCA and HPLC analysis.
TCA precipitation assay
The recovery of intact 125I-leptin
radioactivity in the arterial inflow and CNS tissue and CSF samples was
determined by TCA precipitation assay in all samples. Samples were
mixed with 0.2 ml of 35% TCA, then centrifuged at 6,000 rpm at +4 C
for 8–10 min, and the radioactivity in the precipitate, water fraction
and chloroform fraction determined. The intactness of radio-iodinated
leptin infused into the arterial inflow was > 97% by the HPLC
analysis that was confirmed by the TCA assay. It has been also
demonstrated that TCA assay provides reliable analysis of intact leptin
in the CNS tissues as corroborated with the HPLC analysis (see
below).
Binding to microvessels and transendothelial transport
To distinguish between leptin binding to brain microvascular
endothelium vs. transport across the BBB, in some
experiments brain tissue was subjected to capillary depletion step and
microvessels separated from perfused brain, as we reported (21, 22). In
these studies we used the ipsilateral forebrain tissue consisting of
cortical tissue and subcortical regions (caudate, hippocampus), but did
not contain rapid uptake regions such as the choroid plexus and
hypothalamus that were discarded. Briefly, dextran (FW 70,000) was
added to a final concentration of 13% to brain tissue homogenates in a
physiological buffer (10 mM HEPES, 141
mM NaCl, 4 mM KCl, 2.8
mM CaCl2, 1
mM MgSO4, 1
mM NaHPO4, and 10
mM D-glucose adjusted to pH
7.4). The aliquots of homogenates were centrifuged at 5,400 x
g for 10 min at +4 C. The pellet containing brain
microvessels and the supernatant containing capillary-depleted brain
were carefully separated and the radioactivities of
125I-leptin and
99mTc-albumin determined in these two brain
fractions.
Calculations
Details of mathematical analysis were as we reported (21, 22, 37). Briefly, the uptake values for 125I-leptin
and 99Tc-albumin by the choroid plexus, CSF and
brain BBB regions are expressed as ratios of tracer concentrations in
different tissues/fluids relative to the constant concentration of
their respective isotopes in the plasma arterial inflow. The following
equation was used to calculate the ratios:
CIN/CPL = [cpm./g (tissue
or CSF)]/[cpm/ml (plasma inflow)]. The uptake values for
125I-leptin were based on TCA-precipitable
radioactivity (intact leptin as confirmed by HPLC analysis) and were
corrected for tracer distribution in the vascular brain space and
choroid plexus vascular and extracellular space (i.e. the
choroid plexus has leaky capillaries, but tight epithelium) by
subtracting albumin values as: CIN (LEPTIN) -
CIN (ALBUMIN). Although, short infusion times of
1–3 min may preclude complete equilibration of
99mTc-albumin in the choroid plexus interstitial
space, using different extracellular space markers (e.g.
14C-inulin, FW 5,000 or
3H-mannitol, FW 182) we obtained only slightly
higher values than for albumin, and the respective uptake values at 1
min were 2.3%, 2.5% and 3.9% for albumin, inulin, and mannitol. As
FW of leptin is 16,000, i.e. between albumin and inulin, it
is likely that the amount of leptin tracer that remains in the
interstitial space at 1 min is between 2.3% and 2.5%. Therefore, our
applied correction with albumin would at most overestimate leptin
epithelial uptake by less than 5%, which may not be significant given
that the SD of leptin uptake rate by the choroid
epithelium is close to 20% (Table 1
).
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To determine concentration-dependent transport of leptin into the CSF and across the BBB, the uptake of 125I-leptin was studied at different concentrations of unlabeled leptin. The unidirectional influx, JIN, was calculated as JIN = KINCPL (Eq 7), where KIN is the entry constant of radio-labeled leptin in the presence of increasing concentrations of unlabeled leptin in the arterial inflow plasma, CPL. (For details, see refs. 21, 22, 37 .) Michaelis-Menten analysis was applied to compute the affinity constant (KM) and maximal transport capacity (VMAX) of putative leptin transporters. The possibilities for a single and/or multiple transport sites were considered using the following Eq 8, JIN = VMAX1CPL/(KM1 + CPL) + VMAX2CPL/(KM2 + CPL) + ... VMAXnCPL/(KMn + CPL). In vivo uptake of 125I-leptin by the choroid plexus was also determined in the presence of different concentrations of unlabeled leptin and the JIN values calculated using Eq 7. The JIN values for leptin in the plexus reflect binding of leptin to the choroidal tissue (37), as opposed to transport across the blood-CSF barrier, the binding constant (KD) and maximal binding capacity (BMAX) were calculated. The possibility for a single or multiple binding sites was considered (Eq 9): JIN = BMAX1CPL/(KD1 + CPL) + BMAX2CPL/(KD2 + CPL) + ... BMAXnCPL/(KDn + CPL). Kinetic parameters were calculated with a nonlinear regression analysis using SAAMII program as reported (39). Advanced graphics software (SlideWrite Plus) was used to obtain graphic plots. Data are presented as mean values (± SEM) and compared by two-way post ANOVA.
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Results |
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, A and B).
The choroid epithelial uptake of leptin and its entry into the CSF
exhibited significant departure from linearity after 1 min.
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) was about 12.5–37.5-fold higher than in other
BBB regions. Although the exact significance of the initial spike in
the hypothalamus uptake curve is not clear (Fig. 1C), it is possible
that it reflects high affinity initial binding of leptin to its
hypothalamic receptors followed by ligand-induced rapid receptor
down-regulation, as observed in cells transfected with leptin receptors
(40). Leptin uptake at different BBB regions outside the hypothalamus
was substantially lower and remained linear within the studied 20-min
period (Fig. 1, D–F). Data given in Fig. 1 illustrate the uptake of
intact leptin as determined by the TCA assay and confirmed by the HPLC
analysis. The HPLC analysis of radio-iodinated leptin used for internal carotid arterial infusions indicated that in all batches > 97% of 125I-radioactivity was intact leptin (as supplied by manufacturer). This was confirmed by the TCA analysis of the infusion solution and the arterial plasma inflow, which indicated > 97% TCA-precipitable radioactivity. In the present model, there is no degradation of peptide and protein tracers in the arterial inflow as the radiolabeled material is directly infused into an enzyme free artificial plasma medium used for brain perfusions, and the tracer is completely separated from the systemic circulation and does not come into contact with the animal’s own blood during passage through the brain circulation (21, 22, 23, 24).
Previous studies specifically designed to determine leptin degradation in whole brain homogenates by the acid precipitation and the HPLC methods, and to validate the acid precipitation method by the HPLC, demonstrated an excellent correlation between the two methods if the acid precipitation was greater that 50% (25, 38). It has been reported based on incubation studies of the whole brain homogenates with radio-iodinated leptin that the relationship between the methods was: acid precipitation = 1.1 (HPLC) + 2.13 with an r = 0.983 (25). In the present study, we found with the TCA assay that the amount of intact leptin determined in studied CNS tissues was between 91% and 80%, for the shortest (1 min) and the longest (20 min) time point, respectively. Because the values by the TCA acid precipitation in our study were much higher than 50%, according to reported validation analysis of the acid precipitation by HPLC (25), the HPLC will detect similar amounts of intact leptin in the CNS tissues (25, 38).
The regional CNS uptake curves for 125I-TCA
precipitable leptin in the choroid plexus and CSF were analyzed by
nonlinear regression analysis to compute the KIN
values (Table 1). The KIN values at the BBB
regions were calculated by linear regression analysis and are also
shown in Table 1. The KIN of 0.105
min-1 determined for intact leptin at the
blood-CSF barrier, suggests transport/secretion that is 18- to 53-fold
faster than simultaneously determined leptin uptake at the BBB where
the regional KIN values varied between 0.002 and
0.006 min-1. The rate of leptin uptake by the
hypothalamus as computed from the unidirectional linear phase was 0.076
min-1, comparable with the rates observed in the
choroid plexus and the CSF (Table 1).
In some experiments, a capillary-depletion step was performed to
distinguish between binding of tracer to endothelial binding sites at
the BBB vs. transport into brain parenchyma across the BBB.
Our data indicate that, after 10 min, the majority of tracer is
transported out of the vascular compartment across the BBB into brain
parenchyma (Fig. 2). The value of leptin
uptake into brain parenchyma was approximately 13-fold higher than
sequestration by capillaries. Direct measurements of intact leptin
tracer in the CSF confirmed leptin transport across the choroid plexus
epithelium of the blood-CSF barrier into the CSF of lateral
ventricles.
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, A–C). The
measurements were performed within initial 1 min of the linear
125I-leptin uptake to ensure inhibition of tracer
during its unidirectional uptake and/or transport. In contrast, there
was no detectable rapid (
1 min) leptin influx at the BBB. However,
with a longer infusion time of 10 min, a saturable leptin influx across
the BBB could be demonstrated over a wide range of pharmacological
concentrations, from 10 to 300 ng/ml (Fig. 3, D–F). It is noteworthy
that lower physiological concentrations of unlabeled leptin failed to
inhibit leptin tracer uptake at the BBB (not shown).
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). The KM for
leptin uptake and/or binding to hypothalamus was even lower (0.22
ng/ml). In vivo leptin binding to the choroid plexus
exhibited KD of 2.6 ng/ml. Michaelis-Menten
analysis based on slow ( 10 min) leptin influx at the BBB regions,
revealed a single leptin BBB transporter at the luminal side with a
regional affinity varying from 88 to 345 ng/ml. Slow uptake of
radio-leptin by the caudate nucleus may be affected by uptake across
BBB capillaries as well as uptake from adjacent CSF, as shown
previously for brain regions adjacent to the ventricles (40).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our findings indicate that choroid plexus plays a key role in regulating leptin entry into the CSF under physiological conditions. Plasma levels of leptin in normal lean rats vary between 0.6 to 10 ng/ml (42), and the KM value of 1.1 ng/ml determined for leptin transport across the choroid epithelium of the blood-CSF barrier was close to the lower end of this range. Because leptin transport across the blood-CSF barrier is fully saturated at higher leptin physiological plasma concentrations, it is possible that the choroid epithelium acts as a rate-limiting step to prevent increases in CSF leptin concentrations. This epithelial barrier could also be responsible for "leptin resistance" reported in obese individuals where the increases in plasma leptin were not followed by parallel increases in the CSF leptin levels (11, 15). In the present study the CIN/CPL ratio for leptin in the CSF approaches 1 at the steady state, whereas in normal humans (11, 15) and rats (42) leptin levels are considerably higher in plasma than in CSF. This discrepancy could be possibly attributed to the differences in the CSF sampling sites. In the present study, a small volume of the CSF was obtained from the lateral ventricle (< 5% of the total CSF volume), whereas in previous studies the CSF was sampled either from the spinal subarachnoid space in humans (11, 15) or from the cisterna magna in rats (42). In the spinal and cisternal CSF samples (11, 15, 42), leptin secreted by the choroid plexuses would be considerably diluted into a larger CSF volume that may account for reported differences. A descending CSF gradient of radiolabeled leptin along the axis lateral ventricle-cisterna magna was also observed in the present study (data not shown). In contrast to choroid plexus and CSF, the steady-state values for leptin could not be determined for other brain regions because the uptake was linear over studied period of time.
The molecular nature of putative leptin transporters at the choroid epithelium is not known. Specific leptin receptors and the short splice variant of the receptor have been identified in the choroid plexus (27, 28, 29, 32). It has been speculated that short isoform may serve a transport function moving leptin from the peripheral circulation into the CSF and CNS (27). However, more recent work in transfected cells failed to confirm the transcytotic function of the short form of leptin receptor (36). It has been suggested that all leptin receptor isoforms are linked to cellular signaling (34, 35), leptin internalization, and degradation by a lysosomal pathway (36, 41). The KD of 2.6 ng/ml determined for in vivo leptin binding to the choroid plexus was comparable with KD of 3.3 ng/ml typically determined for leptin binding to cells transfected with the short form of receptor (36, 41). Thus, it is possible that binding of leptin to its short receptor isoform in the choroid plexus and transport across the blood-CSF barrier that exhibits somewhat higher affinity (KM = 1.1 ng/ml) are two distinct processes. Binding to the short receptor isoform may lead to activation of afferent neural inputs to the network that regulates feeding behavior and energy balance as previously suggested (27, 43). On the other hand, a new class of molecularly yet nonidentified transcytotic leptin receptors could be involved in transport across the choroid epithelium supplying the CSF with leptin. The rate of leptin transport across the blood-CSF barrier was somewhat faster that previously reported rates of receptor-mediated transport of vasopressin, transthyretin, ceruloplasmin, and growth factors (21, 37, 44), as well as some water-soluble vitamins (45). The KIN value for CSF uptake of leptin could be compared with KIN values for Na and Cl, suggesting that uptake of leptin is very rapid, similar to that of Na and Cl in the brisk CSF secretory process (46).
Our results indicate that transport of leptin through the BBB has
different properties than across the blood-CSF barrier. The rates of
leptin regional BBB transport were similar to previously determined BBB
permeability of whole brain to circulating leptin in mice (25) and were
within a range of slow to moderate transport determined for several
peptides and proteins in rodents including insulin, transferrin,
insulin-like growth factors, vasopressin, enkephalins, endorphins, and
MSH (21, 22, 23, 24). Although there was no rapid uptake of leptin at the BBB
( 1 min), with longer infusion times of 10 min, slow but saturable
leptin influx across the BBB was demonstrated over a wide range of
higher pharmacological concentrations, from 10 to 300 ng/ml. In
contrast, physiological concentrations of leptin failed to inhibit
125I-Ieptin BBB transport, confirming an absence
of sensitive transport mechanism for leptin at the BBB under
physiological conditions. However, the importance of the BBB in
transporting leptin into the CNS at higher pharmacological
concentrations and at a slow rate should not be underestimated.
Present findings at the BBB in vivo revealed a single low affinity transporter with a regional KM of 88 to 345 ng/ml. An earlier report on human brain capillary plasma membranes suggested two binding sites for leptin with KD of 90 and 16,000 ng/ml (31). Leptin binding to isolated cerebral capillaries demonstrated in a previous study was highly suggestive of the abluminal localization of leptin binding sites at the BBB (31). In contrast, the present study described transport of leptin at the luminal side of the BBB and across the BBB into brain parenchyma. Although short and long isoforms of leptin receptors were shown at the BBB (32, 33), it is unlikely that previous (31) and/or the present study were able to confirm that either of these receptors is transcytotic. On the contrary, the binding kinetic properties of long and short isoforms of leptin receptors determined in transfected cells, i.e. KD from 3.3 to 10 ng/ml (35, 36), were far below the KM for leptin BBB transport determined in this study and/or binding to BBB plasma membranes (31). It is possible that a novel class of leptin transporters and/or receptors at the BBB may regulate leptin supply to brain cells by analogy to transport mechanisms described for other peptides and proteins (21, 22, 23, 24, 44).
The uptake of leptin by hypothalamus that predominantly expresses the long receptor isoform (19, 47) seems to be a special case. Leptin uptake by the hypothalamus was 12.5- to 37.5-fold faster than in other BBB regions and appeared to be mediated by high affinity transporters with KM of 0.2 ng/ml that was significantly lower than the KD determined for leptin binding to a long receptor isoform in cell transfection studies (35, 36, 41). The exact mechanisms remain unclear. Previous study in isolated brain slices also suggested extremely sensitive binding of leptin to hypothalamic nuclei (KD approximately < 1 ng/ml), but the exact binding constants were difficult to determine due to too low maximal binding capacity (48). Many neurons in the hypothalamic nuclei are typically isolated from the circulation by the BBB and express high number of leptin receptors (18, 19). An enhanced autoradiography signal detected in the region of the arcuate nucleus following systemic injection of radiolabeled leptin was interpreted as direct leptin transport from blood to the hypothalamus (25). Alternative possible route is that blood-borne leptin is transported across the blood-CSF barrier and than carried via CSF bulk flow to its CNS targets similar to several major regulatory hormones and micronutrients (21, 43, 45). A third possibility is that leptin may enter the hypothalamus at the median eminence, which lacks the BBB (22) and then reaches its neuronal targets in hypothalamic nuclei by diffusion. Perhaps a combination of diffusion at the median eminence, transport across the BBB as well as transport from CSF across the ependyma mediate hypothalamic leptin uptake.
In conclusion, our study points to differential regulation of leptin CNS transport by the choroid plexus and the BBB. Specific high affinity transport systems for leptin in hypothalamus and across the choroid epithelium of the blood-CSF barrier play a key role in regulating leptin entry into the CNS and CSF under physiological conditions. On the other hand, at higher pharmacological concentrations of leptin and over longer periods of time, transport across the BBB takes over, which in turn could be important for neuropharmacological effects of exogenous leptin.
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Footnotes |
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Received October 12, 1999.
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