1606 Current Pharmaceutical Design, 2008, 14, 1606-1614

The Blood-Brain Barrier as a Cause of Obesity

William A. Banks*

GRECC, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, Division of Geriatrics, Depart-
ment of Internal Medicine, USA

Abstract: The dramatic increase in the number of obese and overweight persons has spurred interest in control of appetite, body weight,
and adiposity. Leptin is the humoral component of a negative feedback loop between adipose tissue and brain. Leptin is secreted from fat
in proportion to the degree of adiposity, is transported across the blood-brain barrier (BBB), and acts in the brain to decrease appetite and
increase thermogenesis, actions that ultimately decrease adiposity. However, leptin fails as an adipostat because leptin resistance arises in
obesity. The BBB transporter is the first part of the feedback loop to fail, producing the so called "peripheral resistance" to leptin. In this
sense, obesity is a disease of the BBB. Failure of leptin as an adipostat raises the question of what its primary role is as does its effects on
reproduction, bone, immunity, breathing, cognition, and neurogenesis. Kinetics analysis shows that the BBB transporter performs most
efficiently at low serum levels of leptin, suggesting that the feedback loop evolved to operate at lower leptin levels than those seen in
ideal body weight. We suggest that low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on
functions other than feeding, such as reproduction and the immune system. This feedback loop is short-circuited when an animal enters
starvation. Hallmarks of starvation include decreased secretion of leptin by adipose tissue and hypertriglyceridemia. Triglycerides inhibit
the transport of leptin across the BBB, thus attenuating the leptin signal across the BBB and providing a mechanism for peripheral leptin
resistance. Triglycerides are elevated in both starvation and obesity. We postulate that hypertriglyceridemia evolved as a starvation signal
to the brain that acts in part to inhibit the transport of the leptin across the BBB. The hypertriglyceridemia of obesity invokes this aspect
of the starvation response, inducing leptin resistance at the BBB. Thus, the BBB plays important roles in both obesity and starvation.

INTRODUCTION THE BBB IN THE LEPTIN NEGATIVE FEEDBACK LOOP

Obesity is at epidemic levels in Western society. Many new
peptide and regulatory proteins have been discovered in the last
decade that act in an integrated way to regulate various aspects of
feeding [1-3]. Key among these is leptin, which forms a negative
feedback loop seemingly designed to control body adiposity [4, 5].
However, the current epidemic of obesity testifies to the ineffi-
ciency of leptin as an adipostat. This raises the question of what is
the main role of leptin.
Here, we examine the role of the blood-brain barrier (BBB) in
the transport of leptin from the blood into the central nervous sys-
tem (CNS). The presence of a saturable, regulated transporter for
leptin across the BBB, likely located at both the capillary bed and
the choroid plexus, provides the mechanism by which circulating
leptin can access and act upon the brain [6-11]. However, an as-
sessment of the relation the BBB creates between serum and CNS
levels of leptin, the impairment of the BBB leptin transporter in
obesity and starvation, and considerations of adaptive responses and
evolutionary pressures leads to a new view of leptin and its role in
maintenance of body weight and caloric expenditure.
As reasoned here, leptin functions as an adipometer, measuring
for the brain the caloric reserves in adipose tissue. When caloric
reserves are sufficient, the CNS directs expenditure of calories on
non-feeding related activities, such as reproduction, immunity, bone
mineralization, cognition, neurogenesis, and breathing. This path-
way is acutely disrupted by starvation, which attenuates both the
secretion of leptin from fat and the transport of leptin by the BBB.
The inhibition of leptin secretion and transport reduces CNS levels
of leptin and so attenuates both the anorectic signal and the expen-
diture of calories on non-feeding activities. The inhibition of leptin
transport across the BBB is mediated in part by triglycerides which
are elevated in both starvation and obesity. Thus, part of the body's
response to starvation, that of inhibition of leptin transport, is
evoked in obesity by virtue of its accompanying hypertriglyceride-
mia. This explains in part the impaired ability of peripherally ad-
ministered leptin to inhibit feeding in obesity.
*Address correspondence to this author at the 915 N. Grand Blvd, St. Louis,
MO 63106, USA; Tel: (314) 289-7084; Fax: (314) 289 6374;
E-mail: bankswa@slu.edu
As originally assessed, leptin mediates a feedback loop (Fig. 1)
between adipose tissue and CNS-mediated events that control adi-
posity [4, 5]. Specifically, leptin is secreted from adipose tissue so
that the level of leptin in blood reflects the degree of adiposity.
Leptin enters the hypothalamus from the blood where it binds to its
receptors at the arcuate nucleus. Activation of this receptor modu-
lates downstream neural circuitries, stimulating anorexic pathways,
inhibiting orexigenic pathways, and enhancing thermogenesis [12].
With inhibition of food intake and increased caloric expenditure,
body fat mass decreases as does leptin levels in blood. The lower
leptin levels mean a reduced anorectic effect and a decrease in ther-
mogenesis. Thus, a classic negative feedback loop is set up between
the CNS and fat mass which is mediated by leptin. Administration
of leptin to humans or animals who are leptin deficient results in
dramatic decreases in body weight [13-15].
Although this outline explains much about leptin, it does not
incorporate other facets of leptin activity. For example, leptin has
receptors in brain outside the arcuate nucleus [16-22] as well as in
peripheral tissues [23-27]. Leptin also affects many functions other
than those involved in control of feeding. Many of these functions
are mediated at least in part through the CNS and include effects on
sexual activity and reproduction [28, 29], immunity [30], bone min-
eralization [31, 32], cognition and neurogenesis [33-36], and
breathing [37, 38]. Leptin seems to play a permissive role in many
of these functions, with impairment of the function in the virtual
absence of leptin, but resumption of activity at very low levels of
serum leptin [39]. In particular, exogenous administration of leptin
can reverse many features seen in low-leptin conditions, such as
starvation and lipodystrophy [40, 41]. These effects of leptin that
are not directly related to an adipostat function may be coordinated
with one another. Thus, inadequate stimulation of leptin receptors
in the arcuate nucleus and elsewhere in the brain may be part of a
unified central leptin insufficiency syndrome [42].
The role of the BBB is in the transfer of leptin from the circula-
tion to the arcuate nucleus and other sites within the CNS. Leptin is
a fairly large protein of 16 kDa and so is the type of molecule that
the BBB prevents from leaking from the blood into the brain [43].
As discussed below, the passage of leptin from the blood to the

1381-6128/08 $55.00+.00 2008 Bentham Science Publishers Ltd.

The Blood-Brain Barrier as a Cause of Obesity Current Pharmaceutical Design, 2008, Vol. 14, No. 16 1607

Thermogenic
Expenditures
ARCUATE NUCLEUS Reproduction
Anorexins Immunity
LEPTIN RECEPTOR Orexins Bone Mineralization
Cognition
Neurogenesis
CNS LEPTIN Breathing
Feeding

PLASMA LEPTIN

FAT MASS
Fig. (1). Leptin negative feedback loop. Fat secretes leptin into the blood so that the level of leptin in the plasma reflects the amount of adipose tissue. Leptin
is transported across the blood-brain barrier (BBB) by a saturable transport system, entering the hypothalamus where it interacts with its receptor in the arcuate
nucleus. Activation of the leptin receptor inhibits orexins and stimulates anorexins so that the feeding drive is diminished. CNS leptin at low levels permits or
stimulates reproduction, immunity, bone mineralization, cognition, neurogenesis and breathing. These activities use calories, promoting thermogenesis. Use of
calories and inhibition of feeding results in a decrease in fat mass, thus completing a negative feedback loop.

arcuate nucleus is by way of a saturable transport system that is
itself regulated.
If this leptin-mediated feedback loop worked as outlined above,
obesity and anorexia should be rare events. The epidemic of obesity
shows that this feedback loop is readily impaired. Furthermore,
leptin levels are typically high in the obese human, not low [44].
Elevated, not low, levels of the humoral mediator of a negative
feedback loop is the hallmark of a resistance syndrome [45]. Pe-
ripheral administration of leptin also illustrates this resistance. Un-
like humans born with a lack of leptin production, those with typi-
cal obesity are much less responsive to weight loss with leptin ad-
ministration [46].
For the classic feedback loop, there is only one cause of resis-
tance: that of receptor or post-receptor insensitivity. But in the case
of leptin, there are two more levels at which resistance could occur:
an impaired transport of leptin at the BBB and an impaired function
of the downstream neuronal circuitries. Impairment at any of these
three levels (BBB transport, receptor/post receptor function, down-
stream neuronal circuitries) would induce a picture of obesity with
high levels of leptin in the blood [47].
LEVELS OF LEPTIN RESISTANCE
Evidence exists for leptin resistance at each of the three possi-
ble levels of BBB transport, receptor/post receptor activation, and
the downstream neuronal circuitries. For example, about 4% of
humans with obesity have a mutation in the melanocortin receptor
MCR4, a part of the downstream neuronal circuitries influenced by
leptin, which results in a decease in the anorectic drive [48] and
about 3% have evidence for a defective leptin receptor [49].
Evidence from human and animal models, however, suggests
that most of the resistance to leptin occurs at the level of the BBB
and the receptor/post-receptor level. In many models, the first level
of leptin resistance in diet induced obesity occurs at the level of the
BBB. Obese humans have a lower CSF/serum ratio than thin hu-
mans, suggesting attenuation of transport efficiency at higher body
weights [8, 50]. Animals fed a high fat diet pass through a stage
where they respond to leptin given directly into the brain but no
longer to leptin given peripherally [51, 52]. This peripheral resis-
tance indicates that a block occurs in the ability of circulating
leptin to signal the brain. With increasing obesity, animals loose
their ability to respond even to leptin given directly into brain. This
central obesity most likely represents failure at the receptor/post-
receptor level. In one rodent model of obesity, it seems that periph-
eral resistance is more severe or precedes central resistance [53].
Kinetics analysis based on the relation between CSF and serum
levels of leptin in humans [54] suggests that transporter and recep-
tor deficits develop in tandem and become increasingly severe as
obesity develops, with the transporter being the more impaired in
early and moderate obesity.
This leptin resistance at the BBB is acquired as adiposity in-
creases and can be reversed with weight loss from food restriction
or leptin administration [55]. A model of diet-induced obesity in
which rats are born with central resistance at the hypothalamus also
acquire an inability to transport leptin as they become obese [56].
Interestingly, these rats show no central resistance at the brain stem.
In summary, it is likely that obesity arising from any of the
three levels (BBB transport, receptor/post receptor activation, and
the downstream neuronal circuitries) will eventually produce leptin
resistance at the other two. Certainly, there is a dynamic relation
between central and peripheral leptin acting to promote one an-
other. In some animal models and probably in humans, the defect at
the BBB seems to precede that of central resistance.
TRANSFER OF THE LEPTIN SIGNAL FROM BLOOD TO
BRAIN
There are several mechanisms by which a blood-borne sub-
stance can affect the functions of the central nervous system [57].
These mechanisms can be divided into five broad categories. First,
a substance can act at afferent nerves. An example of this is the
ability of intraperitoneally injected cholecystokinin to affect appe-
tite [58, 59]. Second, a substance can act at a circumventricular
organ (CVO). The CVOs are small areas of the brain in which the
capillary bed does not possess BBB properties, hence allowing
circulating factors to enter these regions of the brain [60, 61]. The
1608 Current Pharmaceutical Design, 2008, Vol. 14, No. 16 William A. Banks

CVOs are intimately connected with other regions of the brain,
sending and receiving neural projections [62]. Angiotensin II in-
duces thirst by acting at CVOs [63]. Third, a substance can alter
BBB function. Types of alterations include disruption of the BBB,
alteration in key transporters of the BBB, or induction of secretions
by the BBB. As examples, insulin can alter tryptophan transport
across the BBB [64], lipopolysaccharide can induce cytokine re-
lease from brain endothelial cells [65], and blood-borne interleukin-
1 increases body temperature by inducing prostaglandin secretion
from brain endothelial cells [66, 67]. Fourth, a substance can cross
the BBB directly to influence brain function [68, 69]. As an exam-
ple, interleukin-1 alpha crosses the BBB to impair cognition [68].
Fifth, a substance can affect the level of another substance which
then acts through one of the other four pathways. For example,
blood-borne insulin induces hunger, coma, and seizures by lower-
ing blood glucose levels.
Most of the attention on how leptin transduces its signal across
the BBB has focused on activity at the median eminence, a CVO, or
panel). What this means practically is that the ability to convey
information to the brain through an increase in blood leptin levels
becomes increasingly inefficient as blood leptin levels rise. For
example, based on the hyperbolic curve shown in the upper panel of
Fig. (2), when serum leptin levels double from 5 ng to 10 ng/ml,
CSF levels can be estimated to increase by 48% percent. However,
when serum levels double from 20 to 40 ng, the increase in CSF is
only 19% percent. Thus, the ability of the fat mass to speak to the
brain across the BBB becomes increasingly difficult as serum leptin
levels rise. In other words, the influence of serum leptin on appetite
and weight control diminishes with obesity as the BBB attenuates
the amount of serum leptin entering the brain.
Brain CSF
500 1.5
400

Brain (ng/ml)
CSF (pg/ml)
by crossing the BBB. Unfortunately, much of the feeding literature 1.0
has consistently ascribed architectural attributes to the median emi- 300
nence for which there is little evidence for and a preponderance of
evidence against. The ability of blood-borne substances to leak into 200
the median eminence has often been misinterpreted as ability of 0.5
those same substances to subsequently leak from the median emi- 100
nence into adjacent brain tissue. However, the CVOs in adults are
delimited by a barrier [70-73] primarily formed by tanycytes [74, 0 0.0
75] that prevents leakage of substances from the median eminence 0 10 20 40 60
into the arcuate nucleus. This barrier between the CVOs and adja- Vascular Leptin (ng/ml)
cent brain tissue is considered one of several special barriers that
are, overall, part of the blood-brain barrier system [76]. In addition
to there being no anatomical basis for leakage out of the median
eminence in general or for leptin in particular, a leakage model also
could not explain the combination of peripheral resistance with 5 %Max-CSF 100
central sensitivity to leptin. The existence of peripheral resistance
shows that there must be a regulated step in the ability of serum 4
100(CSF/Serum)

leptin to activate its brain receptors. Such a regulated step is pro- 75

vided by saturable entry, but not by leakage as obesity does not
convert nonfenestrated blood vessels into fenestrated ones. There is
evidence that leptin entering the median eminence acts upon projec-
tions to the arcuate nucleus [77]; theorectically, leptin could also
interact with the tanycytic barrier by crossing it, altering its perme-
ability to other substances, or inducing secretions from the barrier
cells. However, all of these mechanisms would be mediated through
receptors that could be regulated and altered in obesity, thus ex-
plaining the peripheral resistance phenomenon.
Direct transport across the vascular BBB from the circulation
into the arcuate nucleus has received the most attention. Leptin is
transported across the BBB by a saturable transport system that
exists at both the brain endothelial cells and at blood-cerebrospinal
fluid (CSF) barrier formed by the choroid plexus in rodents [6-11]
and sheep [11]. The leptin transporter becomes increasingly satu-
rated as serum leptin levels rise into the range seen in obesity [50,
78]. This means that the increase in CSF levels of leptin becomes
increasingly smaller for every incremental increase in serum leptin
as leptin levels in blood rise ever higher. Hence, a saturable trans-
porter for leptin explains the phenomenon of peripheral resistance.
THE BBB AS A CAUSE OF OBESITY
Transport of leptin across the BBB is impaired in obesity [55,
79-82]. Impaired transport develops not only in normal, outbred
animals that develop dietary-induced obesity, but can also develop
in animals that have a CNS basis for their obesity [56, 83]. The
impaired transport manifests itself both by the nonlinear relation
between CSF and serum leptin in humans [50, 84, 8] and by the
relation of the rate of leptin uptake by brain to vascular leptin levels
in animal perfusion studies [78]. Both analyses show a nonlinear
relation between vascular leptin and CNS leptin (Fig. 2, upper
%Max-CSF
3
50
2
%CSF/Serum 25
1
0 0
0 10 25 50 75 100
Serum Leptin (ng/ml)
Fig. (2). Relations between CNS and serum levels of leptin. Upper panel:
The relation of CSF to serum levels of leptin from human studies (open
circles, broken line) is compared to amount of leptin entering the CNS dur-
ing brain perfusion of radioactive leptin in mouse studies (filled circles,
solid line). Both relations are fitted to a one site hyperbola model. Accord-
ing to this model, the maximum CSF level is 411.8 pg/ml and half this value
is reached at the blood leptin of 9.2 ng/ml. At 10 ng/ml (dashed line), both
curves are on the nonlinear portion of the curves. Lower panel: Curves
derived from one-site hyperbolic equation based on CSF data in upper panel
showing CSF-serum relations. Broken line shows that at very low levels of
serum leptin, the leptin level in CSF is over 4% of that of serum, but rapidly
declines as serum levels increase. Solid line shows the percent of maximum
CSF level as a function of serum leptin levels. The linear portion of each of
the lines, which is the region that best conveys the leptin signal from blood
to CNS, is at leptin levels lower than 10 ng/ml.
THE QUANDRY OF KINETICS
These nonlinearities in the relations between CNS and blood
levels of leptin raise the question of under what circumstances does
the system work best. The clearest signal from blood to brain would
occur where the relation between CNS and blood levels of leptin is
The Blood-Brain Barrier as a Cause of Obesity
most nearly linear. It would be in that range that an increase in se-
rum leptin would produce the largest increase in CNS leptin, thus
producing the most efficient blood-to-brain signaling. By extension,
one could argue that this range would have been dictated by evolu-
tionary pressures; that is, it would have been in this range of blood
leptin levels that animals would have evolved to fight their battles
for the acquisition and retention of calories. Both the animal and
human data show that the relation between CNS leptin and serum
leptin is already nonlinear at 10 ng/ml (Fig. 2, upper and lower
panels). This is surprising, because in modern Western societies,
this is approximately the level seen in ideal body weight. Thus, the
quandry of kinetics suggests that what is considered ideal body
weight is actually already above of the physiologic range for serum
leptin levels.
MODULATION OF THE LEPTIN TRANSPORTER
The activity level of the leptin transporter is not static, but is
regulated by pathophysiological events. Specifically, leptin trans-
port is enhanced by glucose, insulin [85], and epinephrine [86] and
impaired with loss of ovarian function [87] and in obesity [55, 79-
82], starvation [88, 89], treatment with lipopolysaccharide [90], and
hypertriglyceridemia [89]. These modulators are responsible for or
at least reenforce many of the unique aspects of the relation of
leptin to obesity as well as starvation. They also give clues to what
might be the real relation of leptin to feeding behavior.
Impaired leptin transport across the BBB in obesity has been
demonstrated by several laboratories. There are two broad mecha-
nisms inducing the impaired transport. The first is that which would
occur with any saturable system and is, in part, a phenomenon of
the way the leptin transport rate is usually measured. Most studies
have measured the unidirectional influx rate (Ki) of leptin with
multiple-time regression analysis after the intravenous injection of
radioactively labeled leptin [91-93]. This measures the rate at which
the radioactive leptin crosses the BBB; this in turn, is a proxy for
the proportion of endogenous leptin in the blood that is crossing the
BBB. It does not, however, indicate the absolute amount of en-
dogenous leptin that is crossing the BBB. To calculate that, one
would have to multiply the Ki by the concentration of leptin in the
blood. Thus, the decrease in Ki found after the intravenous injection
of radioactive leptin could be explained by the competition for its
entry by the higher levels of endogenous leptin found in obesity.
Other studies have used the brain perfusion method to examine
leptin transport. This method perfuses a buffer with a known con-
centration of leptin through the vasculature of the brain and so
eliminates the immediate influence of blood-borne leptin and other
substances. These studies show that obese animals still exhibit an
impaired transport of leptin, although less so than after the iv ad-
ministration studies [79]. Thus, there are two factors underlying the
decreased transport of leptin across the BBB. One is the propor-
tional decrease in leptin transport caused by an ever increasing
degree of self inhibition from the higher blood levels of leptin seen
in obesity. The second is some factor or mechanism which impairs
the transporter itself. The first factor, that of self-inhibition, would
not lower CNS levels of leptin; it would simply attenuate the pro-
portional increase in CNS levels of leptin in comparison to those in
serum. The second factor acting on the transporter does have the
capability, in theory, of lowering CNS levels of leptin.
The existence of this second factor suggests that the leptin
transporter may have physiological regulators that modulate its
activity. Two such modulators have been described to date. Periph-
erally administered epinephrine enhances leptin transport across the
BBB and triglycerides attenuate it [89, 86]. Epinephrine has oppo-
site actions in the CNS and in the periphery, with blood-borne epi-
nephrine inducing anorexia and CNS epinephrine inducing feeding
[94]. Thus, the ability of blood-borne epinephrine to enhance the
transport of leptin into the brain would reinforce its anorectic effect
and could be one of the mechanisms mediating it. Triglycerides are
Current Pharmaceutical Design, 2008, Vol. 14, No. 16 1609
elevated in both obesity and starvation and are likely the reason that
leptin transport across the BBB is decreased in these conditions.
The mechanisms by which these factors alter transport is not
clear. LPS treatment, like obesity, likely acts indirectly by elevating
triglycerides and serum leptin levels [90, 95, 96]. Serum factors
such as triglycerides and epinephrine could produce their immedi-
ate effects on transport through two basic mechanisms: they could
interact with the transporter to alter its affinity with leptin or they
could interact with leptin to alter its affinity with the transporter.
Chronic effects could be mediated by altering receptor number,
splicing, or conformation.
LEPTIN AS AN ADIPOSTAT
The above outline shows that the leptin feedback loop is an
elegant system that informs the brain about the body's caloric re-
serves that are stored in adipose tissue. Thus, leptin was originally
proposed as an adipostat that would function to keep body adiposity
at some predetermined level. However, this view gives rise to sev-
eral mysteries:
1) Why would the feedback loop perform so poorly in preventing
obesity in the presence of unrestricted calories? That is, why
would it fail to perform the task for which it supposedly
evolved?
2) Why is the most sensitive portion of the curve relating CNS and
blood leptin shifted to the left, below the "normal" range for
Western society?
3) Why would the leptin transporter at the BBB fail in both obe-
sity and starvation?
4) How do the other roles of leptin mediated through the CNS
(e.g., reproduction, immune function, cognition and neurogene-
sis, bone mineral density, breathing) relate to its effects on feed-
ing and thermogenesis? In general, even low levels of leptin in
the blood are sufficient to permit these functions.
5) What purpose does inhibition of leptin transport by tirglycerides
serve?
To address these questions further, we now examine the evolu-
tionary pressures on feeding in animals in the wild.
EVOLUTIONARY PRESSURES ON THE LEPTIN FEED-
BACK LOOP
The evolutionary pressures that shaped the leptin feedback loop
in humans is likely reflected in animals still living in the wild. Body
fat mass in baboons living in the wild under non-famine conditions
is about 1-2% of total body weight, whereas in captive baboons, the
percent of body fat can approach 50% [97-99]. Leptin levels are
under 1-2 ng/ml [100, 101]. Thus, animals living in the wild have
by modern Western standards very low levels of caloric reserves.
Most species of animals are likely in a constant struggle of using
calories in the effort to find more calories. Under these circum-
stances, the brain would need a rigorous accounting system to know
exactly the magnitude of its caloric reserves. We propose that this
role of accounting, which resembles an adipometer more than an
adipostat, is one aspect of the function of leptin.
Starvation, rather than adiposity, has been much more common
in the history of mankind than has caloric excess. This has been true
even during periods of high civilization and national prosperity.
Adult height reflects caloric conditions during childhood and so can
be used as an indicator of relative caloric availability in a society.
During the Middle Kingdom of ancient Egypt, for example, the
average height of an adult male was 160 cm (5 feet, 3 inches) and
of a female was 150 cm (4 feet, 11 inches). Sweden in the 17th cen-
tury was at the height of its power with territorial ambitions
throughout the Baltic. She launched in 1628 the Vasa, one of the
largest warships of her day, which sank on her maiden voyage.
Because sailors in the Baltic were never far from land, they were
1610 Current Pharmaceutical Design, 2008, Vol. 14, No. 16
well fed and did not suffer from scurvy or other nutritional deficits
as did their counterparts who sailed far from the coasts. Their adult
heights, then, reflect the nutrition available to them during growth.
The average height of the sailor recovered from the Vasa wreckage
was 166 cm (5 feet, 5 inches), whereas the height of the average
Swede today is 179 cm (5 feet, 10.5 inches). Thus, even in a power-
ful European country during a prosperous period, nutritional re-
sources were limited, at least during childhood.
The constant threat of inadequate calories and even starvation
likely explains another aspect of the leptin feedback loop. Given
that caloric reserves are not great in animals living in the wild, that
food resources can be irregular, and that erring on the side of in-
gesting too few calories is much more disastrous than erring on the
side of ingesting too many calories, it makes sense that any ac-
counting system would have a bias towards ingesting extra calories.
In a society where there is always an opportunity to have excess
calories and never a need to call on those reserves, obesity is a
likely result. For example, if an individual eats 9 more calories per
day than is burnt, less than one percent of the daily caloric expendi-
ture, the person will gain about 1 pound per year. Thus, a person
who weighed 150 lb at age 18 years would weight 182 by age 50
years. Thus, this minor defensive bias in the system can account for
"middle age spread". This bias is seen in wild animals when excess
calories become available to them, as well as the complications of
obesity. As reviewed by Altmann et al. [97], captive baboons have
been measured to have up to nearly 50% of their body weight as fat.
Baboons who live in the wild but raid village gardens and garbage
heaps have essentially an unlimited source of calories that requires
little caloric expenditure to obtain [97]. These baboons have on
average about 23% of their body weight as fat in comparison to
their counterparts who both live and feed in the wild and have 1-2%
of their body weight as fat [97]. Leptin levels are 10 times higher in
the more obese of the garbage eating baboons and some have de-
veloped insulin resistance, hyperglycemia, and dyslipidemia [102].
Thus, the historic and prehistoric pressures exerted on human
ancestors which shaped the leptin negative feedback loop likely
occurred at serum leptin levels much lower than those seen at the
modern definition of ideal body weight. This early history is fossil-
ized in the BBB-mediated relations between CNS and serum levels
of leptin. The above view explains the first two questions posed
above. The feedback loop is poor at preventing obesity because it
evolved to be more of an accounting system of caloric reserve than
a defender of body weight. Its bias towards preventing starvation
rather than obesity produces a tendency to store more rather than
less calories. Thus, in conditions where calories are abundant and
caloric reserves are seldom called upon, body weight drifts upward.
This would explain why the most efficient area of the curve relating
CNS and blood levels of leptin is shifted to the left of where all but
the ill and most athletic reside in Western societies. It helps to ex-
plain why body weight is so hard to maintain in our society, as the
feedback loop, even in those with ideal body weight, is already
operating on an inefficient part of the CNS-serum leptin curve.
THE PRESSURE OF STARVATION ON THE LEPTIN
FEEDBACK LOOP
The adaptations of the leptin feedback loop occur during the
early starvation phase. There are four phases of metabolic adapta-
tion to starvation: the postabsorptive period, early starvation, inter-
mediate starvation, and prolonged starvation [103]. The early star-
vation phase in humans begins within about one day of onset of
inadequate calories, lasts about 7 days, and has as its hallmark a
shifting from the use of glucose as the primary fuel towards the use
of free fatty acids derived from adipose tissue triglycerides. Thus,
free fatty acid and glycerol levels rise in serum as does eventually
triglycerides.
The role of the BBB in controlling leptin transport in starvation
may help to answer the last three questions posed above. Whereas it
William A. Banks
does not make sense to inhibit the transport and action of an anorec-
tic during obesity, it makes a great deal of sense to do so during
starvation. That triglycerides inhibit the BBB transport of that an-
orectic signal is also logical. Triglycerides increase in blood during
starvation; thus, an elevation in serum triglycerides likely evolved
as a serum signal to brain of starvation.
During times of adequate nutrition, leptin would enter the brain
in effective amounts even when leptin levels are relatively low (Fig.
3). In this scenario, leptin in the brain acts as a sort of metabolic
switch. As caloric reserves become adequate as signaled to the
brain by leptin, caloric expenditures shift from that of mainly hunt-
ing for more calories towards those of reproduction, immune main-
tenance, bone mineralization, and cognitive functions. Thus, the
brain would sense whether reserves were adequate to shuttle caloric
expenditure from the task of finding still more calories to that of
other functions permitted by leptin.
When starvation occurs, levels of leptin in blood decrease and
BBB transport is blocked by triglycerides so that brain levels of
leptin diminish [88, 89, 104, 105]. Thus, a signal of caloric insuffi-
ciency is sent to the brain, even if the individual is obese. This sig-
naling results in a reduction in the anorectic signal and preservation
of calories by inhibiting thermogenesis, immune function, and re-
productive activities. Many of these activities are very calorically
expensive, especially immune system maintenance and reproduc-
tion in the female. Forcing an immune response requires enough
calories to cause significant mortality in a starving population
[106]. Some of the actions which leptin allows to be switched on
may be interrelated. For example, sexual activity, especially for
females with multiple sexual partners, is a challenge to the immune
system [107] and the expenditure of extra calories requires more
oxygen, perhaps explaining leptins effects on breathing. Thus,
leptin may be coordinating the onset of a suite of calorically expen-
sive functions that are interrelated at various levels.
BEYOND FEEDING: A SPECULATION ON THE EVOLU-
TION OF COGNITIVE PROCESSES
An interesting coincidence is that many of the feeding hor-
mones intimately involved in feeding are also involved in neuro-
genesis and cognition. These are exemplified by leptin, ghrelin,
insulin, and MSH [33, 108-110]. This coincidence might be ex-
plained on an evolutionary basis.
Feeding and digestion are among the most integrated of all
behaviors. Gastric secretions are stimulated by food in the stomach,
but begin with the site, smell, or thought of food. This cephalic
phase demonstrates the close association of psychological and
physiological processes from the very onset of feeding. The re-
mainder of the digestive process in most species is a complex,
multi-step process involving psychological, electrophysiological,
and hormonal interactions. The decision to seek and to ingest calo-
ries is equally complex for most species. For social animals, com-
plex rules may govern when, where, or who eats. In Western soci-
ety for example, many calories are consumed because of social,
rather than caloric, demands. But social rules also exist in groups of
animals living in the wild, be they predators or prey. Cost-
effectiveness valuations are also important: will the search for food
expend more calories than are likely to be found? What are the risks
of predation or injury in the pursuit of food? Thus, complex neuro-
logical connections already exist in lower animals that relate to
eating and digestion.
Given that evolution tends to adapt preexisting systems to new
uses rather than create them de novo, it makes sense that cognitive
processes would arise from the otherwise most complex neurology.
A knowledge of previous places and strategies that resulted in suc-
cessful acquisition of calories would benefit from enhanced learn-
ing and memory. Cost-effect evaluations like those listed above are
essentially executive functions. This could explain the original im-
petus for links between the cognitive and metabolic brain [111].
The Blood-Brain Barrier as a Cause of Obesity Current Pharmaceutical Design, 2008, Vol. 14, No. 16 1611

CNS Functions Thermogenic

Feeding Expenditures
Leptin
(CNS)
BBB Leptin (Serum)

Serum Leptin
Trig (Serum)
Fed Fast Starve
or Adiposity
Obese
Fat Mass
Deficit Excess

Caloric Balance =
Intake - Expenditure
Fig. (3). Leptin feedback loop during feeding, fasting, and starvation. Fat mass increases when calories eaten exceed caloric expenditure and decreases when
calories eaten are less than calories expended. Serum leptin levels reflect adiposity and CNS (brain and CSF) leptin is derivative of serum leptin. However, the
relation between levels of leptin in CNS and serum is not linear, owing to saturable nature of leptin BBB transporter. CNS leptin inhibits feeding and permits
or stimulates activities that consume calories and so promotes thermogenesis. Serum triglycerides decrease with fasting but increase in early starvation and
with obesity. Triglycerides, in turn, impair the BBB transport of leptin. Fasting and starvation also decrease leptin secretion from fat. These impairments of
leptin secretion and transport decrease leptin levels in the CNS and so attenuate both the anorectic signal and caloric expenditures.

That is, the complexity of feeding may have served as a template why the BBB transporter fails both in obesity and starvation, why
for the complexity of cognition and the first use of enhanced cogni- triglycerides may have evolved to inhibit the BBB transport of
tive abilities may have been to improve decisions relating to the leptin, and how the non-feeding functions of leptin are integrated
acquisition of calories. with its induction of anorexia and thermogenesis.

CONCLUSIONS: A REVISED VIEW OF LEPTIN'S ROLE IN REFERENCES

THE CNS
The above considerations portray leptin as the peripheral signal
by which the brain monitors caloric reserves stored as body fat. As
levels of leptin rise in the blood and brain, reflecting increased ca-
loric reserves, the brain increasingly shifts the use of calories from
feeding-related activities to other metabolically demanding activi-
ties such as reproduction, maintenance of the immune system, cog-
nition and neurogenesis, breathing, and bone mineralization. In this
view, leptin does not act as an adipostat targeting maintenance of
fat mass at a preset level, but more as a gauge of the caloric re-
serves that would be used for activities other than feeding.
This system is short circuited if caloric intake drops so dramati-
cally as to induce early starvation. Leptin secretion from adipose
tissue decreases rapidly and the transport of leptin across the BBB
is progressively impaired as starvation continues. With refeeding,
secretion of leptin from adipose tissue resumes. One major media-
tor of BBB inhibition is triglycerides, whose levels increase in
blood with starvation. Thus, leptin signaling to brain is disrupted on
several levels from the very onset of reduced caloric intake, and the
disruption is likely proportionate to the degree and length of caloric
deprivation. This reduction in leptin signaling in brain would de-
crease anorexia and caloric expenditure on activities not related to
the acquisition of more calories.
These characteristics of the leptin feedback loop as molded by
evolutionary pressures explain many aspects of body weight regula-
tion in humans. They explain why the leptin feedback loop fails in
obesity, why persons of ideal body weight are operating on an inef-
ficient part of the curve relating CNS and serum levels of leptin,
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