Selfish Brain
Transcript of Selfish Brain
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Review
The selfish brain: competition for energy resources
A. Petersa,*, U. Schweigerb, L. Pellerine, C. Hubolda, K.M. Oltmannsb,M. Conradc, B. Schultesa, J. Bornd, H.L. Fehma
aDepartment of Internal Medicine, University of Luebeck, Ratzeburger Allee 160, D-23538 Germanyb
Psychiatry and Psychotherapy, University of Luebeck, Ratzeburger Allee 160, D-23538 GermanycInstitute of Mathematics, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
dInstitute of Neuroendocrinology, University of Luebeck, Ratzeburger Allee 160, D-23538 GermanyeInstitut de Physiologie, Universite de Lausanne, 7 Rue du Bugnon, 1005 Lausanne, Switzerland
Received 1 December 2003; revised 12 March 2004; accepted 17 March 2004
Abstract
The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier,
has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the
peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives
priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary
importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term allocation refers to the
allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitaryadrenal (LHPA)
system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to thebrain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a
glutamate command signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the
blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-
affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This
setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress,
traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine
system. Disorders in the energy on demand process or the LHPA-system can influence the allocation of energy and in so doing alter the
body mass of the organism. In summary, the presented model includes a newly discovered principle of balance of how pairs of high and
low-affinity receptors can originate setpoints in biological systems. In this Selfish Brain Theory, the neocortex and limbic system play a
central role in the pathogenesis of diseases such as anorexia nervosa and obesity.
q 2004 Elsevier Ltd. All rights reserved.
Keywords: ATP, adenosine triphosphate; KATP, ATP-sensitive potassium channels; Na/K-ATPase, sodium potassium dependent adenosine triphosphatase;
BBB, blood brain barrier; LHPA, limbic-hypothalamus-pituitary adrenal; SNS, sympathetic nervous system; MR, mineralocorticoid receptors; GR,
glucocorticoid receptors; VMH, ventromedial hypothalamus; PVN, paraventricular nucleus; LH, lateral hypothalamus; ARC, arcuate nucleus; CRH,corticotropin-releasing hormone; ACTH, adrenocorticotropin; POMC, pro-opiomelanocortin; a-MSH, a-melanocyte-stimulating hormone; MC,
melanocortin; NPY, neuropeptide Y; GABA, g-amino-butyric acid; BDNF, brain-derived neurotrophic factor; NMDA, N-methyl-D-aspartate; AMPA,
amino-3-hydroxy-5-methyl-4-isoxazol propionate; LTP, long-term potentiation; LTD, long-term depression; CREB, cAMP responsive element binding
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. Physiological glucose regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1. Setpoints in the brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1.1. Setpoint of brain ATP regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1.2. Setpoint of limbic-hypothalamic-pituitary adrenal system regulation. . . . . . . . . . . . . . . . . . . . . . . . . 152
2.1.3. Homeostasis: brain ATP and the LHPA system in balance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2004.03.002
Neuroscience and Biobehavioral Reviews 28 (2004) 143180www.elsevier.com/locate/neubiorev
* Corresponding author. Tel.: 49-451-500-3546; fax: 49-451-500-4807.
E-mail address: [email protected] (A. Peters).
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2.2. Load of the brain-supplying regulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2.2.1. Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
2.2.2. Psychological stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.3. Sleep and the consolidation of setpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662.3.1. Stressors and the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
2.3.2. Stress reactions and the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
2.3.3. Memory formation during sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3. Pathological glucose regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3.1. Hypoglycemia unawareness (type 1 diabetes mellitus). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
3.2. Anorexia nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.3. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.4. Type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
1. Introduction
How does the human organism control its energy supply?
The answer to this question is the key to treating many
diseases: obesity and the so-called metabolic syndrome with
diabetes mellitus, hyperlipoproteinemia, hypertension and
cardiovascular diseases belonging to these disorders.
Gynecological diseases including polycystic ovaries or
psychiatric disorders such as depression or eating disorders
are also associated with disrupted regulation of energy
supplies. Two different processes can be distinguished that
regulate energy metabolism: energy supply (appetite, intake
of foods) and allocation (assignment). The various organs ofthe body must compete for the allocation of a limited
number of energy resources.
The brain occupies a special position amongst all the
organs concerning energy metabolism. It is the central
organ for regulating energy supply, and it is able to receive
information about the peripheral organs via peripheral
(e.g. hepatic) sensors and their afferent neuronal pathways.
Conversely, it can also control the functions of many
peripheral organs, e.g. the skeletal musculature, the heart,
the gastrointestinal tract or the sexual organs, via its
efferent nerve pathways. It is probable that this control is
not just restricted to physical movements and the function
of many inner organs, but that it also includes theregulation of energy metabolism. The neuronal discharge
and release of neurotransmitters and neuropeptides requires
exceptionally large amounts of energy [1]. The energy
consumption of the brain, related to its small proportion of
the entire body mass, is much larger than the energy
consumption of all other organs (e.g. muscle). The
proportion of energy consumed by the human brain
exceeds the proportion found in all other known species.
This fact may be relevant for the origin of characteristics
and disorders of metabolism found primarily in humans,
e.g. obesity. The brain is separated from the general
circulation by the bloodbrain barrier. Specific substrates
(such as glucose and lactate) or hormonal signals (such asinsulin or leptin) are transported exclusively by specific
transportation mechanisms across the bloodbrain barrier[2,3]. Thus, the transfer of substrates and hormones into the
brain is very strictly controlled. The capacity of the brain to
store energy is extremely limited, but maintenance of the
energy supply to the brain is of prime importance to the
survival of the whole organism. It is not therefore
surprising that the energy content immediately available
to the brain, i.e. in the form of adenosine triphosphate
(ATP), is strictly regulated within extremely narrow
boundaries. The brain is almost exclusively dependent on
the metabolization of glucose. As such, selection of
substrates by the brain is highly specific, while peripheral
organs (muscle) can metabolize glucose, fat or proteins.
Fatty acids can not traverse the bloodbrain barrier. Only
in special situations, such as with hypo or hypernutrition,
does the organism produce significant amounts of alterna-
tive substrates such as ketones or lactate that can traverse
the blood brain barrier and assume a role in supplying
energy to the brain. Finally, the brain is able to memorize
information about its control actions and their subsequent
effects, and to learn from the outcomes. It can use its
plasticity to optimize its control behavior.
Overall, therefore, the unique position of the brain is
characterized by
1. its physical barrier properties,2. its high energy consumption,
3. its low energy storage capacity,
4. its substrate specificity,
5. its plasticity, and
6. its ability to record information from and to control
peripheral organs.
In order to account for the idiosyncrasies of the brains
energy supply and to establish the meaning of these for the
entire organism, we propose here a new paradigm for the
regulation of energy supply in the organism:
The brain prioritizes adjustment of its own ATPconcentration. For this reason it activates its stress
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system and in so doing competes for energy resources
with the rest of the organism (allocation).
Thebrain then altersthe appetite(foodintake)so that it can
alleviate the stress system and return it to a state of rest.
With these two postulates, the brain simultaneously
represents the highest regulatory authority and the consumer
with the highest priority. The brain looks after itself first.
Such selfishness is reminiscent of an earlier concept in which
the brains selfishness was addressed with respect to
addiction [4]. We chose our title by analogy but applied it
in a different context, i.e. the competition for energy
resources. During stress and times of shortage it safeguards
its own supply even atthe expense ofall the other organs. The
brains obligation to alleviate its stress system in a second
stepand allow it toreturn toa state ofrest isnot trivial.Fromaregulatory-theoretic standpoint we presume that the stress
system is adjusted around a so-called setpoint at which it is at
a state of rest. In the second step the brain therefore pursues
the objective of satisfying its own energetic needs and those
of the entire organism on a long-term basis in the most
economic way possible. The regulation of the mass of the
various body compartments such as the adipose tissue is then
considered to be a secondary objective with this paradigm.
According to traditional paradigms the brain regulates
body mass by changing the intake of foods. Maintenance of
blood glucose within narrow limits is also of key importance
for maintaining health. The lipostatic theory was orig-
inally formulated by Kennedy 1953 [5]. Jeffrey Friedmanand coworkers of the New York Rockefeller University
supported this view in 1994 with their ground-breaking
finding of the hormone leptin [6]. With leptin, a hormone
was discovered in fat and muscle tissue that sends a
feedback signal to the brain so that the brain is informed
about the status quo of peripherally stored energy. Most
researchers considered this to be a closed regulatory system
in which the absorption of nutrients is the regulator, body
mass is the controlled parameter, and leptin is the feedback
signal. Notably, before leptin was discovered, the research
team of Stephen Woods and Daniel Porte at the University
of Washington, Seattle, presented compelling evidence for
insulin being an adiposity signal [7,8]. With the gluco-static theory, blood glucose is considered to be the
regulated parameter in the center of the regulatory system
and it is assumed that endocrine changes (for example
insulin, glucagon, growth hormone, and cortisol) and
behavioral changes are mainly responsible for maintaining
the concentration of blood glucose within narrow limits.
The implicit assumption that an adequate energy supply to
the brain automatically results from the constant behavior of
the fat reserves and the blood glucose is common to both the
glucostatic and the lipostatic theory. Another common
feature is the assumption that with obesity a defect can be
traced to the closed feedback loop. It can indeed be shown
that with most overweight people leptin is not able to restrictthe intake of foods. This phenomenon has been termed
leptin resistance. Such a leptin resistance is found both as
an inherited phenomenon with monogenetic defects [9,10]
and as an acquired phenomenon after overfeeding [11].
A large number of neurotransmitters, neuropeptides and
their receptors that mediate the leptin effect in the brain, e.g.
anorexigens such as Melanocyte Stimulating Hormone
(a-MSH), have been studied in detail over the last few years
[12]. The phenomenon of leptin resistance has as such been
well described, but its origin has so far escaped explanation.
The glucostatic and the lipostatic theories have explicitly
or implicitly provided the basis for a large number of
research strategies and therapeutic interventions for diabetes
mellitus, obesity and other diseases. Against this, however,
a range of observations have accumulated that can not be
satisfactorily explained by these views and research
approaches:
If healthy people are advised in a study to overeat
considerably over a period of months, they do increase
substantially in weight during this time, but within a few
months they can return again to their initial body weight
[13]. Clinical experience on the other hand shows that
although many people show good body mass regulation at
the start of their life, in later life (e.g. in the third decade),
their body mass increases. If these people then attempt to
reduce their body weight by dieting, the yo-yo effect
then sets in, and one gets the impression that body weight
is regulated at a new, raised virtual setpoint [14].
Phenomena such as the yo-yo effect show that the systemof body mass regulation is more complex than previously
assumed. If only a simple defect within the regulatory
system for weight regulation exists, such persons should
be able to return to and maintain their initial body weight
with their normal nutrition after a diet. However, the body
mass often exceeds the previous maximum. The fact that
only fewpeople succeed in reaching andmaintainingtheir
initial body weight means that the traditional view that
changes can be found within the assumed closed loop of
the body mass regulatory system (e.g. single or multiple
gene mutations) is too simple.
The study of metabolic, endocrine and behavioral
phenomena in repeated hypoglycemia has shown thatthe brain has mechanisms for protecting its functionality
actively within certain limits despite the existence of
very variable blood glucose concentrations. The energy
supply of the brain therefore represents more than just a
by-product of the energy supply of the whole organism.
If the energy supply of the brain is threatened, lipostatic
signals do not play any significant role in behavioral
regulation: ravenous hunger with hypoglycemia occurs
independently of the adipose tissue mass of the organism.
Traditional treatment concepts of type 2 diabetes mellitus
are derived from the glucostatic theory and aim at
normalization of blood glucose concentrations. The
United Kingdom Prospective Diabetes Study showedthat tight blood glucose control results in a reduction in
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theriskof microvascular but not of macrovascular diseases
[15]. No effects on theoverall mortality were observed. As
sideeffects of suchconceptsusing hypoglycemic agents or
insulin, undersupply of the brain (recurrent neurogluco-
penic comas) or oversupply of fat stores (body mass gain)
occurred [15]. Peter G. Kopelman from the Bartholo-
mews and the Royal London School of Medicine
commented in the editorial that the inevitable rise in
glycosylated HBA1c witnessed throughout the study
period, despite strict glycemic control, emphasizes the
need fora better understanding of the pathogenesis of type
2 diabetes in susceptible individuals [16].
Traumatization and psychiatric conditions such as
depressive or eating disorders lead to modifications in
the stress hormone system and various central transmitter
systems. They can also lead to considerable increasesand also reductions in body fat, even where defects in
the fundamental mechanisms of lipostasis or glucostasis
have not yet been observed until now. These observations
cast doubt on the priority of lipostatic signals in particular.
Despite intense research and the outstanding methodology
that is now available, genetic defects have been able to
explain only a small proportion of obesity and diabetes
cases up until now. The observed obesity epidemic
throughout the entire industrialized world illustrates this
[17,18]. The fact that people of a similar genetic
background under defined environmental conditions
remain of normal weight or develop excessive overweight
early on, however (e.g. Nauruans or Pima Indians) [19],
supports a significant role of genetic factors. The
traditional view fails to consider that a disorder might
also lie outside the feedback system for weight regulation,
e.g.in a higher-ranking regulatory system providing it withcommands.
Fig. 1. The Fishbone Model of glucose metabolism. The cerebral cortex sends a glutamate cinnabd signal to the subordinate regulatory subsystems: 1. the
allocation sybsystem assigns glucose via the glucose transporter 1 (GLUT1) to the brain, and via GLUT4 to the muscle and adipose tissue (yellow arrow).
2. The appetite regulatory subsystem controls the total amount of glucose available for allocation (red arrow). The energy content of the brain and peripheral
tissues is measured with multiple sensors. The limbic-hypothalamic-pituitary-adrenal (LHPA) system, which includes the sympathetic nervous system, plays a
decisive role in allocating glucose. The activity of the LHPA-system is indicated by the serum cortisol concentration. Feedback signals on the energy status in
the brain (glucose), the peripheral organs (leptin), and on the activity of the LHPA system (cortisol) act on the various hierarchical levels of the system, i.e. thecerebral cortex, the limbic system and the hypothalamic sites for allocation (ventromedial hypothalamus) and intake (lateral hypothalamus) of foods.
Cortical balance. If the brain-ATP is too low, the glutamate command signal is stimulated in the cerebral cortex via high-affinity ATP-sensitive potassium
channels; if the brain-ATP is too high, it is suppressed via low-affinity ATP-sensitive potassium (KATP) channels. In this way the system strives for a balance
whereby the opposing effects of high-affinity and low-affinity KATP channels are of the same magnitude.
Limbic balance. If the serum cortisol is too low, the LHPA system is stimulated via high-affinity brain mineralocorticoid receptors (MR); if the serum
cortisol is too high, it is suppressed via low-affinity brain glucocorticoid receptors (GR). Here, the LHPA system strives to achieve a balance whereby the
stimulating and suppressing feedback signals are of the same magnitude.
Allocation. If the energy content is too great in the muscle and adipose tissue, leptin activates the ventromedial hypothalamus (VMH) that allocates glucose
to the brain; if the energy content of the brain is too large, the brain ATP suppresses the VMH, so that glucose is allocated more to the musculature and adipose
tissue. Thus, the allocation-subsystem strives for a balance whereby the feedback signals from the brain and the periphery are of the same magnitude.
Appetite. If the energy content is too low in peripheral tissues, the appetite stimulating lateral hypothalamus (LH) is activated via NPY; if the
energy content is too large in the periphery, the LH is inhibited via a-MSH. The NPY- and a-MSH-signals are filtered in the arcuate nucleus (ARC)
and conveyed only under certain circumstances to the LH. The key feedback-signal for regulating the intake of foods is brain glucose.
If the stimulatory and inhibitory feedback-signals in the cerebral cortex, in the LHPA system, and in the hypothalamus are balanced, the organism
achieves a state of energetic homeostasis. Coordinates indicate positions in the model that are referred to in the text.
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While most research continues to focus on crucial
hypothalamic circuits, a small group of scientists have
already broken new ground, since recent work has clearly
shown that ingestive behavior is influenced by a widely
distributed neural network, which includes the caudal
brainstem, limbic and cortical structures [2022].
The paradigm proposed by us places the regulation of
ATP-concentration in the brain at the focal point. The brain
initially adjusts its own ATP-concentration by burdening its
own stress system and competing for energy resources
within the body. The brain changes eating behavior so that it
can then alleviate the stress system and return it to a state of
balance. The regulatory principles of this paradigm have
been formulated mathematically as a dynamic system and
graphically illustrated in the form of a so-called fishbone
model [23] (an overview is given in Fig. 1, more details areexplained in chapter 2).
Readers and authors are faced with a dilemma regarding
the needs of simplicity and complexity, i.e. between merely a
suggestive and an explicit representation of specific
mechanisms. The fishbone model has a simple but not a
trivial structure: it represents a hierarchically organized
system with a forward pathway (similar to the spine of a fish)
and multiple paired stimulatory and inhibitory feedback
pathways (the fishbones). Flow charts of complicated control
systems can be simplified by mathematical transformations
[24]. The most simple model for allocating energy resourcesto 2 organs, e.g. to the brain and muscle, has a fishbone like
structure. Such a special model structure is suitable fordealing with different levels of complexity.
Is the model oversimplified or too abstract?
One point of view might be that important hormones
(e.g. resistin, ghrelin) escape mention here so that the true
complexity of energy metabolism is not delved into. We
reviewed the literature and indeed often found two or more
biological mechanisms for each individual component in the
mathematical model. As such there appears to be much
redundancy in glucose regulation. Redundant signal pathways
can be added to the fishbone model (new fishbones) without
changing the basic model structure. The activation of the
sympathetic nervous system is mediated by leptin and insulin
as well. In the model, the hormone leptin conveys a signal tothe brain that energy has been stored in peripheral organs,
particularlyin the adipose tissue, and is not therefore available
at thattime as a substratefor thebrain. Correspondingly,leptin
conveys a signal to certain hypothalamic neurons [25] and in
this way invokes an increase in sympathetic nervous system
activity and thereby an increased allocation of glucose to the
brain. Insulin sends a similar signal analogous to this. Insulin
in the same way informs the brain that glucose is stored and
unavailable for supplying the brain. Correspondingly, insulin
can influence the same hypothalamic neurons in the same
manner [26], so that the sympathetic nervous system is
stimulated and the appropriation of glucose by the brain is
ensured. This example shows that leptin and insulin transmitrelated or similar signals to the brain. There may be
distinguished differences in the timing of their feedback
signals, however, in principle they transmit redundant
messages. The stimulatory insulin feedback pathway can be
integrated into the fishbone model without changing its
fundamentalstructure.Only thedegree of redundancy, andnot
the relevancy of the model, is changed through suchadditions.
Is the model too complex or explicit?
We have in fact refrained from including a large number
of biological mechanisms that might also fulfill functions in
the model. A list of various possible redundant signals was
presentedin an earlier manuscript [23]. However, we decided
to assign only a single functional mechanism and a single
anatomical structure to a single signal pathway in the model.
Leptin acts for example as a substitute for a class of signals
that contains insulin amongst other elements, and which can
fulfill all the functions described in the model. We are awarethat there might be a better selection forsuch a substitute, and
that in the future hormones might be discovered that fulfill
this function better and so have a greater biological relevance
than the ones mentioned here. This may likewise account for
the selection of brain structures referred to in this paper. The
limbic system and the hippocampus for example are
extremely complex structures per se, supporting many
other specific functions not relevant here, and of course,
those relevant here may in part be fulfilled by other redundant
structures. We are also aware that the assignments proposedhere might be the subject of some debate, but we feel that the
specificities of the model presented are less important than
the general basic principle proposed here for energymetabolism. We followed the advice that everything should
be made as simple as possible, but not simpler [27].
The newly presented theory regarding the regulation of
energy supply is only valid within a certain scope. For
example, many experiments that arecitedhere in support of the
model have only been carried out under special experimental
conditionsin in-vitroor inanimalstudies,but have notyet beenconfirmed in humans. Also, many studies in humans cited here
have only been performed in men but not in women. Several
hypotheses can be derived from the presented model. In the
future, testing of such hypotheses shall allow a redefinition of
the scope within which the theory is valid, whether it be
broadened or narrowed. In this review article we would like toapply the selfish brain theory to offer new explanations for
phenomena which until now have escaped clarification.
2. Physiological glucose regulation
2.1. Setpoints in the brain
2.1.1. Setpoint of brain ATP regulation
2.1.1.1. Measurement with two receptors. How does the
brain maintain ATP constant at a specific concentration?
To answer this we propose a principle whereby the braincontrols this concentrationusing high-affinity and low-affinity
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ATP-sensitive potassium channels. ATP-sensitive potassium
channels (KATP) belong to a special class of ion channels that
couple bioenergetic metabolism to membrane-excitability
[28]. KATP is present not only at neurons and neuroendocrine
cells, but also on many other cell types, such as those of
skeletal and smooth muscle [29,30]. These KATP channels are
closed by intracellular ATP. While the energy-rich ATP
closes these potassium channels, the low-energy adenosine
diphosphate (ADP) can open the ATP-sensitive potassium
channels. Forthisreason theintracellularratio of ATPto ADP
is a key regulator for the functional state of the ATP-sensitive
potassiumchannel.ATP andADP bind to specific parts of the
KATP channel: at the nucleotide binding domain of the so-
called sulfonylurea receptor (SUR), that together with the
actual channel pores forms a single morphological unit [31].
The SURprotein belongs to theATP binding cassette (ABC)family [32]. The KATP channel therefore represents a
membranous, molecular structure that fulfills the regulat-
ory-theoretic criteria of an energy sensor (or more simply an
ATP sensor).
If one provides an excitatory neuronwith sufficient energy
reserves, i.e. a high intracellular ATP to ADP ratio, these
membranous KATP channels are closed. With closed KATPchannels a potassium efflux from the cell is prevented via this
ion channel, which enables depolarization. Calcium flows
into the cell interior. The neuron releases neurotransmitter
(such as the excitatory amino acid glutamate) or neuropep-tides (such as the neurotrophin brain-derived neurotrophic
factor; BDNF) from its nerve endings. If the energy contentof the neuron is high enough, the KATP channels allow a
neuronal excitation. If on the other hand a fall in intracellular
ATP content occurs, the KATP channels are opened, the
neuron is hyperpolarized (andthereby electrically stabilized),
and its function is deactivated. The KATP channels therefore
also have a cytoprotective function: with energy deficiency
the function of the cell is turned off and the residual energy is
saved for structural maintenance of the cell [3335].
Interestingly enough, there are two different types of KATPchannels: those with high-affinity and low-affinity ATP-
binding sites. These ATP-binding properties allow them to be
assigned to twosubtypes, i.e. SUR1 andSUR2 [3639]. With
low intracellular ATP content the high-affinity ATP-sensitivepotassium channels are mainly occupied, and are closed as a
result. These high-affinity ATP-sensitive potassium channels
are found in the cortex and in many other brain areas on
excitatory neurons [40,41]. Such neurons are able to be
electrically active with a low ATP content. However, if the
ATP-concentration declines to a very low and thereby critical
concentration for survival of the neuron, these high-affinity
ATP-sensitive potassium channels no longer bindadequately.
The corresponding KATP channels are then opened and the
cell function is deactivated. The high-affinity ATP-sensitive
potassium channels in the neocortex play an essential role in
protecting against seizures and neuronal damage [42].
In contrast, with high intracellular ATP content the low-affinity ATP-sensitive potassium channels are also
occupied. There are KATP channels in the entire cortex
[33,4347], where they are localized both presynaptically
and postsynaptically [48]. In some brain areas presynaptic
KATP channels reduce the liberation ofg-amino-butyric acid
(GABA): e.g. in the hippocampus [49] and in the substantia
nigra [5053]. It is worthy of note that both low-affinity and
high-affinity ATP-sensitive potassium channels have been
found in human neocortex [54]. Although it has not been
confirmed in any single experiment, we do presume from
current data that in human neocortex there are also
presynaptic, low-affinity ATP-sensitive potassium channels
that reduce the GABAergic tone. This assumption is also
supported by the clinical observation that with progressive
energy deficiency in the brain there is initially an excitatory
stage with a raised seizure tendency, followed by a calming
of the cortex. These findings are consistent with apresynaptically mediated GABAergic tone, which with a
slight energy deficit can be reversed via low-affinity
ATP-sensitive potassium channels [53].
If one assumes that the high-affinity ATP-sensitive
potassium channels are located on excitatory neurons, while
the low-affinity ATP-sensitive potassium channels are
localized on inhibitory neurons, this distribution pattern
leads to the following dynamic behavior: with critically
reduced ATP both the excitatory and inhibitory neuron
populations are functionally inactive. This phenomenon has
been described as a global silencing of the cerebral cortex
[55]; itsclinical correlate is the hypoglycemic, or bettersaid
the neuroglucopenic coma. With low, but non-critical ATP-content in both neuronal populations, ATP binds almost
exclusively to the high-affinity ATP-sensitive potassium
channels, i.e. to those on the excitatory neurons that release
glutamate. Contrastingly, with high cerebral ATP concen-
trations the inhibitory neurons also become active, i.e. those
that exert an inhibitory effecton the excitatory population. All
in all, a biphasic activity pattern results for the excitatory
neuronal population that depends on intracellular ATP
content (Fig. 3a). Of decisive importance is the fact that the
balance between excitatory and inhibitory neuronal popu-
lations changes depending on brain ATP concentration. At
low brain ATP concentrations the glutamatergic population is
dominantly active, while at high ATP concentrations theactivity of the GABA ergic population predominates.
An effective regulatory system for brain ATP can be
described with the following overall principle:
1. ATP binds to high- and low-affinity ATP-sensitive
potassium channels.
2. Bound high affinity ATP-sensitive potassium
channels permit glutamatergic neuronal activity,
while bound low-affinity ATP-sensitive potassium
channels permit GABA-ergic activity.
3. Glutamatergic neurons raise brain ATP, while
GABA-ergic neurons lower it.
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Up to now we have demonstrated the first and the second
rule. In the next chapter we shall explain the third rule and
how the glutamate command signal promotes an increase in
the brains energy content. These three simple rules
regarding the interplay between ATP, the two different
affinity ATP-sensitive potassium channels and the glutama-
tergic and GABAergic neuronal populations describe
a secure regulatory system that balances the brain ATParound a certain concentration. This concentration can be
described as a balance setpoint for brain ATP.
2.1.1.2. Astrocytic energy on demand. The brain can
supply itself by requesting energy firstly from the body
periphery and secondly from the environment. For this
purpose the brain must invest considerable expense, e.g.
activate its stress systems or acquire new food resources inorder to actually procure the requested amount of energy. If
there is not an adequate food supply (such as during times of
starvation), the brain has no other possibility but to compete
for energy resources within the organism.
How does the brain compete with the body for energy
resources?
The brain controls the allocation of glucose between the
brain on the one hand and the musculature and adipose
tissue on the other. In order to allocate glucose to itself, the
brain must open the bloodbrain barrier for glucose and cut
off the supply to peripheral tissues.
As mentioned above, it is the glutamatergic neuronal
population that activates the allocation of glucose to thebrain. Although all neurons independently of the type of
neurotransmitter released (glutamate or GABA) use energy,
it has only been verified for the glutamatergic populationthat they also serve for energy replenishment [56].
GABAergic neurons on the other hand do not mediate any
such allocation of glucose to the brain [57], but instead
inhibit the glutamatergic neurons with the help of their
transmitters and only consume energy.
Which molecular mechanisms can glutamate utilize to
enhance energy substrate availability for parenchymal
cells?
The astrocyte, a specific type of glial cell, plays a key
role in allocating glucose across the bloodbrain barrier.The principle energy on demand has been used to describe
the (local) response of astrocytes to glutamatergic activity in
order to provide lactate to active neurons as an energy
substrate [56]. Glutamate that is freed at the synapse upon
excitation is rapidly removed again to allow subsequent
transmission events. Astrocytes enclose most glutamatergic
synapses and collect released glutamate with a highly
efficient and specific transporter system. Transporters are
driven by the electrochemical sodium gradient, a fact that
leads to a tight coupling between glutamate and sodium
uptake [58]. The astrocyte is now confronted with two tasks:
the recovery of glutamate and the restoration of the sodium
gradient. The gradient is restored by the activation of thesodium- and potassium-dependent adenosine triphosphatase
(Na/K-ATPase) [59]. Glutamate is converted into
glutamine which is released by astrocytes and taken up by
the neuronal terminal. There it is enzymatically converted
again into glutamate so that the neuronal glutamate pool is
refilled again. There is no ATP exchange between astrocytes
and neurons, so that each cell type must secure its own
energy supply.
The end-feet of the astrocytes are equipped with specifictransporter molecules, i.e. glucose transporter 1 (GLUT1),
and enclose practically all the capillary walls within the
brain. A close morphological and cytological relationship
exists between astrocytes and cerebral capillaries. In this
way the preconditions for a functional coupling between
synaptic activity and glucose uptake are fulfilled: glutamate
activates its glutamate transporter and stimulates glucose
uptake into astrocytes [60,61]. Glucose is broken down inthis process to lactate, which is then released and
made available as an energy source for neighboring neurons
[62,63]. The energy that arises during the glycolytic
breakdown of glucose to lactate is used in the astrocytes
to support the activity of the Na/K-ATPase and to
convert glutamate into glutamine [59], while in the neuron
lactate utilization will be employed for closing the
postsynaptic KATP channels and for excitation [64]. This
cascade of molecular events represents a direct mechanism
for the coupling between synaptic glutamate release and
glucose allocation to the neuron via the bloodbrain barrier
and the astrocytes.
2.1.1.3. Systemic energy resource request. How can the
brain prevent glucose uptake into muscle and adipose
tissue?
Peripheral glucose uptake can be restricted through
activation of the limbic-hypothalamic-pituitary adrenal
(LHPA) system. The LHPA system is a neuroendocrine
system closely associated with stress in mammals [65]. This
system allows a rapid reaction to stressful stimuli and
ultimately guarantees a return to homeostasis via complex
feedback mechanisms. Hierarchically, the limbic system
therefore represents the highest authority in the control of
stress reactions. In the limbic system there are two core
regions that carry out this control: the hippocampus and theamygdala. These limbic neurons project with axons directly
or via the VMH into the paraventricular nucleus (PVN).
Here, the sympathetic nervous system is activated and
neuropeptides are formed and released such as cortico-
tropin-releasing-hormone (CRH) and vasopressin. These
releasing hormones stimulate adrenocorticotropin (ACTH)
release into the general blood circulation within the
pituitary. ACTH ultimately stimulates the release of cortisol
from the adrenal cortex. The sympathetic nervous system
projects with its efferent nerve pathways to the adrenal
medulla where it stimulates the liberation of adrenaline. The
sympathetic system also innervates the pancreatic b cells
[66] where it suppresses insulin release [6769], as well asthe musculature and adipose tissue where it suppresses
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the uptake of glucose [7072]. In this way, the LHPA
system can increase the glucose concentration in the blood.
In the limbic system, energy needs, in addition to
activating the energy on demand signal (local), also trigger
a systemically effective energy resource request signal
(for the whole brain), with glutamate being the mediator in
both cases. In addition to that direct limbic mechanism
requesting energy (internal sensing or detector area), other
parts of the cortex will also signal their needs to the limbic
system. Thus, the limbic system might act both as a detector
and transducer of global brain energy needs.
What effects do cortical glutamatergic neurons have on
limbic neurons?
Patricia Molina and coworkers of the Louisiana State
University in New Orleans were able to show recently that
primarily glutamate receptors of the NMDA subtypemediate the activation of the LHPA system with brain
glucose deficiency [73]. The NMDA receptor plays a key
role for the pyramidal cells of the limbic system and has a
function not only for setting the tone of the LHPA system,
but also in memory formation (see the chapter memory
formation during sleep). The stimulation of other subtypes
of glutamate receptors also brings about a strong activation
of the LHPA system [74,75]. The above-mentioned team
also succeeded in establishing a link between cortical
glutamatergic activity and the activation of stress systems.
It is well known that stress systems can restrict theallocation of glucose to muscle and adipose tissue. In
summary, cortical glutamatergic neuronal populations areapparently able to adjust the allocation of glucose to the
brain by favoring glucose utilization in brain while
impeding it in muscle and adipose tissue.
The cerebral cortex sends the glutamate command
signal to both of its regulatory subsystems that control
glucose allocation and appetite. Energy supply for the brain
results from the activity of the two regulatory subsystems.
Brain ATP binds to low- and high-affinity ATP-sensitive
potassium channels as a feedback signal. High-affinity
ATP-sensitive potassium channels increase the cortical
glutamatergic tone and in so doing the glutamate command
signal. Low-affinity ATP-sensitive potassium channels
increase the cortical GABAergic tone and in so doingsuppress the glutamate command signal. In this way the
primary regulatory system strives for a cortical balance
between glutamatergic and GABAergic neuronal activity at
which the ATP concentrations are optimal.
How does the brain request energy resources from the
environment?
The LH is a key region of the brain that controls appetite
and eating behavior [76]. Feeding and fasting is not simply
controlled by a hypothalamic center, but rather by quite a
large network of neurons located at many different sites
(thalamus, subcortical nuclei, hypothalamus, brainstem, and
medulla). Signals originating in the LH appear to reach
other brain sites by first descending to the parabrachialnucleus [77]. Here, we assign the LH as one representative
anatomical site to the functional component appetite in
the model.
Glutamate is a potent stimulus that stimulates neurons in
the LH to increase appetite and initiate food intake [78,79].
The LH, however, is under the direct influence of the limbic
system. Upon cortical excitation, multiple locally effective
glutamate command signals from cortical neurons are
integrated within the limbic system. The limbic system
functions as a transducer between this integrated glutamate
command signal and setpoints of subordinate hypothalamic
systems: one setpoint signal is conveyed via neuronal
pathways to the VMH (allocation), and another is conveyed
to the LH (appetite). The limbic system transduces the
signals to the VMH and the LH differently. While the signal
to the VMH is adapted under certain conditions, i.e.
amplified or suppressed [80,81], the signal to the LH israther robust and less altered. As an example, recurrent
hypoglycemia leads to attenuation of VMH-mediated
counter-regulation (e.g. adrenaline, glucagon)[82], but not
to an attenuation of hunger (LH) [83]. The limbic system
also coordinates the order in which the VMH or LH are
activated. The VMH mobilizes glucose for the brain within
seconds, but an activation of the LH only leads after a delay
(and only with sufficient food intake) to an increase in
glucose supply to the brain. The limbic system therefore
conveys the energy resource request signal first to
the VMH, whereas the LH is inhibited by this signal [84].If the output to the VMH is weak, the appetite controlling
LH is disinhibited. The allocation controlling VMH istherefore ranked higher than the appetite controlling LH,
whereby these two components have reciprocal functions
[8587].
The activated neurons of the LH also provide orexi-
genic (i.e. appetite increasing) neuropeptides via
projections to different parts of the brain [88]. These
orexigen-secreting neurons increase the drive for feeding
and ultimately also have an influence on complex
behavioral patterns (e.g. purchasing behavior for foodstuffs)
related to feeding.
Fig. 2a summarizes the command principle once again:
cortical glutamatergic neuronal populations release gluta-
mate upon excitation. On the one hand the glutamatecommand signal triggers an astrocytic energy on demand
process. On the other hand the glutamate command signals
input into the limbic system, where they are transduced into
energy resource request signals. These setpoint signals are
conveyed to the subordinated hypothalamus. Here the VMH
(allocation) and the LH (appetite) are stimulated. The VMH
increases the proportion of circulating glucose to be
assigned to the brain, while the LH strives to increase the
total amount of circulating glucose. Allocation and food
supply therefore determine the proportion of glucose that is
assigned to the brain. The amount of glucose available to the
brain influences the amount of ATP available to it. With low
ATP in the brain the high-affinity ATP-sensitive potassiumchannels are closed for the most part (i.e. those channels
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enabling the stimulation of glutamatergic neuronal popu-
lations), and these demand further energy. If the brain ATP
on the other hand is high, the low-affinity ATP-sensitive
potassium channels are also closed, and the GABAergic
neuronal population decreases the brains energy demand.
In this way a regulatory system results that resembles the
principle of supply and demand in a free market economy,
and which is able to regulate brain ATP around a specific
balance setpoint.
2.1.2. Setpoint of limbic-hypothalamic-pituitaryadrenal
system regulation
How does the brain regulate the activity of its LHPA-
system?
We propose that it regulates this with the aid of high-
affinity and low-affinity brain corticosteroid receptors. Twotypes of corticosteroid receptors are known in the brain.
Starting in the year 1968 with the milestone paper of Bruce
McEwen at the Rockefeller University in New York[89], a
large number of researchers have since managed to
characterize the two brain receptor subtypes both biochemi-
cally and functionally. The type I or MR in the brain
resembles the MR in the kidney and has a high specificity
for selectively binding cortisol, the primarily active
glucocorticoid in humans [65]. In the brain, the MR is
localized most densely in the limbic system, i.e. in the
hippocampus and in the amygdala, where it binds cortisol
with high affinity. Contrastingly, the type II or GR binds
cortisol with a low affinity. The presence of GR receptorshas been confirmed in many brain regions, including the
limbic system, the hypothalamus, and the pituitary. MR
binds cortisol with a 10-fold higher affinity than does
the GR. These receptor properties allow MR and GR to
regulate LHPA system activity. MR is bound with low
cortisol concentrations and develops its effects mainly
during the evening nadir of the cortisol circadian profile. At
high cortisol concentrations, e.g. after morning awakening
or during a stressful incident, MR also bind cortisol, but the
bound GR dominates in its effect and is decisively involved
in ensuring that the LHPA system returns to homeostasis. In
fact, three years later the group showed in vivo that
peripheral injection of a larger dose of a glucocorticoid
reduced hippocampal firing activity [90].
Pyramidal cells in the hippocampus and the amygdala
express both MR as well as GR receptors [91]. One known
function of these limbic MR and GR receptors is to modify
memory storage and retrieval [92,93]. Both receptors are
formed in the cell nucleus and are then released into the
cytosol of the neuron. Cortisol traverses the external cell
membrane of the neuron without a specific transporter and
binds in the cytosol with high affinity to MR and with low
affinity to GR. The cortisol concentration as well as the
number of MR and GR present in the cytosol determine how
many cortisol molecules bind to GR and MR. Only cortisol
bound MR and GR complexes can traverse the nuclearmembrane and reach the cell nucleus where the cortisol-
bound receptors form dimers with one another [9496]:
MR MR homodimers, MR GR heterodimers and GR GR
homodimers. The homodimer MRMR binds to a gluco-
corticoid responsive element (GRE) in the genome. The
other dimer-types compete with theMR MR homodimerfor
these GRE binding sites in the genome and inhibit its effect.
What influences do MR and GR have on the activity of
the LHPA system and with that the secretion of cortisol?
We assume that cortisol-bound MR stimulates the LHPA
system while cortisol-bound GR prevents this stimulation.
This assumption is supported by a unique study in which
cortisol effects over a very broad range of cortisolconcentrations were illustrated [97]. In this study patients
with Cushings disease, who had had both adrenal glands
removed completely, were infused with cortisol. During
infusion, serum cortisol climbed from very low concen-
trations continuously to very high concentrations. With low
cortisol concentrations there was a marked increase in
ACTH secretion, while with high cortisol concentrations
there was a marked decline. This finding is consistent with an
MR-mediated stimulation and a GR-mediated suppression
of the LHPA-system. In this investigation a bell-shaped
Fig. 2. (A) The primary regulatory system for brain ATP regulation. The cerebral cortex sends the glutamate command signal to both of its regulatory
subsystems that control glucose allocation and appetite. Energy supply for the brain results from the activity of the two regulatory subsystems. Brain ATP binds
to low- and high-affinity ATP-sensitive potassium channels as feedback signal. High-affinity ATP-sensitive potassium channels increase the cortical
glutamatergic tone and in so doing the glutamate command signal. Low-affinity ATP-sensitive potassium channels increase the cortical GABAergic tone and in
so doing suppress the glutamate command signal. In this way the primary regulatory system strives for a cortical balance between glutamatergic and
GABAergic neuronal activity at which the ATP concentrations are optimal. (B) The LHPA system as a regulatory subsystem of brain ATP regulation. The
LHPA-system restricts the GLUT4-mediated glucose uptake into muscle and adipose tissue and with this increases the GLUT1-mediated glucose uptake into
the brain. Cortisol is the feedback-signal for the LHPA-system. Cortisol binds in the limbic system to high-affinity mineralocorticoid (MR) and low-affinity
glucocorticoid (GR) receptors. With low cortisol concentrations MR stimulate the LHPA-system, and with high cortisol concentrations GR suppress its
activity. In the hierarchically subordinate hypothalamus (PVN) only GR-receptors act inhibitorily at high cortisol concentrations. The activity of the LHPA-
system determines the allocation of glucose to the brain and the periphery. In this way the LHPA-system defines the setpoint for regulation of body mass.
(C) Leptin and its amplifier. Leptin conveys the feedback-signal regarding energy status in the adipose and muscle tissues to the hypothalamic VMH where
leptin stimulates the allocation of glucose to the brain. An amplification mechanism for leptin activity is localized in the arcuate nucleus (ARC). Here, at low
leptin concentrations, the appetite stimulating NPY is primarily produced, while at high leptin concentrations the appetite suppressing a-MSH is mainlyproduced. a-MSH stimulates the allocation centre (VMH) and thereby amplifies the direct effect of leptin, while NPY on the other hand suppresses the effect of
leptin on the VMH.
R
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dose-responserelationship was shownfor cortisol in humans,
analogous with a similar relationship found by other
investigators in numerous experiments investigating the
effects of cortisol on the excitability of neurons in the
hippocampus [98,99].
There is a debate as to whether limbic MR act in a
stimulatory or inhibitory way on the LHPA-system.
Pharmacological interventions with MR-inhibitors result
in elevated basal glucocorticoid concentrations, possibly
suggesting an inhibitory effect of MR [100]. However,
it must be considered that with such interventions
the underlying process is not a simple ligand receptor
interaction, and that heterodimerization (see above) or the
autoregulation (see below) of MR and GR can cause
paradoxical effects (as have clearly been demonstrated in
literature [101,102]). Thus, conclusions based on pharma-cological inhibition may be erroneous. Processes like
heterodimerization and autoregulation are so-called non-
linear [24], and it is this very nonlinear property that makes
an experimental analysis difficult, but at the same time
makes the LHPA-system particularly stable.
Neurons of the limbic system are the starting point for the
stimulation of the LHPA system. Here, MR and GR regulate
the expression and transcription of a large number of genes.
One group of genes controls the behavior of ion channels
(e.g. calcium channels), a second gene group regulates
ligand-bound ion channels (e.g. glutamate receptor coupledchannels) and a third group influences G protein-coupled
receptors. Ronald de Kloet and Marian Joels at theUniversity of Amsterdam/Leiden, Netherlands, discovered
many such corticosteroid effects and described them in a
number of comprehensive reviews [98,99]. Thus, MR has
the ability to influence the excitability of limbic neurons via
the expression and transcription of a variety of gene
products. MR and GR modulate amongst other things
glutamate-mediated signal input [103].
Here we focus on the effects of MR and GR on
limbic neurons that stimulate the hypothalamic neurons.
The neurons stimulate via direct or indirect neuronal
pathways the hypothalamic release of CRH and vasopressin.
The latter release-hormones activate the formation of pro-
opiomelanocortin (POMC) peptide in the pituitary, fromwhich ACTH is cleaved. Pituitary ACTH is secreted and
stimulates the adrenal release of cortisol. Therefore, in this
model MR promotes and GR inhibits the release of cortisol
via a range of intermediate steps.
Circulating cortisol is metabolized in the liver and
eliminated with a half-life of about 120 min. The clearance
function for cortisol corresponds to an elimination of the first
order, i.e. the clearance rate of cortisol is proportional to its
concentration. The higher the cortisol is in the serum, the
higher is its hepatic elimination. ACTH has a half-life of
about 20 min and CRH a half-life of about 9 min.
Individuals who no longer have adrenal glands, e.g. patients
with Addisons disease, can no longer produce any cortisolthemselves; in such individuals cortisol is removed from
thecirculationaccording to itshalf-life: after 2, 4, and6 h it is
reduced to 1/2, 1/4 and 1/8. This means that without adrenal
production and secretion of cortisol more than 85% of the
cortisol is already eliminated from thecirculationafter6 h. In
the cortisol circadian profile it falls continuously to a
minimum in the evening from a morning maximum after
awakening. However, this drop-off rate is much slower than
that of the hepatic cortisol clearance. The slow reduction in
cortisol over the day therefore requires a continuous release
of cortisol from the adrenal gland which slows the fall in
cortisol. One can see that the limbic system has to stimulate
the hypothalamic center continuously in order to prevent a
rapid reduction in serum cortisol. The stimulatory effect of
thelimbic systemmust be even greater if oneconsiders that at
hierarchically lower levels CRH, ACTH and cortisol are still
subject to a GR-mediated feedback-inhibition (Fig. 3b).We propose the following general principle to illustrate
how the activity of the LHPA system is regulated:
These three simple rules regarding the interplay between
cortisol, the two differing affinity receptors MR and GR and
the various MR and GR homo- and heterodimers describe a
control system that regulates cortisol secretion around
a setpoint. This concentration can be designated as a
balance-setpoint for the activity of the LHPA system, which
in humans is usually achieved during the evening. The
reader will surely notice at this point that the regulation
principle underlying brain ATP regulation and LHPA
system regulation is the same. It would not be surprising
if during evolution a reliable and simple regulatory principle
that has proven its worth with one aspect of metabolism
should also be encountered in other areas.
2.1.3. Homeostasis: brain ATP and the LHPA
system in balance
The hierarchical positions of brain ATP regulation and
LHPA regulation are different. The brain ATP regulation
has the highest biological priority. It therefore represents a
primary regulatory system. This primary regulatory system
for brain ATP regulation operates with the glutamate
command signal. This signal is conveyed to its two
regulatory subsystems, i.e.: (1) to the LHPA system, and
(2) to the appetite-regulating LH. The LHPA system
determines the allocation of glucose to the brain and the
body periphery while the LH is essential for eating behavior.Thus, the brain has two ways of fulfilling its demand
1. Cortisol binds with high affinity to MR and lower
affinity to GR.
2. Cortisol bound MR and GR assemble into three
forms of dimers: MRMR, MRGR or GRGR.
3. MR MR homodimers stimulate the LHPA system
and thereby cortisol secretion, while GR interferes
with this effect.
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Fig. 3. (A) Setpoint for brain ATP regulation. The rate of change in brain ATP over time [dATP/dt] (ordinate) depends on the brain ATP itself (abscissa). High
affinity ATP-sensitive potassium channels on glutamatergic neurons are closed at low brain ATP concentrations so that the neurons can become functionally
active (green function). Low affinity ATP-sensitive potassium channels on GABAergic neurons permit functional activity only at higher brain ATP
concentrations (red function). Since the GABAergic neurons are inhibitory towards glutamatergic neurons, a reduction of glutamatergic neuron activity occursat higher brain ATP-concentrations (green function). Inset on the upper right: Dependency of the energy balance of glutamatergic neurons on brain ATP is
shown here: glutamatergic neurons stimulate glucose transport across the bloodbrain barrier using the energy on demand signal. These neurons require
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for energy. On the one hand it can alter glucose allocation,
i.e. the percentage of glucose transported across the blood
brain barrier, and on the other it can alter food intake, i.e. the
total amount of glucose available for distribution. If
sufficient energy resources are available to the organism,
the brain can request energy via both regulatory subsystems
(i.e. allocation andappetite). This means that the greater the
allocation to the brain the less food intake is necessary or
vice versa, the greater the amount of food consumed by the
organism the less allocation to the brain is necessary. The
reciprocal relationship between allocation and food intake
required to satisfy the energy needs of the brain is
represented graphically in Fig. 5a.
This reciprocal relationship between allocation and
required food intake can be mathematically derived as
follows. Glucose uptake into the brain is b [g min
21
kg
21
]while m represents glucose uptake into muscle and fat
[g min21 kg21]. The ratio between the two glucose uptake
rates is defined as allocation:
Allocation b
m1
IfB is designated as the mass of the brain [kg] and M that of
the muscle/fat [kg], the required intake of foods is:
Necessary nutrient uptake bB mM 2
If one inserts m from Eq. (1) into Eq. (2), the following
relationship between food intake and allocation results:
Necessary nutrient uptake b B M
Allocation
3
If one assumes that the brain keeps its ATP content constant,
the variable b in Eq. (3) is regulated within very narrow
limits and kept almost constant. The mass of the brain B is a
constant parameter. Eq. (3) is represented in Fig. 5a. All
values of this function are characterized by the fact that the
brain ATP concentration is held at a constant concentration,
whereby the high- and low-affinity ATP-sensitive potassium
channels are balanced. Depending on the magnitude of
allocation, a food quantity arises from this relationship that
the brain requires to fulfill its demand for energy.
There is a substantial difference between the two
regulatory subsystems for allocation and food intake. The
LHPA system that determines allocation can be burdened in
unusual crisis situations, e.g. in times of starvation, but it
always strives to return to its resting balance. This resting
balance is designated as the so-called MRGR brain
corticosteroid balance. In Fig. 5a all the points are
represented in a second function, in which MR and GR
are balanced for the LHPA subsystem.
A special situation therefore occurs in which both high-
and low-affinity ATP-sensitive potassium channels are in
a state of balance, i.e. whereby both the brain ATP is
constant and the MR and GR are in a state of balance,meaning that the LHPA system is at a resting state.
At exactly this intersection point the energy metabolism
is in a state of homeostasis, graphically depicted in Fig. 5a.
If brain ATP regulation and the LHPA system are in
a state of balance, a certain required food intake
results from that. If this food intake can be realized,
the organism can remain stable in this metabolic
equilibrium state. The body mass is, however, already
adequately set by this balance. The idea of an independent
system that regulates body mass therefore becomes
superfluous.
Basically, this balance-setpoint represents an ideal
equilibrium state which in fact is rarely achieved. Theorganism is instead continuously exposed to stresses and the
nutrient supply is variable so that it must continually strive
to achieve this ideal balance state.
2.2. Load of the brain-supplying regulatory system
Loads can put stress on the brain-supplying regulatory
system. Does the newly proposed paradigm comply with our
knowledge on how the organism reacts to these situations?
energy themselves for their excitation. The green function (D energy) shows how glutamatergic neurons provide energy for themselves and for GABAergic
neurons depending on the brain ATP. GABAergic neurons on the other hand are not able to promote glucose transport across the bloodbrain barrier in thisway; instead they only consume energy. At low brain ATP concentrations it is the glutamatergic neurons that mobilize glucose and increase brain ATP content
that are mostly active; at high brain ATP-concentrations GABAergic neurons that only consume energy and thereby lead to a lowering of brain ATP-content
are mostly active. The setpoint for brain ATP regulation is found at the intersection point of the green and red functions (upper panel); here, the rate of change
in brain ATP is equal to zero and the regulating system is at a state of balance (lower panel). (B) Setpoint of the LHPA-system. The rate of change in cortisol
over time dCortisol=dt (ordinate) depends on the cortisol concentration itself (abscissa). High-affinity mineralocorticoid receptors (MR) are active at low
cortisol concentrations and stimulate the LHPA system and with that adrenal cortisol production and release. Low-affinity glucocorticoid receptors (GR) are
active only at high cortisol concentrations and inhibit the LHPA system so that adrenal cortisol production and secretion are decreased (green function). The
hepatic clearance rate of cortisol depends on the cortisol concentration itself (red function). The setpoint of the LHPA-system is found at the intersection point
between the green and red functions (upper panel); here, the rate of change of cortisol is equal to zero and the LHPA system is at a state of balance (lower
panel). (C) The leptin amplifier in the arcuate nucleus. The neuronal activity of NPY and POMC neurons in the ARC (ordinate) depends on the leptin
concentration (abscissa). Leptin inhibits the activity of NPY neurons so that at low leptin concentrations the NPY neurons are spontaneously active. Leptin
stimulates the POMC neurons so that at moderate leptin concentrations they are activated. NPY and POMC neurons are glucose responsive and feature ATP-
sensitive potassium channels that are opened at high leptin concentrations; for such reasons these neurons become deactivated at high leptin concentrations.
The ARC neurons project into the VMH. POMC neurons act inhibitorily while NPY neurons act in a stimulatory manner in the VMH. The combined output of
both neuronal populations to the VMH is illustrated in the lower panel. With low leptin concentrations the inhibitory NPY neurons predominate, at moderateleptin concentrations the stimulatorya-MSH predominate, and at high leptin concentrations both neuronal populations are inactivated. It is worth noting that
leptin at high concentrations can no longer activate the ARC neurons, and these neurons therefore appear to be leptin resistant.
R
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From the aspect of competition for energy resources, two
types of stress are possible: a pending energy deficiency in
the brain and an excessive glucose-utilizing body mass.
According to the selfish brain paradigm, the brain must be
informed continuously about the magnitude of these two
stressors in the form of feedback-signals. Its integrating
centers receive feedback signals for this purpose from all
brain areas as well as from the glucose-utilizing muscle and
adipose tissues. The feedback signal from the brain itself is
ATP, while the feedback signal from muscle and adipose
tissue is leptin [12]. Leptin is formed and secreted in fat
tissue and musculature in a manner closely coupled with
the glucose uptake of these tissues [104,105]. Leptin
conveys a signal describing the quantity of peripherally
stored energy; it is closely correlated with body mass. From
the standpoint of the new paradigm, leptin can be under-stood as a load signal that informs the brain of the size of
the metabolic stressors, i.e. the muscle and fat mass
competing for glucose. If this load signal is interrupted, as
is the case with leptin receptor defects, a key stimulus is
missing for the allocation of glucose to the brain. The
development of db=db mice expressing a leptin receptor
defect has confirmed that the brain mass in the first postnatal
weeks develops only slowly and inadequately, while the
body mass increases disproportionately [106]. Leptin can
therefore be assigned as a class of cytokine due to its
functional and biochemical properties and can be under-
stood as a load signal targeted towards the brain.
Why is the regulatory system burdened by increasingbody mass?
The more food an organism consumes, the larger
becomes the peripheral mass that must compete with the
brain for glucose. With increasing body mass, leptin
increases as an indicator of this metabolic load. Leptin
stimulates the sympathetic nervous system in the hypo-
thalamus and in so doing the allocation of glucose to the
brain [107109]. This functional feedback between intake
of foods and glucose allocation is mediated via the feedback
effect of leptin (see Fig. 5b).
2.2.1. Malnutrition
2.2.1.1. Metabolic stressors. In this chapter we basically
repeat the principles of the model while focusing on its
dynamic behavior. We also provide more insight into
biological details by assigning one representative specific
metabolic or neuroendocrine mechanism as well as one
specific anatomical site to each component of the fishbone
model.Thereare 14 components (flow-chart arrows) in Fig.1
which are referred to, e.g. as model a1a2 in the following
text. Mechanisms and neuroanatomical structures involved
are explained with the help of a case study on malnutrition
oriented towards the studies of Per Opstad [110]:
Case 1: The 25-year old Olaf goes on a 10-daywilderness expedition to the mountains of Norway as
part of a ranger training exercise. On the 5th day he loses
all his provisions through an accident. He manages to
survive the remaining 5 day journey without practically
any intake of foods, although during this time he loses
4 kg in body mass, and arrives exhausted in the training
camp before indulging in a heavy meal. In the subsequent
2 weeks his food intake is also increased until his original
body mass returns.
In healthy individuals the brain ATP concentration is
strictly regulated so that a marked reduction in ATP is not to
be expected during a 5 day fasting period [111]. Never-
theless, the brain is able to measure even only a tiny
reduction in brain ATP. As already mentioned in the chapter
balance-setpoints, cortical high- and low-affinity
ATP-sensitive potassium channels play a decisive role.With a tiny reduction in brain ATP, only the low-affinity
ATP-sensitive potassium channels react while the high-
affinity ATP-sensitive potassium channels remain closed.
A minor activation of the low-affinity ATP-sensitive
potassium channels reduces the GABAergic tone in the
entire cerebral cortex. The balance between active gluta-
matergic and GABAergic neurons is displaced with a slight
ATP deficit to the benefit of glutamatergic excitation (see
Fig. 4a).
Glutamate is taken up by the astrocytes where it
stimulates glucose uptake, and this in turn is closely coupled
with the transport of glucose via the bloodbrain barrier
(Fig. 4e) (model a2e2). GLUT1 transports glucose boththrough the luminal and abluminal cell membranes of the
cerebral endothelial cells. Activation of the glutamate
receptors has not only this rapid effect on GLUT1, but it
also exerts a prolonged stimulatory effect on the expression
of GLUT1 mRNA [112]. Glutamate therefore facilitates the
passage of glucose across the blood brain barrier in a
number of cortical regions and can in this way correct areduction in brain ATP partly or even completely.
In parallel a glutamatergic tone in the cerebral cortex
ensures via a series of intermediary steps that the
musculature utilizes fatty acids instead of glucose. Gluta-
mate stimulates the glutamate receptor on limbic neurons
via projections that innervate the limbic system fromvarious cortical regions (see Fig. 4b) [73] (model a2b2).
According to Larry Swansons topographical model ofcerebral hemisphere organization, both hippocampus and
amygdala pyramidal cells contribute to triple descending
projectionswith excitatory, inhibitory, and disinhibitory
componentsextending to specific parts of the hypothala-
mus (VMH and PVN) [113]. Excitatory components include
the amygdala basolateral complex and the hippocampal
CA13 fields; inhibitory components include the amygdala
central nuclei and the lateral septum; and disinhibitory
components include the bed nuclei stria terminalis and the
medial septal/diagonal band complex [113]. Signals from
hippocampus and amygdala, which are transmitted via thesemultiple descending pathways, have been shown to affect
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Fig. 4. (A) Cerebral cortex. Excitatory neurons produce the neurotransmitter glutamate and the neuropeptide brain-derived neurotrophic factor (BDNF). These
neurons project into the limbic system where they release glutamate and BNDF. They are permanently under feedback control: (1) Postsynaptic high-affinity
ATP-sensitive potassium channelsare localized on these neurons.These channels are themselves closed at low glucose concentrations and ensure the functional
activity of the excitatory neurons. (2) Low affinity ATP-sensitive potassium channels are localized presynaptically on GABAergic neurons. These channels are
closed at high glucose concentrations so that the nerve endings release the inhibitory neurotransmitter GABA that inhibits the excitatory neurons. Low glucose
concentrations act permissively, and high glucose concentrations inhibitorily on the activity of cortical excitatory neurons. (B) The limbic system. Excitatoryneuronsare localized in thecore regionsof thelimbic system. These neuronsprojectwith their neuronalpathways intothe ventromedialhypothalamus or intothe
paraventricular nucleus. They are stimulated by cortical glutamate that binds to the membranous glutamate receptors (Glu-R). These excitatory limbic neurons
aresubjectto theinfluence of presynapticGABAergic glucoresponsiveneurons. Theexcitatorylimbicpyramidal cells producetwo important types of proteinsin
their cell nucleus: Under the influence of cortisol and its two receptors MR and GR they form proteins that define the excitability of these neurons. Under the
influence of BDNF and its two receptors trkB and p75 they form so-called CREB-proteins which determine the number of membranous glutamate receptors
during the process of long-term potentiation(LTP). At low cortisolconcentrationsMR are primarily active and these downregulatetheir ownsynthesis. MR also
promote the synthesis of BDNFreceptors (trkB). At highcortisol concentrations GR are mainly active, and these alsodownregulate their own production. Under
theinfluenceof GR,BDNF-receptors(p75)are produced. BDNFstimulatesvia itshigh-affinity trkBreceptorsthe CREBgene, while it inhibitsthe CREBgene via
itslow-affinity BDNFreceptors(p75).CREB-proteins leadto LTP anda durablealterationin thenumberof membranousglutamate AMPAreceptors.In thisway
glutamatergic transmissionis subjectto modulation by cortisoland BDNF, andthis canbe stabilizedover thelong-termby LTP.(C) Ventromedial hypothalamus.
Ventromedial hypothalamus-(VMH)-neurons stimulate the CRH-neurons in the paraventricular nucleus (PVN) and with that both the sympathetic nervous
system and ACTH-release from the pituitary. These excitatory VMH neurons also mediate GABAergic output to the lateral hypothalamus. Limbic neurons
stimulate VMH neurons. These excitatory VMH neurons are also subject to a dual feedback-control: At high brain-glucose concentrations, ATP-sensitive
potassium channelson presynaptic GABAergic neurons are closed, which as a result release GABAand act inhibitorily on the excitatory VMH neurons.At high
leptin concentrations thesame ATP-sensitive potassium channels on thepresynapticGABAergicneurons areopenedso thatthe neuronsreleaseless GABAand a
stimulatory effecton the excitatory VMH neurons results.a-MSHfrom the ARC amplifiesthe stimulatory effectof leptin on the excitatory VMH neurons,whileNPY from the ARC decreases the leptin effect. The neurons of the VMH measure the difference between the peripheral (leptin) and central (brain-glucose)
feedback signals and generate the VMH output from this result. (D) Lateral hypothalamus. The glucose-sensitive neurons of the lateral hypothalamus release
orexigenic peptides and in so doing stimulate food intake. The orexigenic neurons are stimulated by glutamatergic neurons and inhibited by GABAergic VMH
neurons. They are subject to feedback-inhibition by brain glucose. With high brain glucose concentrations their sodium/potassium ATPase is activated so that
these neurons become hyperpolarized and stop releasing orexigens. In addition, neuropeptides from the ARC also exert a modulatory influence. In energetic
homeostasis,however, thestimulatory influenceof NPYand the inhibitory influenceofa-MSH are at a state ofbalance.(E) Theblood brain barrierand thecell
membranes of muscle/adipose tissue.Glucoseis transportedby glucosetransporter1 (GLUT1) across theblood brain barrier.Neuronal glutamate is taken up by
the astrocytes and stimulates glucose uptake across the bloodbrain barrier. Glucose is transported by the insulin-sensitive GLUT4 across the membranes of
muscle and fat cells. The sympathetic nervous system regulates glucose uptake into muscle and adipose tissue by inhibiting pancreatic b-cells, thereby limiting
the insulin-receptor (IR) mediatedglucose uptake intoperipheral tissues.Both neuronalglutamate release andactivation of the sympatheticnervoussystem lead
to an allocation of glucose to the brain, whereby both processes restrict peripheral glucose uptake. (F) Arcuate nucleus. The glucose-responsive neurons of the
arcuate nucleus produce POMC and NPY. Both neuronal populations project into the VMH and the LH. In these two core regions the POMC neurons release
a-MSHand theNPY neuronsNPY. In theARC, leptin binds to theleptinreceptor (LR),thereby stimulating thePOMC-neurons, andinhibitingthe NPY-neurons.
In addition, leptin directlyaccesses the VMH.At veryhigh leptin concentrations the ATP-sensitive potassium channelswhich arelocalized on bothARC-neuron
types are opened so that these neurons become hyperpolarized and deactivated.
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Fig. 4 (continued)
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Fig. 4 (continued)
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the hypothalamus-pituitary adrenal system [114116]
(model b2 c2). Hippocampal stimulation or microinjec-
tions have been shown to activate both VMH neurons [117]
and PVN neurons [118121] (see Fig. 4c). A subsequent
rise was observed in the hormones ACTH, corticosterone,
epinephrine, norepinephrine [121123] and in the substrates
blood glucose and lactate [122,124]. We want to emphasize
that although these structures and functions are understood
as potential candidates they do not represent the absolute and
final mechanisms. In summary, glutamatergic cortical
signals can activate limbic structures that enhance
hypothalamic neuronal activity, and in so doing request
and mobilize circulating fuels.
A minor reduction in ATP opens the KATP channels in
the presynaptic VMH-neurons so that the VMH neurons are
not just stimulated by the limbic system, but they are alsolocally disinhibited. These hypothalamic KATP channels
belong to the network of hierarchically organized ATP
sensors that maintain glucose homeostasis [125128].
The VMH governs glucose allocation by limiting
peripheral glucose uptake (model c2e2). Local or systemic
glucoprivation increases signal output from the VMH [129,
130]. VMH neurons project towards the PVN, where they
can stimulate CRH and vasopressin release [131,132]. At
the same time, GABA- and BDNF-containing neurons are
activated in the VMH [133,134] which project to the LH and
inhibit appetite. Both a release of ACTH from the pituitaryand cortisol from the adrenal gland as well as a stimulation
of the sympathetic nervous system coincide with thestimulation of PVN neurons. The sympathetic nervous
system innervates the pancreatic b cells [66,135] where the
stimulation of a2-adrenergic receptors suppresses the
secretion of insulin [68,69], and antagonizes insulin effects
on muscle and adipose tissue [70]. As a result, less glucose
transporter 4 (GLUT4) is translocated onto the cell
membranes of muscle and adipose tissue (Fig. 4e). The
sympathetic nervous system also innervates the musculature
where it can open KATP channels, and this also decreases the
insulin-mediated glucose uptake [136,137]. Since GLUT4 is
the main glucose transporter for these peripheral tissues, a
decreased peripheral glucose uptake is seen during fasting.
Glucose is therefore guided past the peripheral tissues and isinstead available for uptake by the brain [138,139]. Again,
each particular mechanism identified here can fulfil its role
in the model, although the whole theory is not necessarily
bound to any specific one.