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).
http://www.elsevier.com/locate/neubiorevhttp://www.elsevier.com/locate/neubiorev


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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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10/38

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



13/38

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.

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