The selfish brain: competition for energy resources

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Abstract

Although the brain constitutes only 2% of the body mass, its metabolism accounts for 50% of total body glucose utilization. This delicate situation is aggravated by the fact that the brain depends on glucose as energy substrate. Thus, the contour of a major problem becomes evident: how can the brain maintain constant fluxes of large amounts of glucose to itself in the presence of powerful competitors as fat and muscle tissue.

Activity of cortical neurons generates an “energy on demand” signal which eventually mediates the uptake of glucose from brain capillaries. Because energy stores in the circulation (equivalent to ca. 5 g glucose) are also limited, a second signal is required termed “energy on request”; this signal is responsible for the activation of allocation processes. The term “allocation” refers to the activation of the “behavior control column” by an input from the hippocampus–amygdala system. As far as eating behavior is concerned the behavior control column consists of the ventral medial hypothalamus (VMH) and periventricular nucleus (PVN). The PVN represents the central nucleus of the brain's stress systems, the hypothalamus–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS). Activation of the sympatico-adrenal system inhibits glucose uptake by peripheral tissues by inhibiting insulin release and inducing insulin resistance and increases hepatic glucose production. With an inadequate “energy on request” signal neuroglucopenia would be the consequence. A decrease in brain glucose can activate glucose-sensitive neurons in the lateral hypothalamus (LH) with the release of orexigenic peptides which stimulate food intake. If the energy supply of the brain depends on activation of the LH rather than on increased allocation to the brain, an increase in body weight is evitable. An increase in fat mass will generate feedback signals as leptin and insulin, which activate the arcuate nucleus. Activation of arcuate nucleus in turn will stimulate the activity of the PVN in a way similar to the activation by the hippocampus–amydala system.

The activity of PVN is influenced by the hippocampal outflow which in turn is the consequence of a balance of low-affinity and high-affinity glucocorticoid receptors. This set-point can permanently be displaced by extreme stress situations, by starvation, exercise, hormones, drugs or by endocrine-disrupting chemicals. Disorders in the “energy on request” process will influence the allocation of energy and in so doing alter the body mass of the organism. In this “selfish brain theory” the neocortex and the limbic system play a central role in the pathogenesis of diseases, such as anorexia nervosa, obesity and diabetes mellitus type II.

From these considerations it appears that the primary disturbance in obesity is a displacement of the hippocampal set-point of the system. The resulting permanent activation of the feedback system must result in a likewise permanent activation of the sympatico-adrenal system, which induces insulin resistance, hypertension and the other components of the metabolic syndrome. Available therapies for treatment of the metabolic syndrome (blockade of α- and β-adrenergic receptors, insulin and insulin secretagogues) interfere with mechanisms, which must be considered compensatory. This explains why these therapies are disappointing in the long run. New therapeutic strategies based on the “selfish brain theory” will be discussed.

Introduction

We are witnessing a world-wide surge in the incidence of obesity and type 2 diabetes. There is evidence that the increase in longevity that has been observed over the last 150 years might be arrested by obesity and its major consequence, i.e. the so-called metabolic syndrome. The necessity to understand the pathophysiology of obesity and type 2 diabetes in more detail has never been as urgent as it is now. Fortunately, over the last 10 years there has also been dramatic progress in understanding the brain's fundamental role in energy homeostasis and body fat mass regulation. This development started with the discovery of leptin, a hormone produced in fat tissue which communicates the status of body energy stores to the central nervous system (CNS) (Zhang et al., 1994). Well before the discovery of leptin, insulin was known to exert similar effects; however, at that time these findings were widely neglected (Woods et al., 1984). The discovery of leptin also led to a reappraisal of the fundamental role of cortisol in the regulation of body weight and energy homeostasis (Jeanrenaud and Rohner-Jeanrenaud, 2000). More recently, a number of peptides have been described that are released from the intestinal tract and are able to induce sensations of satiety (Schwartz et al., 2000). All these paved the way for elucidating the role of the CNS in regulating body weight and energy homeostasis. In the wake of these findings, a number of orexigenic and anorexigenic neuropeptides have been identified that are produced in hypothalamic neurons and which integrate peripheral and CNS signals to control food intake (Fig. 1). Given the large number of factors and hormones, which participate in this regulation, it has become a major task to understand how these factors interact and define their relative importance. In an attempt to build a foundation to deal with this problem the “selfish brain theory” (Peters et al., 2004) has been developed, which aims to define the fundamental role of the brain in regulating food intake and energy homeostasis, and which emphasizes the brain's primacy in the control of energy fluxes.

Section snippets

Maintenance of glucose fluxes to the brain

Although the brain constitutes only 2% of the body mass, its metabolism accounts for 50% of total body glucose utilization, i.e. it takes up approximately 100 g of glucose each day (Owen et al., 1967). In comparison to other organs the brain is the most energy demanding. This precarious situation is aggravated by the fact that the brain depends on glucose as its energy substrate; in contrast to muscle and fat tissue it preferentially utilizes glucose instead of other energy substrates such as

The role of the hippocampus/amygdala system in energy homeostasis

The hippocampus and amygdala are well known for their role in the formation of new memories (Bliss and Collingridge, 1993). Excitatory synaptic transmission in these brain regions depends on glutamate. This neurotransmitter is released into the synapse by the presynaptic neurons and binds to receptors on the postsynaptic neuronal membrane (Fig. 3). There are two types of glutamate receptors: AMPA receptors, which regulate basal synaptic transmission, and NMDA receptors, which modulate a

The balance between food intake and glucose allocation

The cortico-hypothalamic circuits described above create two main outputs, i.e. control of eating behavior and allocation behavior. Given the high-energy requirements of cortical areas it is evident that any change in food intake must be accompanied by a corresponding change in allocation activity. The reciprocal relationship between the need for food intake and the need for allocation to supply the brain with sufficient fuel can be described using a simple hyperbolic curve (Fig. 4). Since the

Obesity and diabetes mellitus type 2 as a brain disease?

A constant weight reduction can be achieved only with a displacement of the set-point to the right, while obesity can only occur with a displacement to the left.

What are the consequences of a permanent displacement of the set-point to the left? The inevitable increase in body weight will activate the feedback mechanisms. Even in this situation a stable situation will result, however, with increased body weight and a slight but permanent activation of the stress systems and their malign

Future treatment strategies for obesity and diabetes mellitus type 2

An ideal therapeutic strategy for treating type 2 diabetes would be to correct the displacement of the metabolic set-point. Such correction is theoretically feasible since set-points are defined by the activity of neurons in the hippocampus/amygdala, and this activity is prone to plasticity. Metabolic set-points can be “learned” and “relearned” similar to other types of memory, and mechanisms which control memory consolidation and long-term potentiation are also related to metabolic set-points.

Conclusions

Given the extraordinary requirements of the brain with regard to the amount of energy and the types of fuel, it is clear that the brain must be capable of controlling energy fluxes within the body. The mechanisms exerting this control are described in the “selfish brain theory”, which emphasizes the brain's primacy in the allocation of energy fluxes to the brain. The main players, i.e. the HPA-axis and the SNS, are well characterized, although they have usually been viewed in different contexts.

References (42)

  • T.V. Bliss et al.

    A synaptic model of memory: long-term potentiation in the hippocampus

    Nature

    (1993)
  • J. Born et al.

    Sniffing neuropeptides: a transnasal approach to the human brain

    Nat. Neurosci.

    (2002)
  • D.J. Clegg et al.

    Differential sensitivity to central leptin and insulin in male and female rats

    Diabetes

    (2003)
  • H.L. Fehm et al.

    The melanocortin melanocyte-stimulating hormone/adrenocorticotropin (4–10) decreases body fat in humans

    J. Clin. Endocrinol. Metab.

    (2001)
  • B. Fruehwald-Schultes et al.

    Protective effect of insulin against hypoglycemia-associated counterregulatory failure

    J. Clin. Endocrinol. Metab.

    (1999)
  • J.E. Gerich et al.

    Hypoglycemia unawareness

    Endocr. Rev.

    (1991)
  • M. Hallschmid et al.

    Intranasal insulin reduces body fat in men but not in women

    Diabetes

    (2004)
  • Y. Ikegaya et al.

    BDNF attenuates hippocampal LTD via activation of phospholipase C: implications for a vertical shift in the frequency-response curve of synaptic plasticity

    Eur. J. Neurosci.

    (2002)
  • B. Jeanrenaud et al.

    CNS-periphery relationships and body weight homeostasis: influence of the glucocorticoid status

    Int. J. Obes. Relat. Metab. Disord.

    (2000)
  • B.M. King et al.

    Hyperinsulinemia in rats with obesity-inducing amygdaloid lesions

    Am. J. Physiol.

    (1996)
  • B.M. King et al.

    Obesity-inducing amygdala lesions: examination of anterograde degeneration and retrograde transport

    Am. J. Physiol. Regul. Integr. Comp. Physiol.

    (2003)
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