The selfish brain: competition for energy resources
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.
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