For years the focus of investigations of appetite control has centred upon the termination of eating. This is because the termination of an eating episode—being the endpoint of a behavioural act— was perceived to be an unambiguous event around which empirical studies could be organized. Consequently satiety came to be the concept which formed the basis for accounts of appetite.
However, some 50 years ago there was an equal emphasis on the excitatory or drive features of appetite. This was embodied in Morgan's 'central motive state' and in Stellar's location of this within the hypothalamus (10). One major issue was to explain what gave animals (and humans) the energy and direction which motivated the seeking of food. These questions are just as relevant today but the lack of research has prevented much innovative thinking. In the light of knowledge about the physiology of energy homeostasis, and the utilization of different fuel sources in the body, it is possible to make some proposals. One source of the drive for food arises from the energy used to maintain physiological integrity and behavioural adaptation.
Consequently, there is a drive for food generated by energy expenditure. Approximately 60% of total energy expenditure is contributed by the resting metabolic rate (RMR). Consequently RMR provides a basis for drive and this resonates with the older concept of 'needs translated into drives'. In addition, through adaptation, it can be envisaged that other components of energy expenditure would contribute to the drive for food. The actual signals that help to transmit this energy need into behaviour could be reflected in oxidated pathways of fuel utilization (11), abrupt changes in the availability of glucose in the blood (12) and eventually brain neurotransmitters such as neuropeptide Y (NPY) which appears to be linked to metabolic processes. Leptin is also likely to play a role via this system.
In turn this drive to seek food—arising from a need generated by metabolic processing—is given direction through specific sensory systems associated with smell, but more particularly with taste. It is logical to propose that eating behaviour will be directed to foods having obvious energy value. Of particular relevance to the current situation are the characteristics of sweetness and fattiness of foods. In general most humans possess a strong liking for the sweet taste of foods and for the fatty texture. Both of these commodities indicate foods which have beneficial (energy yielding) properties.
Accordingly, appetite can be considered as a balance between excitatory and inhibitory processes. The excitatory processes arise from bodily energy needs and constitute a drive for food (which in humans is reflected in the subjective experience of hunger). The most obvious inhibitory processes arise from post-ingestive physiological processing of the consumed food—and these are reflected in the subjective sensation of fullness and a suppression of the feeling of hunger. However, the sensitivity of both the excitatory and inhibitory processes can be modulated by signals arising from the body's energy stores.
It should be noted that the drive system probably functions in order to ensure that energy intake at least matches energy expenditure. This has implications for the maintenance of obesity since total energy expenditure is proportional to body mass. This means that the drive for food may be strong in obese individuals in order to ensure that a greater volume of energy is ingested to match the raised level of expenditure. At the same time whilst there is a process to prevent energy intake falling below expenditure, there does not seem to be a strong process to prevent intake rising above expenditure. Consequently, any intrinsic physiological disturbance which leads to a rise in excitatory (drive) processes or a slight weakening of inhibitory (satiety) signals would allow consumption to drift upwards without generating a compensatory response. For some reason a positive energy balance does not generate an error signal that demands correction. Consequently the balance between the excitatory and inhibitory processes has implications for body weight regulation and for the induction of obesity.
SIGNALS FROM ADIPOSE TISSUE: LEPTIN AND APPETITE CONTROL
One of the classical theories of appetite control has involved the notion of a so-called long-term regulation involving a signal which informs the brain about the state of adipose tissue stores. This idea
Figure 8.4 Diagram indicating the proposed role of the OB protein (leptin) in a signal pathway linking adipose tissue to central neural networks. It has been postulated that leptin interacts with neuropeptide Y in the brain (see text) to exert effects on food intake (and indirectly on adipose tissue) and on the pancreas (release of insulin). The leptin link between adipose tissue and the brain is only a part of a much more extensive peripheral-central circuit. EE, energy expenditure; EI, energy intake
Figure 8.4 Diagram indicating the proposed role of the OB protein (leptin) in a signal pathway linking adipose tissue to central neural networks. It has been postulated that leptin interacts with neuropeptide Y in the brain (see text) to exert effects on food intake (and indirectly on adipose tissue) and on the pancreas (release of insulin). The leptin link between adipose tissue and the brain is only a part of a much more extensive peripheral-central circuit. EE, energy expenditure; EI, energy intake has given rise to the notion of a lipostatic or pon-derstatic mechanism (13). Indeed this is a specific example of a more general class of peripheral appetite (satiety) signals believed to circulate in the blood reflecting the state of depletion or repletion of energy reserves which directly modulate brain mechanisms. Such substances may include satietin, adipsin, tumour necrosis factor (TNF or cachec-tin—so named because it is believed to be responsible for cancer induced anorexia) together with other substances belonging to the family of neural active agents called cytokines.
In 1994 a landmark scientific event occurred with the discovery and identification of a mouse gene responsible for obesity. A mutation of this gene in the ob/ob mouse produces a phenotype characterized by the behavioural trait of hyperphagia and the morphological trait of obesity. The gene controls the expression of a protein (the OB protein) by adipose tissue and this protein can be measured in the peripheral circulation. The identification and synthesis of the protein made it possible to evaluate the effects of experimental administration of the protein either peripherally or centrally (14). Because the OB protein caused a reduction in food intake (as well as an increase in metabolic energy expenditure) it has been termed 'leptin'. There is some evidence that leptin interacts with NPY, one of the brain's most potent neurochemicals involved in appetite, and with melanocortin-4 (MC4). Together these and other neuromodulators may be involved in a peripheral-central circuit which links an adipose tissue signal with central appetite mechanisms and metabolic activity (Figure 8.4).
In this way the protein called leptin probably acts in a similar manner to insulin which has both central and peripheral actions; for some years it has been proposed that brain insulin represents a body weight signal with the capacity to control appetite.
At the present time the precise relationship between the OB protein and weight regulation has not been determined. However, it is known that in animals and humans which are obese the measured amount of OB protein in the plasma is greater than in lean counterparts. Indeed there is always a very good correlation between the plasma levels of leptin and the degree of bodily fattiness (15). Therefore although the OB protein is perfectly positioned to serve as a signal from adipose tissue to the brain, high levels of the protein obviously do not prevent obesity or weight gain. However, the OB protein certainly reflects the amount of adipose tissue in the body. Since the specific receptors for the protein (namely OB receptor) have been identified in the brain (together with the gene responsible for its expression) a defect in body weight regulation could reside at the level of the receptor itself rather than with the OB protein. It is now known that a number of other molecules are linked in a chain to transmit the action of leptin in the brain. These molecules are also involved in the control of food intake, and in some cases a mutation in the gene controlling these molecules is known and is associated with the loss of appetite control and obesity. For example, the MC4-R mutation (melanocortin-4 receptor) leads to an excessive appetite and massive obesity in children, just like the leptin deficiency (16).
These findings lead to a model of appetite control based on the classic two-process idea involving the stimulation (drive) to eat, and a quick-acting short-term inhibition of food consumption which decays rapidly. The drive for food would be reflected in high levels of hunger which are normally subjected to episodic inhibitory (satiety) signals. There are strong logical reasons why the drive (need) for food should be related to energy expenditure of metabolism and physical activity. Evidence suggests a role for NPY (which produces excessive food intake in animal studies) and leptin (whose absence releases the hunger drive in humans). This interpretation of leptin action is consistent with the suggestion of a dual role of leptin (24). Within the interaction between excitatory (drive) and inhibitory (satiety) processes there is ample room for the operation of a large number of mediating 'orexic' or 'anorexic' neuro-modulators (2).
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