Pharmacological aspects of appetite: implications for the treatment of obesity

Bionled & Pknnnncorh~ 0 Elsevier. Paris

( 1994) 48, I 19.125

119

Dossier “Obesity”

Pharmacological aspects of appetite: implications for the treatment of obesity JE Blundell, A Greenough BioPsycholo,qy

Group.

Deporrmenr

oj’ Psychology.

Uniwrsify

of’ Leeds,

Leeds.

LS2

9JT.

UK

- The properties of an ideal weight-reducing drug would be 10 produce a sustaineddecrease in body fat. to oppose the recidivism in obese patients and to improve compliance 10 dietary requirements. More specifically rhe drug would have to decreasehunger, be active in the long term, preferably produce no tolerance or rebound effects. and prevent

Summary

any decrease in basal metabolic rate. Moreover, the drug should reduce the intake of dietary fat which is now regarded as a major cause of weight gain (and regain) [ 141. Can this be achieved? Can drug-induced appetite control be used 10 combat obesity’? Some drugs have already demonstrated a capacity 10 adjust appetite so as lo produce significant improvements in the pattern of eating and the control of body weight. What mechanisms are responsible for such an action and how can new drugs be developed so as lo advance the pharmacological control of appetite?

drugs

Drug

/ obesity

action

/ appetite

and regulatory

principles

The expression of appetite can be considered to arise from an interaction between biological and environmental influences. From a biological point of view the control of food intake must function as part of a homeostatically regulated system. However, it appears that eating can also be stimulated (or suppressed) by environmental or cognitive factors independently of biological requirements. Indeed, such external influence indicates that the operation of the biologically regulated system is not symmetrical. The system displays a very strong defence against undernutrition (for example, dieting) but there is only weak resistance to overnutrition. On the one hand, undereating is normally the result of a conscious effort and can be regarded as an active process. On the other hand, since it can be assumed that overweight people are not actually trying to eat more in order to increase their weight, their weight gain is probably due to passive overconsumption [IO]. There is now some good evidence that this unintentional (and biologically unnecessary) overconsumption is largely due to the amount of fat in the diet [25]. Dietary fat appears

to produce weaker effects on satiety (suppression of appetite) than protein or carbohydrate [l2]. What is the significance of these issues for the drug treatment of appetite in overweight people? First, it appears that when trying to reduce their food intake, overweight people do not get any help from their fat stores. That is, fat depots do not seem to depress the biological drive to eat. Indeed, owing to their greater body cell mass, overweight people have a higher resting metabolic rate and therefore require a higher energy intake in order to achieve energy balance. Attempts to undereat in overweight people appear to provoke the same counteractive biological drive as in normal weight individuals. Indeed, it has recently been suggested that obese individuals display a defect in appetite control which is manifest as a drive to overeat [35] rather than a defect in energy expenditure. Second, many overweight people are making conscious, though often unsystematic efforts to restrict their pattern of eating. These attempts at conscious control are countered by physiologically-mediated stimuli (biological drives) which thwart any intended undereating. A drug acting on the appetite control system could moderate the intensity of biological

120 impulses thereby making conscious control easier. In this way, a drug would provide support for the self-management of appetite rather than mechanically stopping behaviour. Therefore it appears that a drug will probably have to be effective in two ways. First, to inhibit and overcome the active biological drives which oppose any form of food restriction. Second, to combat the passive overeating that appears to occur casually and unintentionally in the prescncc of an abundant high fat food supply.

The bio-psychological control

system

of appetite

The biopsychological system which is concerned with the expression of appetite can be conceptualized on three levels (fig I). These are the level of psychological events (hunger perception, cravings, hedonic sensations) and behavioural operations (meals, snacks, energy and macronutrient intake); the level of peripheral physiology and metabolic events; and the level of

neurotransmitter and metabolic interactions in the brain. The essence of the approach advocated here is that appetite can best be understood by adopting a systems view in which the expression of appetite reflects the synchronous operation of events and processes in the three levels [3]. Neural events trigger and guide behaviour, but each act of behaviour involves a response in the peripheral physiological system; in turn these physiological events are translated into brain neurochemical activity. This brain activity represents the strength of motivation and the willingness to feed or refrain from feeding. It is useful to distinguish between the processes of satiation and satiety. Satiation is the process which brings a period of eating (meal) to an end while satiety refers to the inhibition of hunger and eating brought about by food consumption itself. The capacity of food to induce satiety is known as satiating efficiency [21] and this phenomenon is markedly influenced by the total energy and composition of the food consumed [S]. Satiety is initiated and maintained by a series of overlapping mediating processes which can be referred to as the satiety cascade [9]. Satiation (control of meal size) and satiety (control of post-meal interval) are influenced separately by the nature and timing of physiological processes.

Biological

-salietin Cacheclin Adiprln’ GA. HORMONES

TASTE

COttiC* -steroids CHEWING

.--. SATlATlON+II

AAs (T:LNAA)

-SATIETY

-------+II

Fig 1. Postulated relationships among three levels of the Biopsychological system of appetite control. The three levels are behavioural operations (meals, snacks, energy and macrnnutrient intakes), peripheral physiology and metabolic events, and neurotransmitter and metabolic interactions in the brain.

targets

for drug

action

A consideration of the various components of the biological system suggests many sites, in the brain and periphery, at which pharmacological agents could be aimed to suppress appetite. For example in the periphery, drugs could blunt positive afferent information or intensify inhibitory afferent information; agents could stimulate chemo-receptor activity in the gut or modulate gastrointestinal functioning via the network of neurotransmitters in the enteric plexus. Drugs could also mimic or substitute for proposed appetite regulating factors in blood, alter oxidative metabolism in the liver, adjust metabolic satiety signals, change amino acid profiles or affect steroid levels reflecting energy metabolism which in turn influence neuronal function. Drugs affecting digestion or absorption would be expected to alter the timing and pattern of nutritional information reaching-the brain. Within the brain, drugs can alter appetite via a number of receptors, involving a variety of neurotransmitters and neuro-

121 modulators at a number of specific sites. This complex pattern of neurochemical activity reveals that the appetite system is vulnerable to pharmacological action and this is reflected in the large number of chemicals which have been reported to inhibit food intake [7]. The probable site and mode of action of many of these chemicals can be approximately located in figure 1. Despite this abundance of pharmaceutical activity, safe and effective appetite controlling drugs have been difficult to develop.

Peripheral

sites of action

A great deal of interest in peripheral sites of action for the suppression of appetite has focused upon peptidergic inhibition of food intake. Many peripherally administered peptides lead to an anorexic response and good experimental evidence for a natural role exists for cholecystokinin (CCK), pancreatic glucagon, bombesin and somatostatin [38]. Recent research has now confirmed the status of CCK as a hormone mediating satiation and early phase satiety. The consumption of protein or fat stimulates the release of CCK which activates CCK-A receptors in the pyloric region of the stomach. This signal is transmitted via vagal afferents to the nucleus of the tracfu~ solitarius (NTS) from where it is relayed to the medial zones of the hypothalamus including the paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The anorexic effect of systemically administered CCK can be blocked by vagotomy [39] and by the selective CCK-A receptor antagonist, devazepide (MK-329). Significantly, there now exist many reports demonstrating that the CCK-A type antagonist administered alone leads to an increase in food intake in experimental animals [ 131. Interestingly, trypsin inhibitors which block the inactivation of CCK produce a suppression of food intake in animals [31] and humans [20]. Not surprisingly, considerable research activity has been directed toward the development of CCK analogues or peptoids with anorexic potency. Many products now exist but their future as clinical appetite suppressants may depend upon finding ways to prevent adaptive responses in the pancreas which appear to develop with repeated administration. The pharmacological actions of glucagon in suppressing food intake is notable but there is currently no evidence on how glucagon induces vagal afferent signals [16]. Another peptide, in-

sulin, appears to have significant peripheral and central actions. Peripheral effects on CHO metabolism are well known but it appears that an appetite or body weight signal may be generated by CSF insulin [42].

CNS sites of action The influence of central neurochemical activity on the expression of appetite is complex and involves numerous interactions between different loci and different receptors which result in shifts in the magnitude, direction and quality of eating behaviour. A good deal of evidence has been accumulated from the direct application of chemicals to the brain either via the CSF or directly into specific sites. Most agents suppress intake but a significant number stimulate eating, sometimes in a dramatic fashion. The most frequently demonstrated action is the stimulation of feeding following activation of alpha-2 adrenoceptors in the PVN [26]. It is also known that spontaneous feeding is associated with endogenous release of noradrenaline in the PVN and with an increase in PVN alpha-2 receptor density [27]. The PVN also contains glucosensitive neurons and therefore may be a point of interaction for neurotransmitter activity and metabolic states reflecting energy regulation. Circulating corticosteroids have been demonstrated to influence noradrenaline receptor sensitivity and it has been argued that noradrenaline and S-HT act antagonistically to influence the release of corticotropin releasing factor (CRF). Since the PVN is also a potent anorectic drug binding site [I], neurochemical activity in this area may serve to integrate behavioural, metabolic and neuroendocrine responses. In more lateral areas of the hypothalamus (perifornical zone) feeding is suppressed by micro-injection of agents which activate dopamine D2 or adrenergic beta2 receptors. Consequently, noradrenaline, 5-HT and dopamine produce quantitative shifts in feeding from closely-related sites in the hypothalamus. Potent feeding responses can also be obtained by micro-injection of peptides to the brain. Many peptides such as insulin, CCK, calcitonin, bombesin, neurotensin, THRH, somatostatin, VIP, CRF, and glucagon suppress feeding after cerebroventricular administration [32]. A smaller number of peptides increase food intake and this group includes beta-endorphin, dynorphin, neuropeptide-Y, peptide YY and galanin. When in-

122 jetted into the PVN, NPY and PYY can induce 50% of daily food intake within one hour. The stimulation of feeding by galanin appears to be specific to the PVN and closely related sites [28]. Classic research of a decade ago indicated how projections between the brainstem and hypothalamic nuclei were involved in neuroendocrine regulation [37]. This pattern of projection is also important for feeding; peptides such as NPY and galanin appear to originate (in part) in adrenergic (Cl, C2) or noradrenergic (Al, A2, A6) nuclei in the brainstem. In summary, peptides such as CCK, CRF, THRH, NPY, opioids and galanin appear to have important central roles in conjunction with noradrenaline, 5-HT and dopamine in the organization of the expression of appetite (and energy balance more generally). These actions are generated in response to visceral and metabolic information which reflects the immediate past history of feeding and the body’s nutritional status. Other neural mechanisms involving cholinergic, benzodiazepine and GABAergic receptors may also be implicated at some point.

Strategies processes

for the controlling

action of appetite

drugs

on

It follows from the discussion above that potential drugs could be targeted on any component in the complex neural matrix which controls food intake and contributes to energy balance. In principle it may be more effective to direct attention to some components rather than others. Such strategies can be decided in part by considering the accessibility of the component and also its role in the overall system.

Pre-absorptive

or post-absorptive

action

The earlier consideration of the satiety cascade drew attention to the separation of post-ingestive and post-absorptive processes in the mediation of satiety. The pre-absorptive phase of satiety is largely dependent upon mediation by afferent stimuli arising in the upper gastro-intestinal tract following food consumption. This information reaches the brain via neural pathways - especially the vagus nerve. Clearly this pre-absorptive information reaches the brain earlier than the monitoring of post-absorptive information. It should

be noted that the qualitative nature of the food consumed (including its nutrient composition) can be detected pre-absorptively by chemo-receptars in the gastro-intestinal tract as well as by monitoring of the digested products after they have been transported into the blood supply. What is the significance of this separation of processes for drug action? It is noticeable that following a period of food consumption the intensity of satiety (inhibition of hunger, suppression of the tendency to eat) is strongest immediately after eating has stopped and then satiety gradually dissipates and hunger returns. Consequently the mechanisms subserving early phase satiety (pre-absorptive stage) have a potent inhibitory action on consumption. In contrast, it appears that the post-absorptive phase of satiety (mediated by the effects of blood-borne metabolites) exerts a milder suppression over appetite. It follows therefore that effective drug action may arise from targeting pre-absorptive mechanisms and by attempts to prolong the duration of action of such mechanisms beyond their normal shortlasting period. In functional terms it seems likely that the strong early post-ingestive inhibitory action serves to exert control over the pattern of eating and to ensure that epochs of eating are appropriately separated. The post-absorptive processes are probably far more intimately involved in the monitoring of calories and in the processes of energy balance. Any drug which acted on both pre- and post-absorptive components would be likely to give rise to a meaningful modulation of the pattern of eating and also influence physiological processes involved in energy balance.

Nutrition nutrient

and intake

pharmacology

-

macro-

Significantly, in, recent years many researchers have begun measuring the intake of macronutrients (fat, protein, carbohydrate), hedonic aspects of food (particularly sweet taste), and have taken an interest in the relationship between nutrition and pharmacology [2]. The outcome has been a revelation. For example, the stimulation of feeding by PVN injections of a-2 agonists is represented primarily by an increase in carbohydrate intake [29]. This action is limited to the early dark phase of the diurnal cycle when the rat’s selection’ of carbohydrate is normally high. Administration of serotoninergic agonists (central or peripheral) during this period suppress the

123 selection of carbohydrate. This effect gives support to a provocative hypothesis which links the dietary proportions of protein and carbohydrate consumed to brain serotonin activity by way of adjustments in plasma ratios of tryptophan (serotonin precursor) to other large neutral amino acids [43]. In this hypothesis, specific neurotransmitter activity is the mediating link between nutrition and psychological phenomena (mood changes, food choice). Interestingly, the feeding response to NPY, like that of noradrenaline, reflects a preferential selection of carbohydrate rather than protein or fat. In contrast, the stimulation of eating by galanin is reported to be directed mainly toward fat 1221. Conversely, it is believed that the anorexic action of VPDPR (ValPro-Asp-Pro-Arg), because of its association with fat digestion, will preferentially suppress the intake of fat [ 151. These findings represent a significant development in the pharmacological study of appetite control and they have theoretical and clinical implications. Theoretically these data suggest new ways of looking at the periphcral processes of macronutrient digestion and absorption and their relationship to ncurotransmitter pathways in the brain. Clinically, the devclopment of drugs which could prevent a high intake of fat (by whatever mechanism) would have, great anti-obesity potential.

Serotonin, adox

satiety

signals

and the fat par-

In considering the relationship between fat and satiety, a paradox becomes apparent. On the one hand, fat in the intestine does appear to generate potent satiety signals [36). On the other hand, cxposure to high fat foods leads to a form of passive overconsumption which suggests that fat has a weak action on satiety [25]. The paradox can be expressed as the puzzle of fat-induced satiety and high fat hyperphagia. It has been demonstrated that the infusion of intralipid (an emulsified fat) into the intestine inhibits hunger and slows the rate of gastric emptying [41]. However, intralipid infused intravenously has no inhibitory effect on appetite. Similar effects have been demonstrated in rats [ 181. Moreover, the inhibitory action of intralipid can be blocked by lorglumide, an antagonist of CCK-A type receptors [ 171. Taken together, these studies suggest that fat in the intestine generates

potent pre-absorptive satiety signals which are mediated, at least in part, by a cholecystokinin mechanism However, when rats are placed on high fat diets or given fat supplements they take in excessive amounts of energy and rapidly gain weight. Moreover, human subjects exposed to a range of high fat foods also increase their energy intake and gain weight compared with subjects eating a medium or low fat diet [30]. In addition, high fat foods markedly increase meal size (measured in terms of energy) [IO] and this effect is particularly marked in obese subjects [25]. What is the explanation for the apparent contradiction between fat-induced satiety signals and the easy overconsumption of high fat foods? Although pure emulsified fat delivered to the intestine (duodenum or jejunum) produces prompt satiety signals, consumed fat will take some time to reach the intestine in a similar form and its action is likely to be diluted by other nutrients. Hence, consumed fat may engender more slowly arising satiety signals. Two features of fat favour the rapid consumption of energy. First, fat produces potent oral stimulation which facilitates intake and second, high fat foods normally have a high energy density. This means that a large amount of fat energy can be consumed before the fat-induced satiety signals become operative. The signals are apparently too weak or too delayed to prevent the intake of a large amount of energy. It is clear from published experiments that certain serotoninergic drugs which potently antagonize the consumption of high fat foods, may cause selective avoidance of fats and reduce daily lipid intake [23]. What mechanism is responsible for this phenomenon? One possibility involves pre-absorptive satiety signals [4]. Fat in the intestine appears to inhibit appetite via CCK-A type receptors. In turn, it has been shown that the inhibitory effect of CCK on food intake can be antagonized by 5-HT blockers [40] and this probably involves 5-HTIC (now called 5-HTzc) receptars [34]. Moreover, 5-HTzc receptors are critically involved in the mediation of dex-fenfluramine- induced suppression of eating [24, 331. In addition, the effect of dex-fenfluramine is blocked by the CCK-A type receptor antagonist devazepide [I I]. Since fat is a potent stimulus for CCK release, the involvement of serotonin receptors in this circuit provide a cogent explanation for the inhibitory effect of dex-fenfluramine on fat intake.

124 Considering the paradox of fat-induced satiety signals and high fat hyperphagia, it may be proposed that any agent which could intensify or advance the fat-induced satiety signals would enhance the likelihood of blocking high-fat hyperphagia. This would take the form of a reduction in the size of meals and this is known to be one of the main effects of serotoninergic drugs l5.61.

Codetta As noted earlier, bodily fatness does not appear to suppress appetite; large adipose stores do not reduce the biological drive to eat. Fat people therefore need all the help they can get - pharmacological or other - to restrain the expression of their appetites. Evidence already indicates that drugs which modulate satiation and satiety should produce the most effective control. Moreover, long term studies on the action of drugs on body weight [ 191 appear to indicate a 2-phase process. First, a period of weight suppression followed by a period of weight maintenance. This pattern is quite consistent with the idea that certain drugs have the capacity both to oppose the active biological resistance to caloric deficit and also to prevent passive overconsumption. In this way, pharmacological agents can provide biological assistance to allow obese people to achieve a better management of their appetites.

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31

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