Investigations into the control of appetite are hampered by the difficulties in studying the internal milieu of the brain. In this regard animal experiments have been useful because unlike humans, animals can be sacrificed to allow access to brain tissue. However, even with data from animal experiments, understanding of the systems that control food intake have been slow to develop and most are still incompletely characterised. Further, as the true complexity of the system is revealed, with its regulatory and counter regulatory sub-systems, it is evident at least to the enlightened scholar that the dream of a magic obesity drug is an illusion based on little more than hope and propaganda. The fact that many substances that regulate appetite are also involved intricately in other physiological systems suggests that even if a potential drug target could be identified, the side effect brought about by its control might be too high a price to pay. Indeed, this is the pattern that has been seen with many weight loss drugs that have made it to market thus far.
It is interesting from a nutritional perspective to understand the main regulators of appetite even if their control is not realistic pharmacologically. The complexity of the systems involved and their inaccessible and subtle nature makes conclusions from such investigations difficult. The generally accepted model of obesity and weight gain is clearly lacking. The old paradigm suggests that weight gain is simply a case of eating too much food due to greed and doing too little exercise due to laziness. However, recent research suggests that this simplistic ‘eat-too-much, do-too-little’ model is flawed, because obesity and excessive weight gain is a disease characterised by metabolic dysfunction. In this regard the satiety signal becomes disconnected from both the stored energy reserves and the energy intake. Signals such as leptin and insulin, that normally regulate energy intake and satiety, become modified and as a result the signals from regulatory chemicals they control also go awry, leading to imbalance and disease.
Opioids have been implicated in the regulation of appetite since studies using the opioid antagonist naloxone caused a decrease in the food and drink intake in rats. Other more recent studies have built on these early investigations by reporting similar findings in humans. For example, in one study researchers used the opioid agonist butorphanol tartrate to increase the food intake of human volunteers1. The short term nature of the drug, being active from about two hours after administration, suggests that opioids are short term regulators of appetite. The effects of opioids on appetite have also been investigated with respect the role they may play in the development of bulimia (here). Other data has shown that opioids are able to alter macronutrient preferences. For example infusion of naloxone may decrease carbohydrate, but increase fat intake in humans. Rat studies confirm that opioids may increase preference for high fat foods while the opioid antagonist naloxone can cause decreases in fat intake.
Appetite is known to decrease when illness is present and this is likely the cause of the poor vitamin status attributed to hospitalised patients, when compared to free living healthy individuals. The decrease in appetite upon development of infection is well reported and it is likely that the negative nitrogen balance and weight loss seen during serious infection are a results from this decrease in appetite. Evidence from the nutritional literature suggests that interleukin-1 may be involved in the acute satiety caused by infection. Fasted rats injected with interleukin-1 show decreased food intakes compared to control rats when refeeding commences2. This may in some way explain the acute phase response to fever that includes a release of interleukin-1, a reduction in appetite, and a decreased appeal of even palatable foods. The weight loss and negative nitrogen balance seen during such periods likely results from the decrease in food intake combined with the roughly 10 % increase in metabolic rate.
The examples of interleukin-1 and the opioids highlight the complexity and nuances of appetite regulation. As more is understood about the synergism required between different hormonal and neuronal systems in the regulation of appetite, it becomes evident that controlling the system to produce beneficial weight loss is not possible with single target drugs. However, high quality diets can control the system because they work with the body to return the naturally efficient system for energy balance. Evidence now supports a role for low quality Western style diets in the development of metabolic dysfunction, and part of this undoubtedly causes aberrations in the appetite regulatory mechanisms. As dysfunction develops, hypothalamic control of energy balance deteriorates and energy intake becomes disassociated from the feedback mechanisms that regulate appetite. Changes in the metabolism of regulators such as interleukin-1 and the opioids not doubt reflect this disassociated state.
RdB
