Regulation of food intake in obese people: is there any evidence for an antiobesity drug?

Meghan Medlock

WHAT IS OBESITY?

The most common eating disorder in our society is excessive eating which includes craving and compulsive eating which can quite often result in obesity (http://www.nutramed.com/zeno/addictive.htm#exorphins). Obesity is a body condition where a person's body mass index is greater than 30. Other diseases that can accompany or follow obesity include diabetes, hypertension, and heart disease. Also, obese people are at a greater risk of certain kinds of cancer like breast, colon, and uterine cancer. Nori Geary, an associate professor of psychiatry at Cornell University, did a great deal of work on the physiological control of feeding behavior (http://www.med.cornell.edu/rasp/gdir/geary.html).

Some people respond well to proper diet and exercise to overcome obesity. For those who do not, however, antiobesity drugs are gaining popularity in pharmaceutical compnaies. One potential antiobesity drug that was recently developed by scientists in France and England is butabindide. This drug works to regulate appetite by breaking down a neurotransmitter that signals satiety. This drug has not yet been administered to humans, but its development may provide information to help with the development of other antiobesity drugs in the future (Jack 1756).

FEEDBACK MECHANISMS AND FAT INTAKE

A number of biological and psychological factors are involved to consolidate energy intake, expenditure, and storage to satisfy specific biological or biophysiological processes. The degree to which these processes control eating behavior is regulated by sensors in the gastrointestinal tract, the liver, and the brain which all work to control this system through a process of positive and negative feedback system. Many forces, such as the taste of the food and the surrounding atmosphere, control the amount of food eaten. The receptors in the gastrointestinal tract manage the size and times of eating behavior while metabolic cues oversee energy consumption with respect to what the body needs. Overeating causes a greater amount of fat storage than did carbohydrate overfeeding. Studies of the appetites of obese women prove that energy intake during a high-fat lunch was much higher than during a high-carbohydrate lunch and this remained for the next 24 hours. The reason that has been hypothesized for this is that the metabolic rates of fats and carbos are different. Carbohydrates are more rapidly absorbed and contribute to the suppression of appetite. Fat storage, on the other hand, is almost without limit with a lower satiety calibre. Carbohydrate storage in the body, in the form of glycogen, is limited, and need to be constantly refilled. Obesity is a disorder that is related to a "disease" of the fat storage mechanisms and if a person is obese, there will be a presence of lipids already in the small intestine that delay the emptying of gastric fluids. These fatty acids in the stomach relax the stomach and therefore, cause the stomach to be able to adapt to a greater capacity of food. When the stomach receptors are stimulated, the gastric sensitivity is transformed to accommodate a meal while the positive sensations of enjoyment are also aroused so that this experience is repeated again. Studies have shown that people show feelings of sleepiness and enjoyment while fat is in the intestines demonstrating the significance of the association between eating and contentness (Read 1-3).

HORMONES AND NEUROTRANSMITTERS

Appetite is controlled in the brain by way of a series of signals triggered by dietary breakdown and by autonomic signals produced by distension of the stomach and intestines (Jack 1756). All of these signals combined are processed by complex interactions by the neuronal networks and neurotransmitters. Among the most important of the neurotransmitters is cholecystokinins (CCK) that are a family of hormonal and neuronal peptides that link the stomach and the brain. CCK is also involved in appetite control by producing a satiety signal in response to food intake. CCK has been found to be low in some women with bulimia, causing them to binge (http://www.bixler.com/brainnet/eatingdi.html). Also, when essential amino acids, especially phenylalanine, are present around the stomach, the release of CCK increases (Aceto 97). Studies have also shown that CCK sensitivity changes with age as well (Rolls, Dimeo, and Shide 931).

The question in studying the CCK system is whether human food intake can be regulated by controlling this system. Studies with rats have shown that CCK may act by increasing the sensitivity of the stomach to distension. However, this same study was conducted with humans and the results were slightly different; the release of CCK in humans desensitizes the gastric afferent neurons maybe by acting at the same level as the brain stem (Read 6). Another observation that challenges this notion that CCK regulates satiety is that the data on humans is not consistent unlike the data on animals (Read 6). It seems that gastric distention by itself does not cause the normal comfortable feeling of satiety; distension combined with duodenal lipid infusion perhaps is related to some effect of the lipid on the central processing of the afferent details (Read 6).

In terms of oral administraion of this neurotransmitter to help maintain food intake to minimum, CCK is rapidly broken down in the gastrointestinal tract before it can be absorbed. Intravenously, CCK administration also failed because it is short-lived due to peptidase digestion. So, instead of trying to raise levels of CCK externally, scientists are trying out new ways to block the breakdown of endogenously produced CCK to cut back on food intake (Jack 1756).

The process involved in this reaction is as follows: scientists have recognized a stomach enzyme (serine pepidase) that digests CCK with little to no effect on other neuropeptides involved in the control of gallbladder contraction, gastric emptying, and intestinal mobility. If CCK were used to overcome hunger, this might illustrate the observation that infusion of lipid into the duodenum slowed the rate of ingestion (Read 8). Michael Lean, a professor of nutrition at Glasgow University, said "'Appetite is the most fundamental and potent life-force of all. It is unlikely to be regulated by a single system or common pathway. The CCK patha dramatic effect on appetite or energy balance (Jack 1756).'"

CCK as an appetite suppressant could appear to look convincing if it were not for the experiments showing that certain CCK antagonists have not shown a convincing effect on the eating patterns in humans. Other hormones including bombesin, gastric inhibitory polypeptide, glycogen-like insulino-tropic peptide, and pancreatic glucagon may also alter satiety, but the data showing that these hormones really have an effect is not persuasive enough (Read 8).

Works Cited

Aceto, Chris. (1996) Fat Burners. Joe Weider's Muscle and Fitness. 57: 90-100.

Jack, David. (1996) Fighting Obesity the Franco-British Way. The Lancet. 347: 1756-1758.

Read, Prof. (1994) The Role of the Gut in Regulating Food Intake in Man. Nutrition Reviews. 52: 1-9.

Rolls, B., Dimeo, K., amd Shide, D. (1995) Age-Related Impairments in the Regulation of Food Intake. The American Journal of Clinical Nutrition. 62: 923-935.