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...since fat contains twice as many calories per gram as other dietary components, it may be that rats, and perhaps people, who chronically eat high-fat diets become less sensitive to satiety signals and eat far too many calories before becoming satiated.

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We had some clues about the brain substrates of satiation from the work of Gaylen Edwards, now at the University of Georgia, and Elizabeth South, now at the University of Idaho. While he was with my laboratory Edwards discovered that, under some circumstances, rats with damage in a part of the brain that receives input from the vagus nerve, which innervates the gastrointestinal tract, eat very large meals. Elizabeth South, also in my lab at the time, found that when a substance that selectively inactivates sensory nerves, but not motor nerves, is injected into this same brain area, rats also eat large meals. Could these effects be related to intestinal signals that terminate meals?

We subsequently discovered that when the vagus nerve itself is damaged, rats no longer reduce their food intake in response to fat or sugars in the intestine. The vagus nerve carries messages from the GI tract to the brain. But it also transmits commands from the brain to the GI tract. However, Dan Yox and I were also able to demonstrate that selective, chemically induced damage to the sensory component of the vagus also prevented satiation by intestinal fat and sugar infusions. Therefore, it appears that fat or sugars enter the small intestine where they somehow activate sensory nerve fibers in the vagus nerve, which transmits this information to the brain and produces satiation.

Knowing that the vagus nerve carries satiety signals from the intestine to the brain is an important insight. However, the vagus is a complex nerve with tens of thousands of nerve fibers, only a fraction of which can be involved in satiation. We would like to know exactly how fats and sugars in the intestine are able to activate a subpopulation of nerve fibers in the intestinal wall. One possibility is that fats and sugars release chemicals from intestinal epithelial cells or nerve cells within the wall of the intestine. These substances may secondarily activate vagal sensory fibers. Dr. Gerry Smith, a colleague at Cornell Medical Center, had shown that CCK, a peptide hormone released by food in the intestine, reduced food intake by acting on the vagus. As part of her doctoral research, Ellen Ladenheim, now at Johns Hopkins University Medical School, discovered that selective chemical destruction of vagal sensory nerves eliminated reduction of food intake produced by injections of CCK. In collaboration with Bob Speth, one of our colleagues in the Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology (VCAPP), she also showed that prior chemical destruction of vagal sensory fibers prevented the vagus from binding CCK. Could it be that CCK released from the intestine by components of food is involved in satiation by intestinal fat and sugar?

Lynne Brenner, a research assistant professor in VCAPP, demonstrated that drugs that block the ability of CCK to bind to its receptors on the vagus nerve reduced the ability of fats and sugars to cause satiation and increased meal size when given by themselves. Amy Jagger, a veterinary student currently working in my laboratory, together with Jennifer Grahn, has traced vagal sensory nerves, believed to be responsive to nutrients and CCK, into the intestinal wall. In addition, Connie Tamura, a former pharmacology/toxicology graduate student, found that chemically induced depletion of another peptide (CGRP) from nerve fibers just below the intestinal epithelial surface also reduces the ability of fat to cause satiation. We subsequently found that fat infused into the intestine causes secretion of this neuropeptide.

Finally, Gil Burns, an assistant professor in VCAPP, working with veterinary student Lisa Fleischman, has found that a specific blockade of receptors for certain chemicals—excitatory amino acids—increases meal size in a very selective manner. Burns thinks that excitatory amino acids may be released in the brain when food enters the gastrointestinal tract and that this event may be involved in meal termination. All of these findings are like pieces of a puzzle, which must be correctly assembled to provide an accurate picture of how the satiation process works. However, the currently available data suggest that when food enters the small intestine, peptides are released from epithelial cells and nerves in the intestinal wall. These peptides activate the sensory fibers of the vagus nerve, which in turn may release excitatory amino acids in the brain, causing satiation. This picture is only an educated guess—a hypothesis. But if we are correct, then a better understanding of the satiation processes may allow us to control satiation in the interest of controlling food intake and body weight.

But if nature has provided such intricate mechanisms to control meal size, why do overeating and obesity occur at all? Furthermore, why has the tendency to become obese actually increased dramatically over the past 50 years? One thing that has changed a lot in the past 50 years is the quantity of fat calories in the Western diet. Currently, Americans consume as much as 50 percent of their calories as fat. Could it be that high-fat diets interfere with satiation?

Mihai Covasa, a postdoctoral fellow in my lab, has found that fat in the intestine is roughly 50 percent less effective in producing satiation when rats are maintained on high-fat diets than when they are fed a low-fat diet. Furthermore, since fat contains twice as many calories per gram as other dietary components, it may be that rats, and perhaps people, who chronically eat high-fat diets become less sensitive to satiety signals and eat far too many calories before becoming satiated.

In fact, this may be happening with Covasa's rats. When he feeds them a high-fat diet, diluted with fiber so that it has the same number of calories as the low-fat diets, the animals do not exhibit normal satiation in response to intestinal fat, but the fiber in the diet appears to enable them to avoid obesity. Perhaps the mechanical effects of the fiber provides an important satiety signal in these animals. On the other hand, rats eating a high-fat, low-fiber diet, with increased calories and reduced bulk, quickly become obese. Covasa and I believe that chronic high-fat diets may interfere with satiation mechanisms by altering sensitivity to hormones or changing the chemistry of the vagal sensory innervation to the intestine.

The physiological and neurochemical processes that control the cycles of meal initiation and satiation have had millions of years to develop. They are now the focus of intense research. Clearly, the controls of meal termination are not the only things we need to appreciate to understand the control of food intake and body weight. We also need to know how changes in fuel metabolism guide our desire to begin eating (hunger) and how need for specific nutrients may guide our choice of foods. These are areas of inquiry being pursued by Sue Ritter and her group in VCAPP. The rapid progress of our species toward providing continual ready access to calorically dense foods has outstripped the pace at which controls of food intake can adapt to these radically new conditions. Consequently, understanding the details of how these intricate controls operate not only is a search for truth and beauty in nature, but a search for avenues through which we may be able to protect ourselves from our own success.