The Tummy Clock
by Kathleen Carr 

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    A worker sits in his windowless cubicle, engrossed in the morning's work. Gradually, he becomes aware of an encroaching restlessness and inability to concentrate. A vague rumbling from his midsection adds to his discontent. He glances at the clock on his wall, but its hands have been stuck at half past seven for the past week--victim of a dead battery. But he hardly needs a clock to tell him what time it is. His stomach knows--it's lunch-time! 

    Since the early 1970s, scientists have known that an internal biological clock governs our daily lives. This circadian rhythm regulates sleep, body temperature, and hormone production, keeping us on a 24-hour schedule. Now it appears that our digestion has a biological clock of its own, but one that works independently of the clock that tells us when to wake and when to sleep. 

    FSU neuroscientist Dr. Frederick Stephan (Ph.D. Berkeley) has been investigating these "gastro-rhythms" since the late 1970s, searching for the location of the body's internal dinner bell and how it "rings" its message to the brain. Although he hasn't found all the answers yet, he and his laboratory team are discovering tantalizing clues about how our stomachs make plans for dinner. 

    Stephan, director of the university's Program in Neuroscience, has made the study of biological clocks a research career. In 1972, at the University of California, Berkeley, he and his major professor, Dr. Friedrich Irving Zucker, discovered the location of the body's primary timekeeper. Tucked away in the hypothalamus, the region of the brain that controls the body's basic functions, lies a cluster of cells called the suprachiasmatic nucleus (SCN). Smaller than a pinhead, the SCN is the biological pacemaker that keeps us all on a 24-hour schedule. 

    Nearly every cellular form of life found on Earth has a biological clock keeping it on a roughly 24-hour schedule. In humans, the SCN imposes a 24.5 hour schedule, slightly longer than an day, which means that it has to continually readjust to stay matched to the actual schedule of day and night dictated by the Earth's rotation. Daylight is the most important cue, resetting the SCN clock every morning, just as you might reset a cheap, but otherwise reliable, alarm clock every morning because it runs a bit slow. Activity and exercise also cue the SCN, reinforcing our daily schedules. Without those cues, we'd all be inclined to sleep a half-hour later every day. And that's exactly what happened when volunteer test subjects lived in isolation without any environmental cues about time of day. 

    In animal experiments in which the SCN was destroyed, although the sleeping/waking functions were disrupted, the animals continued to function relatively normally, running, eating and drinking the same amount every 24 hours. Without the SCN's influence, however, the animals engaged in these activities on a random basis throughout the 24-hour period, rather than at particular times. 

    In the late 1970s, Stephan became intrigued by two studies about feeding behavior in rats. One study showed that rats fed only once a day anticipated their feedings one to three hours ahead of time. This suggested that a biological clock might be influencing their feeding behavior. Another study, however, found that rats in whom the SCN had been destroyed, still anticipated being fed at the same time each day, suggesting that there was a separate clock besides the SCN for regulating feeding activities. 

    Stephan set out to prove that independent factors were influencing feeding behavior, and that it was NOT influenced by an internal clock. 

    "Much to my surprise," he says now years later, "it was." 

    He and his students did two experiments whose results have added support to the theory of an independent gastronomic clock--a mechanism entirely separate from the time-keeper in the brain. One test showed that rats would anticipate feedings if they were fed once a day within a window of time around 24 hours, such as every 23 hours, every 27 hours, or even 29 hours. (If they were fed every 24 hours, then it would be difficult to rule out other cues, such as the rats hearing the elevator as people entered the building, sound the animals could learn to associate with an impending meal.) 

    The rats lost the ability to anticipate scheduled feedings if they occurred outside that window, such as every 21 hours or every 30 hours. All of these are best explained by the existence of an internal clock controlling the rat's ability to anticipate a feeding, just as the SCN tells it when to wake and when to sleep. 

    A second set of experiments showed that, like any phenomenon governed by a clock, the rats could not adjust in one cycle if feeding schedules shifted by a large amount of time. If feeding schedules were shifted by eight hours, it would take two to five cycles for the rats to anticipate being fed at the new time. But unlike the SCN, which can only shift one to one-and-a-half hours per day, the gastronomic clock can be shifted by as much as four hours per day. 

    With the fact of gastro-rhythms established, now Stephan and his lab are looking for the actual location of this clock, what its cues are, and how it signals the brain to change the behavior of the organism. At present, Stephan speculates that the cells that make up this clock are located somewhere in the digestive system itself or possibly in the liver. 

    While he hasn't been able to establish what cues affect the clock and can reset its timing, he has ruled out possibilities such as volume (the mere presence of a substance) or taste (e.g. saccharin flavored water). A paper soon to be published discusses the results of his study that found that fat doesn't affect the clock, but glucose (a type of sugar) does. 

    Other studies have pretty much ruled out a direct neural connection to the brain as a mechanism for altering the animal's feeding behavior, so the Stephan team has been looking for factors being secreted into the blood that would act on the brain. Blood chemistry being as complex as it is, it's a bit like looking for the proverbial needle in the haystack, but there are some clues about what those factors might be. 

   To simplify the search, Stephan is studying the rats before they feed, rather than after they've eaten. As it turns out, for all the studies about what happens after an animal eats, there have been few studies about what's going on with the animal before it eats. And since there isn't the chemistry of a meal to take into account when looking for factors in the blood, it makes for a somewhat simpler study. In this case, they look for changes in the rats' blood before and after they begin to anticipate their next meal. 

    One change they've found so far is in the animals' levels of glucagon, a pancreatic hormone that raises the concentration of glucose in the blood. The rats' glucagon levels dropped as the rats begin to anticipate their meal. Upcoming studies will try infusing glucagon into the rats' bloodstream to see if that fools them into thinking that it's not yet time to eat. 

    More evidence has also come from electrophoresis studies, which showed a change in two peptides when rats began to anticipate a feeding. Stephan hopes to have those isolated and DNA sequenced in the next year in his continuing search for clues. 

    While almost nothing has been known about the genetic basis for biological clocks in mammals (until recently, such has only studied in fruit flies and slime molds) , that's begun to change. In just the past year, mammalian clock genes and the products of their expression have begun to be identified. 

    Developing an understanding of the gastronomic clock could pay off in many ways, biologically and medically. Traditionally, the digestive system has been viewed as a passive system that simply waits for food, then reacts to it. On the contrary, Stephan says. The fact that it's using an internal clock means that digestion is a proactive physiological process, secreting enzymes and stomach acids in anticipation of the meal that is to come. "It prepares your body for what is about to happen," he says. 

    The upshot? Our mothers were right--regular meals are important, a fact that shouldn't be lost upon a society that eats on the run, anytime, anyplace. And that fact shouldn't be lost upon doctors who are treating an epidemic of digestive disorders, particularly among shift workers. Eating when our bodies aren't prepared for digestion may be taking its toll. 

    The human body is proving to be an incredibly complex system of survival instincts, a web of unconscious behavior that anticipates our needs and our actions before we've given them a thought. With all due respect to the Swiss, the most elaborate, sophisticated timepieces in the world are the wonderful biological systems that tick away inside each of us from the moment we're born.

Source: Florida State University Research in Review, Fall & Winter 1998/1999  Issue