November 1, 2004

Molecular Clock Genes Influence Metabolism
of Sugar and Dietary Fats
Implications for Better Understanding of Diabetes, Metabolic Syndrome, and Obesity

(Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine have discovered that components of the internal molecular clock of mammals have an important role in governing the metabolism of sugars and fats within the body. They found in mice that two of the well-studied proteins in the clock control the ability of animals to recover from the fall in blood sugar that occurs in response to insulin.

The investigators demonstrate a role for the circadian clock proteins, Bmal1 and Clock, in regulating the day-to-day levels of glucose in the blood. Suppressing the action of these molecules eliminates the diurnal variation in glucose and triglyceride levels. In addition, they found that a mutated Clock gene protected mice from diabetes induced by a high-fat diet. Together these findings represent the first molecular insight into how timing of what we eat - via the clock - can influence metabolism. The findings appear in the November 2 issue of the online journal PLoS Biology.

The master molecular clock in mammals is located in the brain in an area called the suprachiasmatic nucleus, clusters of neurons in the hypothalamus. Many of our basic functions, including regulating body temperature and hormone levels, vary throughout the day and night. Some of these changes may relate to being asleep or awake and on the job, but others are under the control of a biochemical timepiece that sets and resets daily.

Over the last several years, researchers have begun to appreciate that the molecular components of the clock exist in most, if not all, tissues of the body. Some years ago, a team led by senior author Garret FitzGerald, MD, Chairman of Penn’s Department of Pharmacology, discovered a molecular clock in the heart and blood vessels and described for the first time how the master clock in the brain could use a hormone to control such a peripheral clock.

During the course of the group’s research they found that many metabolic genes were among the roughly 10 percent of genes that oscillate in activity in a 24-hour period. “We noticed a variation in the recovery of blood glucose with clock time,” says Dan Rudic, PhD, a Research Associate in the Department of Pharmacology and a lead author on the current study. “We were stunned when we found that inactivating clock genes abolished this response.”

Food is also an important cue in directing the daily oscillations of metabolism and blood-sugar levels. As such, what you eat, as well as how much and when, all interact with this process. Normally, after eating, insulin notifies several organs to take up excess sugar in the blood and store it as glycogen. Conversely, when the sugar level in blood dips between snacks, glucagon notifies the body to break down stored energy like glycogen and fat to release as glucose. The molecular clock genes work somehow to orchestrate this complex system. However, when this finely tuned scenario is upset, all-too-familiar diseases arise: diabetes when there is too much sugar; hypoglycemia when there is too little.

What’s more, the researchers found that a high-fat diet amplified the oscillation in blood sugar over a 24-hour period and that disabling the Clock gene markedly reduced this effect. Indeed, a mutated Clock gene protected mice from diabetes induced by a high fat diet, a model of type-2 diabetes in humans. How this works is as yet unclear, but the researchers think that the clock mediates the impact of a fatty diet. “This suggests that altering when fat calories are eaten might be exploited to reduce the likelihood of inducing diabetes,” says FitzGerald.

Poor dietary habits and a sedentary lifestyle have been linked to diabetes, high blood fats, and high blood pressure, all characterized in an epidemic called metabolic syndrome, which is reaching alarming proportions in both developed and developing countries, says FitzGerald. This work adds to the understanding of physiological control of metabolism and therefore possibilities of working with the body’s natural rhythms to fight disease.

Over time humans have moved from eating our fill at one sitting after the hunt to continuous availability of fast food. Nutritionists have long speculated that it might matter whether we “nibble” or “gorge” our calories, and that this makes a difference in how our bodies handle a high-fat diet. “These results suggest that it may not just be what we eat, but also, to some extent, when we eat it,” concludes FitzGerald.

This research was funded in part by the National Institutes of Health and the American Heart Association. Co-authors on the paper are: Peter McNamara, Phenomix Corp., Calif.; Anne-Marie Curtis, Penn; Raymond C. Boston, Penn School of Veterinary Medicine; and Satchidananda Panda and John B. Hogenesch, The Genomics Institute of the Novartis Research Foundation, Calif.

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