July 2000 -- Obesity-news

Access to this newsletter is available with a subscription to Obesity-news. To subscribe please fill out our subscription information form. We take American Express, VISA or Mastercard on our secure server. We also take credit card orders by fax at 703/960-7462.

In the News	Do you know why you get the munchies? Calorie restriction and aging. Medical device to control weight developed. Dexfenfluramine corrects insulin resistance.
Drugs in Development	Fatty acid synthase inhibitors and weight loss. New thiazolidinedione prevents weight gain.
Leptin Studies	Dopamine, leptin and hyperphagia.
OTC Supplements	Anti-obesity effects of an herbal lipase inhibitor. Herbal metformin?
Subcription Information A one year on-line subscription to Obesity-news is $104.00. You may subscribe or renew on-line using American Express, VISA or Mastercard on our secure server. Fax orders may be sent to 703-960-7462.

It turns out that when your mother yelled "Chew your food!" at you years ago, she may have been right. Scientists at the University of Florida and the University of Texas Health Science Center have found that changes occurring in the hypothalamus after eating correspond to levels of glucose and insulin in the blood, the traditional biochemical indicators of satiety. But it takes around 10 minutes for the satiety signal to reach the brain, and possibly longer in the obese.

In a letter published in the June 29 issue of Nature, Dr. Yijun Liu reported the results of functional MRIs conducted on twenty one subjects (11 males, 10 females) before, during and after they ingested a glucose solution. Functional MRIs (fMRIs) measure changes in cerebral metabolism and blood flow, volume and oxygenation, and produce high-resolution images of the brain's activity. Using a mathematical model called "temporal clustering analysis" (TCA), Liu's team was able to determine how long it took the brain to respond to the glucose and which brain regions were involved in the response.

The experiment. 21 participants fasted for 12 hours after which they underwent a continuous brain scan for 48 minutes. Ten minutes after the start of the scan the subjects drank a solution containing 75 grams of dextrose. Blood samples were obtained simultaneously for testing of plasma glucose and insulin levels. To provide control data, 8 of the participants also took an fMRI on a separate day after ingesting distilled water. Three of the participants were excluded from the results because they moved their heads too much during the test.

Two peaks in brain response detected.

After the glucose ingestion, two peaks in brain response were detected. One occurred at 90 seconds and the other at about 10 minutes. The first peak corresponded to gustatory responses, like the taste and smell of food, and other food ingestion processes. But the more important, and sustained response began at 10 minutes after the ingestion. This peak, reflecting the brain's satiety signal, lasted for about two minutes and corresponded directly with an increase of insulin in the blood. In addition, the changes during the second peak were traced to the hypothalamus, the satiety center of the brain, whereas the first peak was found in the cerebellum. There were no brain activity peaks in the control group.

In an earlier study, Liu found that the brain's response to food was significantly delayed and diminished in participants who were obese compared to those who were lean. Although the reason for the variation is not known, Liu hypothesized that "thrifty genes" may explain the difference. The "thrifty gene theory", proposed in 1962 by geneticist James Neel, theorizes that populations exposed to alternating periods of feast and famine, developed these "thrifty genes" to store fat in times of plenty so that they would survive times of famine. According to the theory, the starvation environment caused genetic mutations leading the development of insulin resistance and hyperinsulinemia, both of which favor the storage of excess adipose tissue.

The major finding of the Nature study was the discovery of the dynamic interaction between the fMRI response and the plasma insulin signal using the TCA model. In the 1999 study, Liu was able to show that obese individuals had a slower and weakened hypothalamic response to a glucose load, but was not able to tie the response to insulin levels in the body. Although the exact role in regulating food ingestion remains to be established in humans, the temporal information helps us to understand how the brain generates a signal of satiety. Further, TCA-based fMRI should provide scientists with more information on the effects and timing of drugs on the brain, thus assisting in the development of new, and more effective drugs to treat obesity and type-2 diabetes.

In a letter published in the May issue Nature Genetics, investigators report that dopamine deficiency overrides the potent appetite stimulation present in ob/ob mice. While leptin deficient (ob/ob) mice display extreme hyperphagia, double mutant mice that lack both dopamine and leptin, starve to death within a few days.

Dopamine released in certain parts of the brain is associated with pleasurable and rewarding events. It also facilitates the sensory cues related to hunger and food searching in animals. Dopamine deficient mice with normal leptin levels die of starvation unless they are given a daily dose of l-dopa, which restores brain dopamine, locomotion and feeding.

In these experiments, Dr. Richard D. Palmiter and colleagues bred dopamine and leptin deficient mice (DDxLep(ob/ob)), which were maintained on a daily dose of l-dopa. DDxLep(ob/ob) mice grew faster and gained twice as much weight as dopamine deficient (DD) mice, but gained only half as much weight as ob/ob mice. Although smaller, the DDxLep(ob/ob) had the same body shape as ob/ob mice.

DD and DDxLep(ob/ob) mice became hyperactive in response to l-dopa. But it had no effect on ob/ob or wild-type mice. Typically, DD mice given l-dopa experience an activity peak at 3 hours after which movement declines, until 12 hours after injection they hardly move at all. DD mice experience 2nd and 3rd waves of activity up to 56 hours after l-dopa injection, although it is not enough to simulate eating.

The pattern seen in DD mice was identical to that seen in DDxLep(ob/ob) rodents. When l-dopa was withdrawn from the double mutant mice, food consumption all but ceased and body weight dropped by 15 percent by day 3, even though they were very active during the period.

The results show dopamine is required for food intake, even when leptin is absent. This indicates that dopamine suppresses the leptin-melanocortin pathway in controlling feeding. Scientists are uncertain as to how dopamine functions to motivate food intake. But Palmiter hypothesizes that dopamine-deficient mice are unable to process the signals that stimulate eating, and that the lack of signaling may prevent the strong appetite stimulus normally associated with low leptin levels.

Obesity-news is a publication of Hirsch Communications. An on-line subscription is $104.00 per year, payable in advance by check, money order, American Express, VISA or Mastercard. Subscribing is simple using our secure on-line subscription form. Obesity-news also accepts fax orders at 703/960-7462. Copyright 1997-2009, all rights reserved.

IMPORTANT: All information in this publication is believed to be accurate and true. Publisher is not liable for omissions or inaccuracies. Information in this newsletter is for educational purposes only and should not be construed as medical advice, or be used in lieu of consultation with a health care provider.

DO YOU KNOW WHY YOU GET THE MUNCHIES?

Contents

Two peaks in brain response detected.