Stress and Its Long-term Effects On Body Weight
Date: January 23rd, 2003
Title: “Chronic Reduction in Body Weight of Rats Exposed to Acute Stress”
Speaker: Ruth B. S. Harris, University of Georgia, Athens, GA
It is well established that stress inhibits food intake and weight gain. Rats exposed to 3 hours restraint stress on 3 consecutive days (repeated restraint) are hypophagic and lose 5 to 10% body weight.
This response has been observed in rats exposed to other types of stress such as sleep deprivation and social defeat and occurs in both male and female mature rats but not in young (5 week old) rats. In the repeated restraint protocol food intake, body temperature and energy expenditure of the rats return to normal once stress ends, but body weight does not return to that of non-stressed controls for at least three months.
Weight loss during restraint is lean tissue but fat is lost during the period immediately following stress and is associated with a temporary increase in the number of adipocyte b-adrenergic receptors. Weight loss is exaggerated in rats exposed to a second bout of repeated restraint but not by increasing the number of days included in one bout of repeated restraint.
Rats that are food restricted or overeating on the days of restraint return to a lower body weight than non-stressed controls when ad libitum feeding is restored.
Activation of CRF receptors in the hypothalamus initiates the response, but there is no evidence of chronic activation of this system. Mice that over-express agouti protein show an exaggerated stress response, suggesting that the melanocortin system normally antagonizes the weight loss, but acute agonism or antagonism of melanocortin receptors does not modify the response to stress, therefore, the role of the melanocortin system is questionable.
The endocrine response to a subsequent mild stress is greatly exaggerated in rats that have been subjected to repeated restraint stress, therefore, we are currently exploring the possibility that the chronic suppression of body weight is associated with an increased reactivity of the CRF system.
Q. Where are the CRF-R2 receptors located?
A. They have been identified in regions near the hypothalamus and brain stem.
Q. Is this restraint-stress manipulation conducted during the light or dark phase?
A. We have studied this stress paradigm in both light and dark phases, and found that the outcome differs depending on the time of day. Most of our studies are conducted at the start of the light cycle.
Q. Do the rats develop ulcers? If so, what percentage?
A. These rats did not develop ulcers. They probably would develop ulcers if they were kept in restraint for longer periods of time.
Q. Have you ever let them exercise afterwards?
A. No, but it would be interesting to see if exercise, after a period of restraint, would lessen the impact of the stressor.
Q. Since both restrained and control rats are housed and tested in a common area, do you think the controls might be somewhat ‘stressed’ from mere exposure to this procedure? Observing this event may be a stressor itself, which might blunt the actual size of any difference observed between the groups.
A. We have considered this potential confound, but completely separating the groups will introduce other potential confounds.
Q. Have you attempted to measure the rats’ ultrasonic vocalizations?
A. We haven’t, but it is most likely occurring.
Q. Have you tried using yoked controls?
A. Yes, and the controls return back to their baseline food intake and body weight levels… they did not respond like the stressed rats.
Q. How did you measure energy expenditure in your studies?
A. We used indirect calorimetry.
Q. Did the stressed rats’ respiratory quotient (RQ) change during restraint? Was there any evidence that nutrient oxidation had changed?
A. The RQ of the stressed rats decreased during stress but returned to baseline levels once stress ended.
Q. David Levitsky conducted a study in which rats were temporarily food-deprived until they lost weight, and then the rats were not allowed to compensate; these rats regained their weight, despite their lack of compensation…
A. Energy expenditure would most likely have been reduced in these rats.
Q. Is this stress response a ‘one-time only’ event, or can you elicit the weight-loss effect repeatedly?
A. We can elicit the effect repeatedly, and when we repeat the restraint-cycle, the weight-loss is even more robust.
Q. Do you know why the stress effect is only seen in older rats? Have you determined whether the effect is specifically age-related, or might it depend on something coincident with aging, such as age-associated weight-gain? Since the amount of weight lost is relatively small, maybe the effect only becomes significantly different from baseline when the rats reach their heavier weights… as they get older.
A. We haven’t evaluated this possibility but it’s an interesting consideration.
Q. Have you measured sympathetic activity?
A. We haven’t yet measured activation of the sympathetic system.
Q. If CRF activity was blocked only one time (on the first day), do you think you’re observing a pharmacologic effect, or inducing some genomic changes?
A. We have not blocked CRF on only one of the 3 days of restraint. Because the CRF system does not appear to be chronically activated once stress ends, we think we are inducing changes in protein expression at some level.
Q. Have you conducted a dexamethasone-suppression test?
A. We plan to conduct those tests in the near future.
Q. Are you planning to test novel stressors?
A. We plan to study novel stressors and are starting with saline injections.
Q. Adrenalectomized animals become hypophagic and lose weight; is this effect related to your observations?
A. Results from our experiments suggest that chronic down-regulation of weight in restrained rats is independent of stress-induced corticosterone release.
Q. Have you looked at catecholamine levels?
A. Central levels are elevated during stress, but they return to normal soon after the end of restraint.