Effect of weight loss and regain in RYGB surgery in a rat mode
Date: January 18th, 2007
Speaker’s Name and Affiliation: Michael Meguid, M.D. Syracuse University
Title: “Weight loss and regain after RYGB surgery in a rat mode”
Roux-en-Y gastric bypass (RYGB) is the most effective therapy for morbid obesity, resulting in weight loss pattern. A 10-20% “weight loss failure rate” has been reported. We developed a RYGB model in diet induced obese rats that reproduces the temporal pattern of body weight (BW) loss in humans to determine mechanisms contributing to successful RYGB outcome. We also observe a failure rate; RYGB-S rats that successfully lost weight (75%) and rats that initially lost weight, but then started to fail RYGB operation and started to gain weight (RYGB-F;25%).
We hypothesize that the ultimate success of RYGB to sustain BW loss depends on a multifactorial set of variables involving GI- and non GI-related factors including nutrient absorption, fecal output (FO), food efficiency (FE), gut, adipose and thyroid hormones, vagal signaling, mitochondrial function and hypothalamic neuropeptide expression.
RYGB-S, RYGB-F and Pair Fed (PF) rats vs. controls showed rapid BW decrease accompanied by increase in caloric intake (CI), followed by sustained BW loss in RYGB-S. RYGB-F and PF gradually increased BW. Lower CI, higher FO, and lower FE of RYGB-S rats contributed to their greater BW loss and were associated with higher plasma PYY expression and up-regulated expression of hypothalamic leptin, orexin and CRF receptors as well as PYY and orexin. Additionally, the numbers of skeletal muscle mitochondria decreased with weigh loss, but increased with weight gain associated with corresponding changes in UCP-2 expression, and a decrease in vagal signaling to upper GI tract in RYGB-S rats vs. RYGB-F contributing to their greater BW loss.
Q. Do patients complain after surgery because they can’t eat much?
A. After surgery, they change their food selection, and instead of going for carbohydrate snacks, they often prefer proteins. Some do find it difficult to adhere to a different eating plan.
Q. Do patients have a problem with dumping syndrome?
A. Yes, this is a problem, but it is usually the result of a failed adherence to post-operative diet instead of surgical technique.
Q. The figures you put up that detail the caloric intake of patients before surgery, and during periods of weight gain, it seems that 2600-3000 kcal per day is not a lot, certainly not enough to sustain a BMI over 40. How do you interpret this?
A. That’s a good point, and it is the crux of the problem we are trying to get at. These calories sustain the changing LBM, and not the fat mass or total body weight. However, we know that overweight patients tend to underreport what they eat.
Q. Am I correct in saying that before the study, you did not know which rats would be failures (would gain weight after surgery), and which rats would be successful?
A. Yes, that’s correct. We separated them out prospectively via our daily statistically analysis of body weight, caloric intake and fecal output.
Q. Do you have direct evidence of a decrease thermogenesis in animals that are failures?
A. The answer would be by measuring oxygen consumption and CO2 output etc. But, although useful and we have become to rely on these number and take some comfort in them, one needs to remember that they reflect a metabolic integrative picture. Thus we have preferred mitochondrial phosphorylation and a concomitant knowledge of hormonal changes which we know influence the oxidative phosphorylation pathway.
Q.How do you test the curve shift on your figure for significance?
A. You are refereeing to the upward and left hand shift of proton leak (synonymous with heat production) of mitochondrial oxidative phosphorylation between Obese rats and those given CB-1 receptor blocker. The stats we use is one way ANOVA with post-hoc t-test.
Q. What is known about the phenotypes of UCP knockouts?
A. I’m not sure off hand, but I know they have placental differences when they are born. They aren’t complete knockouts, as some UCP activity remains.
Q. What about in obese patients who have surgeries? It is obviously not possible to give them a CB1 blocker to prevent them from gaining weight, so that this would be a practical application of your rat research?
A. Well, Rimonabant is currently available in Europe, and in theory it will probably be used as an off-license application in some use patients to maintain post-surgery weight loss. That depends on how rigorous the drug is controlled.
Q. What is the current protocol in humans for dealing with weight regain after surgery?
A. We increase the length of the bypass limb from 100 to 150 cm and if evidence exists that gastric pouch enlargement has occurred, then this too will need revision.
Q. From a theoretical point of view, you have a rat model of success and failure. How can you determine, prospectively, which rats will succeed and which will fail?
A. It is not a shotgun approach, but we are looking for a variety of metabolic factors that might affect the ability to maintain weight loss after surgery. Once these are established, we will have a better idea which rats (and perhaps humans) will be the most successful.
Q. Don’t you also have a pair fed group of animals? What happens to them?
A. They behave metabolically similar to the failures. They are conserving energy. But their hormonal profile is dissimilar.
Q. Are other surgical procedures, besides RYGB, still done, and do they have as many failures?
A. Yes, they are done, and they have the same success rate. I still think there might be a benefit to gastric banding, in some patients, especially those who need to lose less weight quickly, in preparation for other surgical procedures eg: hip or knee replacement, to ensure its greater success.
Q. What are the effects of exercise post-op, in terms of mitochondria per cell?
A. That’s an intriguing question. Intuitively one would imagine as muscle mass increases so too would mitochondrial mass so as to increase energy utilization and maintain body weight. But I am not certain such studies have been performed or are in the process of being performed. It sort of falls in the domain of exercise physiology, from which I am sure we could learn..