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Department of Metabolic Medicine, Imperial College, London W12 ONN, United Kingdom
Address all correspondence and requests for reprints to: Prof. Stephen R. Bloom, Department of Metabolic Medicine, Imperial College, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.
When a patient with obesity seeks medical help, that patient expects to be cured. A cure means permanent return to normal body weight. The physician is delighted when, after a year’s treatment, the average patient loses 10% of his/her body weight. In contrast, the patient is annoyed. He/she expects to become lean, which often requires a weight loss of 30% or more. Furthermore, a year later still, the patient’s weight has frustratingly risen back to where it started. What is desperately desired is a therapeutic approach that produces major weight loss and is permanent. The only currently available option is a surgical procedure.
The Roux-en-Y gastric bypass (gastric bypass) was originally devised as a means of producing malabsorption and thus weight loss. Unfortunately, malabsorption lasted only a few weeks and then the gut adapted. Unexpectedly, weight loss continued, due to a dramatic loss of appetite (1, 2). The mechanism behind this loss of appetite was an enigma, especially because the excessive appetite and morbid obesity returned if for any reason the bypass had to be reversed.
The exponential advance in the epidemic of obesity has led to a phenomenal increase in surgical procedures for obesity (3). Other therapies have proven statistically effective at causing weight loss, but the magnitude and permanency desired by many patients and physicians cannot yet be delivered. We face a stark choice between the comorbidities of obesity and the complications of bariatric surgery. The dramatic speed at which type 2 diabetes mellitus resolves after the gastric bypass procedure has led to the hypothesis that many of the health benefits may be independent of weight loss (4). Renewed attempts to unravel the mechanism underlying gastric bypass are thus underway.
The three traditional explanations for weight loss after gastric bypass included first the idea that gastric volume reduction caused early symptoms of satiety. However, plain gastric restrictive operations such as gastric banding require production of much smaller gastric volumes and tighter outlet obstructions before significant weight loss occurs. Restrictive procedures are less effective than gastric bypass, both for weight and appetite control (5). Second, and most obvious, the bypass procedure was thought to cause weight loss through malabsorption of nutrients. Although transiently true (6), once the gut has adapted, malabsorption is not observed. Enhanced hunger, which usually occurs with malabsorption, is also not seen after gastric bypass. Third, it was suggested that rapid transit of food down the gut, secondary to bypass, somehow decreased appetite (7). Observation of transit rate in postoperative patients, however, suggests slow transit to be the norm.
We now know that ghrelin, produced in the stomach, acts as an orexogenic signal through the appetite centers in the arcuate nucleus within the hypothalamus (8). The peak before a meal and the decrease postprandially are consistent with ghrelin’s role as a hunger hormone (8). Other gut hormones such as peptide YY (PYY) and glucagon-like peptide 1 may act as anorexic signals (9, 10). These two hormones are produced from the distal gastrointestinal tract and peak postprandially (10, 11). Administration of PYY3–36, glucagon-like peptide 1, and oxyntomodulin have been shown to result in loss of appetite in volunteers (9, 12, 13), and the positive associations of the degree of postprandial rise of these hormones with size of meals and time to reach peak plasma levels implicate them as potential satiety factors (11, 13).
The contribution of Korner et al. in this issue (14) lies in the detailed description of the profiles of total ghrelin and octanoylated ghrelin changes after a small meal. This study reported subtle differences in postprandial profiles of total ghrelin compared with octanoylated ghrelin in patients after gastric bypass, obese controls, and normal-weight controls. The octanoylated or active ghrelin, although lower in the gastric bypass and obese groups, showed similar percentage decreases to the normal-weight controls. The same profile was not seen in total ghrelin, as the obese control group had an attenuated postprandial decrease. This study confirms that gastric bypass patients’ appetite may be suppressed because ghrelin levels are low or fail to show the expected rise associated with other forms of weight loss (15).
The PYY observations are interesting and important. Korner et al. (14) showed that obese subjects had a blunted response to a small meal, consistent with previous reports (16, 17). However, despite patients still being technically obese after gastric bypass, an early and exaggerated PYY response was observed compared with normal-weight subjects. The reported satiety and hunger visual analog scale data should be interpreted with caution, due to their cross-sectional nature, but there appears to be an association between the enhanced satiety and the exaggerated PYY response. This study also illustrates that postprandial hormone responses should be considered when hunger and satiety are examined, because the differential rise in PYY could not have been predicted from the basal PYY plasma levels that were similar in the groups.
The work of Korner et al. (14) raises three important questions. First the discrepancy between the total ghrelin and octanoylated ghrelin profiles in the obese group suggests that the obese may well have a normal active ghrelin response pattern to a small meal and that total ghrelin measurements may be misleading. Second, this observation opens the issue of the measurement of PYY, which is currently only possible with the use of a polyclonal antibody that cross-reacts 100% with PYY1–36 and PYY3–36. Only PYY3–36 has so far been shown to reduce appetite and food intake in humans (9, 16), although PYY1–36 may also do so. It is unclear in patients with gastric bypass which moiety contributed to the increased postprandial rise. Third, cross- sectional data on hunger and satiety are helpful but, due to the relative small groups used in the report by Korner et al., statistical power was lacking, and thus future prospective data are necessary to clarify appetite changes after gastric bypass.
The most intriguing question raised by Korner et al. is why PYY is elevated after gastric bypass. The suggestion that nutrients reach the PYY-producing L cells in the distal gut earlier requires confirmation. Gut motility has been observed to be reduced after gastric bypass; indeed, a described function of PYY would be to reduce gut transit to allow longer time for nutrient absorption (18). The gastric bypass procedure alters the gastric emptying mechanism and usually reduces the length of small bowel by about 100 cm, the length of the biliopancreatic limb. Given the wide variation of small-bowel length considered as normal, a 100-cm length reduction may not be enough to explain the early and exaggerated PYY response.
In this study, fasting PYY was not different between the three groups, suggesting that fasting PYY remains unchanged after weight loss. A previous study (16) showed fasting PYY to be lower in obese compared with normal-weight subjects. The PYY observation may be similar to ghrelin: despite surgically induced weight loss, ghrelin remains unchanged from levels associated with obesity, despite being higher in lean subjects (15, 19). It thus remains to be determined whether plasma PYY, either fasting or postprandially, changes after diet-induced weight loss.
Bypass surgery is the most effective weight loss intervention, with the Roux-en-Y gastric bypass procedure currently the best compromise between effectiveness and complications. In the foreseeable future, procedure capacity will have to be expanded to cope with the ever-increasing number of patients that qualify and request the surgery. In the longer term, however, it may be possible to unravel the secrets of the surgical procedure and thereby harness the gut-brain axis to effect weight loss in morbidly obese patients without the need for surgery.
Footnotes
Abbreviation: PYY, Peptide YY.
Received November 10, 2004.
Accepted November 15, 2004.
References
This article has been cited by other articles:
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  R. Morinigo, V. Moize, M. Musri, A. M. Lacy, S. Navarro, J. L. Marin, S. Delgado, R. Casamitjana, and J. Vidal Glucagon-Like Peptide-1, Peptide YY, Hunger, and Satiety after Gastric Bypass Surgery in Morbidly Obese Subjects J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1735 - 1740. [Abstract] [Full Text] [PDF]
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O. B. Chaudhri, B. C. T. Field, and S. R. Bloom From gut to mind--hormonal satiety signals and anorexia nervosa. J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 797 - 798. [Full Text] [PDF]
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