Correspondence
Weight Loss and Plasma Ghrelin Levels
N Engl J Med 2002; 347:1379-1381October 24, 2002
- Article
To the Editor:
Cummings et al. (May 23 issue)1 report that, unlike diet-induced weight loss, weight reduction after gastric bypass is associated with markedly low levels of ghrelin. We would caution against concluding, as they do, that suppression of ghrelin is responsible for the weight-reducing effect of gastric bypass. First, the plasma ghrelin concentration is negatively correlated with the body-mass index (the weight in kilograms divided by the square of the height in meters).2 In the study by Cummings et al., the mean preoperative body-mass index of surgical patients was 68, whereas the diet-treated obese controls had an initial body-mass index of 48; because of the lack of preoperative testing in the surgical group, the authors cannot exclude the possibility that this greater degree of obesity may have influenced their results.
Ghrelin was measured an average of 1.4 years after gastric bypass and after a weight loss of 36 percent. There would have been more support for the authors' conclusions if the suppression of ghrelin had been shown to precede the weight loss.
We recently found that a significant decrease in the levels of insulin, insulin-like growth factor I, and leptin, as well as a significant increase in the level of corticotropin, occur as early as three weeks after gastric bypass, despite an unaltered body-mass index.3 These data suggest that gastric bypass results in complex hormonal changes before weight loss occurs, which supports the hypothesis that the procedure has an endocrine mechanism of action. Whether and how ghrelin plays a part in this mechanism remain unclear. Ghrelin secretion might in fact be modified by other gastrointestinal hormones whose levels change in response to the altered gastrointestinal anatomy. Ghrelin suppression can perhaps explain the loss of appetite after gastric bypass; however, since obesity is associated with lower levels of ghrelin,4 it seems unlikely that reducing the level of ghrelin would, by itself, induce weight loss.
4 ReferencesFrancesco Rubino, M.D.
Institute for Research into Cancer of the Digestive System–European Institute of Telesurgery, 67091 Strasbourg, France
f.rubino@lycos. com Michel Gagner, M.D.
Mount Sinai Medical Center, New York, NY 100291
Cummings DE ,Weigle DS ,Frayo RS , et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623-1630
Full Text | Web of Science | Medline2
Shiiya T ,Nakazato M ,Mizuta M , et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002;87:240-244
CrossRef | Web of Science | Medline3
Rubino F ,Gagner M ,Gentileschi P , et al. The effect of Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Gastroenterology 2002;123:Suppl:44-45
Web of Science4
Tschop M ,Weyer C ,Tataranni PA ,Devanarayan V ,Ravussin E ,Heiman ML . Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707-709
CrossRef | Web of Science | Medline
To the Editor:
The study by Cummings et al. raises several issues that remain unresolved. The slowing of gastric emptying induced by weight loss1 may have contributed to increases in the ghrelin level due to a longer duration of contact between nutrients and gastroduodenal mucosa. The effects of increased ghrelin levels on gastric emptying and accommodation were not ascertained in the patients in this study. Similarities between ghrelin and motilin in sequence homology, cyclic fluctuations, effects on gastric emptying, site of release, and cross-binding with receptors2 suggest that activity attributed to ghrelin may not be specific and that studies with selective antagonists are required. Moreover, given that motilin agonists impair gastric accommodation,3 it is conceivable that ghrelin might decrease gastric accommodation to increase satiation.
The increased levels of ghrelin in the diet group would be expected to induce greater appetite and weight gain rather than loss. In rats, ghrelin secretion is reduced by a high-fat diet.4 Thus, the change from a high-fat to a low-fat diet may have contributed to the higher ghrelin levels in the group with weight loss.
Given the relatively small differences in ghrelin levels before and after the dietary intervention, we suggest that other factors (e.g., visiting the dietitian two to three times per week for six months, delayed gastric emptying, and a low-fat diet) might have contributed to the observed weight loss. Without studies of gastric function and the use of a ghrelin antagonist to elucidate its biologic effects, it is premature to postulate that ghrelin is a potential target for medical treatment of obesity or cachexia.
4 ReferencesMichael Camilleri, M.D.
Filippo Cremonini, M.D.
Mayo Clinic, Rochester, MN 559051
Verdich C ,Madsen JL ,Toubro S ,Buemann B ,Holst JJ ,Astrup A . Effect of obesity and major weight reduction on gastric emptying. Int J Obes Relat Metab Disord 2000;24:899-905
CrossRef | Web of Science | Medline2
Hill J ,Szekeres P ,Muir A ,Sanger GJ . Molecular, functional and cross-species comparisons between the receptors for the prokinetic neuropeptides, motilin and ghrelin. Gastroenterology 2002;122:Suppl:A-54 abstract.3
Liau S-S ,Camilleri M ,Kim D-Y ,Stephens D ,Burton DD ,O'Connor MK . Pharmacological modulation of human gastric volumes demonstrated noninvasively using SPECT imaging. Neurogastroenterol Motil 2001;13:533-542
CrossRef | Web of Science | Medline4
Greeley GH Jr ,Englander EW . Dietary regulation of stomach ghrelin secretion. Gastroenterology 2002;122:Suppl:A-141 abstract.
To the Editor:
Cummings et al. elegantly show that ghrelin levels are elevated before meals and fall afterward, suggesting that ghrelin promotes hunger. Although the authors do not call attention to it, the circadian patterns in Figure 1 and Figure 2 of their article reveal that the ghrelin level falls the most at night during sleep, despite prolonged fasting, and may help suppress hunger-induced awakenings. Indeed, the amount of rapid-eye-movement sleep can be reduced by ghrelin.1 Moreover, the ghrelin level increases only moderately before breakfast, when food intake is usually lowest, increases somewhat more before lunch, when intake is greater, and then increases the most just before dinner, when intake is greatest, at least in the United States. Cummings et al. found that after diet-induced weight loss in obese persons, ghrelin levels increase as if to promote food intake and weight regain. Nevertheless, even at these higher levels, the ghrelin level still follows the same patterns at night and before meals.
The authors hold out hope for a ghrelin antagonist to reduce food intake in obese persons. However, obese persons already have lower ghrelin levels — about 27 percent below those of normal-weight persons, as demonstrated by Tschop et al.2 The lower levels in obese persons suggest that changes in ghrelin levels occur in response to, rather than cause, overeating and the overweight state. Nevertheless, a ghrelin antagonist may still help decrease food intake in obese persons by reducing meal intake throughout the day: a small breakfast would be followed by a small lunch and a small dinner, resulting in weight loss.
2 ReferencesAllan Geliebter, Ph.D.
St. Luke's–Roosevelt Hospital Center, New York, NY 10010
ag58@columbia.edu 1
Tolle V ,Bassant MH ,Zizzari P , et al. Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats. Endocrinology 2002;143:1353-1361
CrossRef | Web of Science | Medline2
Tschop M ,Weyer C ,Tataranni PA ,Devanarayan V ,Ravussin E ,Heiman ML . Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707-709
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. Rubino and Gagner emphasize that circulating ghrelin levels correlate negatively with body-mass index and suggest that the high body-mass index before gastric bypass might account for the very low ghrelin levels after surgery. This possibility seems unlikely because, at the time of sampling, the average body-mass index among the subjects who underwent gastric bypass was about the same as that among matched obese controls, whose ghrelin levels were 3.5 times as high. Furthermore, the weight loss that had occurred before testing in subjects who had undergone gastric bypass would be predicted to increase ghrelin levels if it had been achieved by other methods. We agree, however, that a role for ghrelin in the efficacy of gastric bypass is only suggested, not proved, by our circumstantial evidence and that more definitive intervention studies are required. Although postoperative changes in other gastrointestinal hormones could theoretically suppress ghrelin, it is unlikely that reductions in insulin, leptin, or insulin-like growth factor I mediate this effect, given the evidence indicating that a decrease in any of them would either increase or not affect ghrelin.1,2
Drs. Camilleri and Cremonini suggest that slow gastroduodenal emptying might contribute to increased ghrelin levels after dietary weight loss. Because ingested nutrients suppress ghrelin more effectively than do parenteral nutrients,3 we submit that an increased duration of contact between nutrients and gastroduodenal mucosa might actually enhance prandial ghrelin suppression or simply alter its time course. Studies examining the effect of ghrelin on gastric motility report conflicting results, and we agree that this is an important area for further investigation. We also agree with the assertion that increased ghrelin levels after weight loss would be expected to induce greater appetite and weight gain. In our study, diet-induced weight loss occurred because of an imposed restriction on caloric intake, and the compensatory increase in ghrelin levels suggests that ghrelin may participate in adaptive responses that promote recovery of lost weight.
Dr. Geliebter notes that ghrelin levels decline during sleep, despite continued absence of nutrients in the gut — a condition associated with high daytime ghrelin levels. This finding is unexplained and warrants further study. Dr. Geliebter and Drs. Rubino and Gagner astutely question whether ghrelin antagonists will reduce weight in obese persons, given that such persons have low base-line ghrelin levels. It is important to note that weight reduction by various methods increases ghrelin levels,4,5 a response that may promote weight regain. Thus, pharmacologic blockade of ghrelin might ultimately prove more useful in the maintenance of a reduced weight after loss has been achieved by other means.
5 ReferencesDavid E. Cummings, M.D.
University of Washington, Seattle, WA 98195
davidec@u.washington. edu Jonathan Q. Purnell, M.D.
Oregon Health and Science University, Portland, OR 97201David S. Weigle, M.D.
University of Washington, Seattle, WA 981951
Saad MF ,Bernaba B ,Hwu CM , et al. Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 2002;87:3997-4000
CrossRef | Web of Science | Medline2
Asakawa A ,Inui A ,Kaga T , et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 2001;120:337-345
CrossRef | Web of Science | Medline3
Shiiya T ,Nakazato M ,Mizuta M , et al. Plasma ghrelin levels in lean and obese humans and effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002;87:240-244
CrossRef | Web of Science | Medline4
Otto B ,Cuntz U ,Fruehauf E , et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001;145:669-673
CrossRef | Web of Science | Medline5
Nagaya N ,Uematsu M ,Kojima M , et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 2001;104:2034-2038
CrossRef | Web of Science | Medline
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