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Logo of ijpepInternational Journal of Peptides
 
Int J Pept. 2010; 2010: 217267.
Published online 2010 January 27. doi:  10.1155/2010/217267
PMCID: PMC2911614

Ghrelin and Metabolic Surgery

Abstract

Metabolic surgery is the most effective treatment for morbid obesity. Ghrelin has been implicated to play a role in the success of these procedures. Furthermore, these operations have been used to study the gut-brain axis. This article explores this interaction, reviewing the available data on changes in ghrelin levels after different surgical procedures.

1. Introduction

Surgical procedures are currently the most effective therapy for long-term weight loss [1]. Furthermore, some of these operations lead to the rapid remission of type 2 diabetes in a weight loss independent manner [2]. The mechanism that leads to sustained weight loss as well as diabetes remission after bariatric operations remains to be fully elucidated. However, it is becoming evident that these procedures modulate the gut-brain axis by altering the anatomy of the gut and affecting gut hormones [3]. In fact some of these procedures are now considered suitable models to study the gut brain axis. The landmark study of Cummings et al., which showed a profound suppression of ghrelin levels following Roux-en-Y gastric bypass, has brought the interaction of weight loss operations and the gut-brain axis into focus [46].

1.1. Ghrelin

Ghrelin is a 28-amino acid peptide produced from the fundus of the stomach and the proximal intestine [57]. It is the only known orexigenic gut hormone. Central and peripheral administration leads to increased food intake [8, 9]. Ghrelin levels increase prior to meals and are suppressed postprandially in proportion to the amount of calories ingested, therefore suggesting a possible role in meal initiation [10, 11]. The 24-hour profile of ghrelin increases following diet-induced weight loss supporting the hypothesis that ghrelin has a role in the long-term regulation of body weight [4]. Obese individuals have lower fasting ghrelin levels, and significantly reduced postprandial ghrelin suppression compared to normal weight individuals [12].

1.2. Metabolic Surgery

Surgical procedures were designed to promote weight loss by reducing stomach volume (laparoscopic adjustable gastric banding (LABG), laparoscopic sleeve gastrectomy (LSG)), malabsorption of nutrients (biliopancreatic diversion (BPD), duodenal switch (DS)), or a combination of both (Roux-en-Y gastric bypass (RYGB)). It is now known that standard proximal Roux-en-Y gastric bypass causes only malabsorption of micronutrients and not of calories, and restriction does not play a major role. A number of studies have shown that changes in gut hormone concentrations may partly explain the weight loss following weight losss surgery.

Furthermore, following these procedures a vast improvement in glycaemic control has been observed. A meta-analysis reported improved glycaemic control and remission of type 2 diabetes in 83.8% of patients following gastric bypass and 47.8% following gastric banding [2]. The fact that these procedures improve manifestations of the metabolic syndrome, often in a weight-loss independent manner has led to the development of the concept of metabolic surgery. In fact a number of scientific societies have changed their name in order to include this term.

2. Ghrelin and Roux-en-Y Gastric Bypass

RYGB is the most common metabolic procedure worldwide [13]. Cummings et al. showed a profound suppression of ghrelin levels (24-hour profile) following RYGB [4]. However, the data published since are inconclusive. Different studies showed a decrease in fasting and postprandial ghrelin levels [1421], no change in fasting and postprandial levels [2232], and an increase in fasting ghrelin levels after RYGB [3337]. The reason for this heterogeneity has not been elucidated and multiple explanations have been proposed. Differences in the methods used for evaluating ghrelin levels are possible, but unlikely. It has been suggested that even in the studies reporting an increase in fasting ghrelin levels, ghrelin does not increase to the extent reported with diet-induced weight loss or of nonobese individuals [26]. In a study which investigated the intraoperative changes in ghrelin during RYGB, the complete division of the stomach and the formation of a vertical pouch contributed to the decline in the circulating ghrelin [18]. Moreover, an intact vagus nerve appears to be required for ghrelin to have an appetite effect [38]. Technical differences in the procedure in regards to preservation of the vagus nerve may be responsible. Iatrogenic vagal nerve dysfunction caused intraoperatively might also play a role, as shown by a study which demonstrated a decrease in ghrelin levels on the first postoperative day after RYGB, followed by an increase to preoperative levels at 1 month and a further increase at 12 months [35]. An alternative theory has suggested that the different configuration of the pouch might be responsible [39]. In a vertical pouch, ghrelin producing cells are more likely to be excluded, compared to a horizontal pouch [40]. Finally, hyperisulinaemia and insulin resistances are associated with ghrelin suppression in obese individuals [40]. Therefore, preoperative differences as well as differences in the postoperative improvement in these parameters may cause this inconsistency.

3. Ghrelin and Biliopancreatic Diversion

BPD is an operation that does cause malabsorption of calories. A study on patients prior to and 5 days and 2 months after BPD showed a similar response with an initial reduction in fasting ghrelin, followed by a return to the preoperative levels when food consumption resumed to almost preoperative levels [41]. This finding supports the hypothesis that although the primary source of ghrelin is the gastric mucosa, small intestinal nutrient exposure is sufficient for food-induced plasma ghrelin suppression in humans and gastric nutrient exposure is not necessary for this suppression [42]. However, different studies have shown an increase [4346] or no change [36, 41, 47] in ghrelin levels after BPD.

A decrease in ghrelin levels has been noted after DS [48, 49]. In this procedure, the reduction in the stomach volume is achieved with a sleeve gastrectomy. It is important to stress the anatomical difference between BPD as described by Scopinaro with horizontal gastrectomy where the fundus remains intact and gets in contact with nutrients, whereas in DS type duodenal switch with sleeve gastrectomy the fundus, the main area of ghrelin production, is resected.

4. Ghrelin and Gastric Banding

LAGB has been shown to reduce hunger and increase satiety [50]. No association with ghrelin levels was demonstrated in the same study [51]. Schindler et al. showed an increase in fasting ghrelin accompanied by a paradoxical decrease in hunger after LAGB suggesting that weight loss is independent of circulating plasma ghrelin and relies on changes in eating behaviour induced by gastric restriction [51]. Further studies on patients following LAGB demonstrated both increased fasting ghrelin levels [7, 19, 25, 5254] and a blunted postprandial suppression of ghrelin [17, 32]. However, we, as well as others, were not able to show any changes in ghrelin levels after laparoscopic gastric banding [22, 5557].

5. Ghrelin and Sleeve Gastrectomy

LSG is a relatively new bariatric operation which was designed as a restrictive procedure. Recent studies challenge this classification showing accelerated gastric emptying after LSG [58]. However, another study of patients undergoing LSG showed no difference in gastric emptying compared to preoperatively and therefore the controversy remains [59]. The fact that the fundus of the stomach, the main location of ghrelin-producing cells, is excluded in this procedure led to speculation that ghrelin could play a role in the mechanism of action. Three studies confirmed a decrease in fasting ghrelin levels after LSG [54, 57, 60]. A prospective, double-blind study comparing RYGB and LSG confirmed a significant postprandial suppression of ghrelin postoperatively, while there was no change in the RYGB group [30]. In the same study, the marked suppression of ghrelin levels after LSG was associated with greater appetite reduction and excess weight loss during the first postoperative year compared to RYGB [30]. An even more recent prospective randomised comparison of LSG and RYGB confirms that both operations reduce fasting and meal stimulated ghrelin levels, significantly more so after LSG, so resection of the fundus has more impact on the ghrelin levels compared to just bypassing it [61].

6. Conclusion

The role of ghrelin in the success of bariatric and metabolic surgery remains to be further elucidated. Some of the findings of the initial studies have not been confirmed in more recent investigations. Different gut hormones as well as having an incretin effect have been implicated to be key players in appetite control. However, the hypothesis that ghrelin might play a role in the mode of action of metabolic surgery has been crucial in the development of the field. The weight loss as well as the remission of type 2 diabetes experienced after metabolic surgery is not exclusively attributed to pure restriction or malabsorption any more. A lot of research is focused on exploring the hormonal and metabolic changes after metabolic surgery as well as the mechanism of action.

References

1. Sjöström L, Narbro K, Sjöström CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. New England Journal of Medicine. 2007;357(8):741–752. [PubMed]
2. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. Journal of the American Medical Association. 2004;292(14):1724–1737. [PubMed]
3. Pournaras DJ, Le Roux CW. Obesity, gut hormones, and bariatric surgery. World Journal of Surgery. 2009;33(10):1983–1988. [PubMed]
4. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New England Journal of Medicine. 2002;346(21):1623–1630. [PubMed]
5. Cummings DE. Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery. International Journal of Obesity. 2009;33(supplement 1):S33–S40. [PubMed]
6. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660. [PubMed]
7. Frühbeck G, Diez Caballero A, Gil MJ. Fundus functionality and ghrelin concentrations after bariatric surgery. New England Journal of Medicine. 2004;350(3):308–309. [PubMed]
8. Wren AM, Small CJ, Abbott CR, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001;50(11):2540–2547. [PubMed]
9. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. Journal of Clinical Endocrinology and Metabolism. 2001;86(12):5992–5995. [PubMed]
10. Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC, Weigle DS. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. Journal of Clinical Endocrinology and Metabolism. 2004;89(3):1319–1324. [PubMed]
11. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50(8):1714–1719. [PubMed]
12. Le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. Journal of Clinical Endocrinology and Metabolism. 2005;90(2):1068–1071. [PubMed]
13. Buchwald H, Williams SE. Bariatric surgery worldwide 2003. Obesity Surgery. 2004;14(9):1157–1164. [PubMed]
14. Geloneze B, Tambascia MA, Pilla VF, Geloneze SR, Repetto EM, Pareja JC. Ghrelin: a gut-brain hormone. Effect of gastric bypass surgery. Obesity Surgery. 2003;13(1):17–22. [PubMed]
15. Tritos NA, Mun E, Bertkau A, Grayson R, Maratos-Flier E, Goldfine A. Serum ghrelin levels in response to glucose load in obese subjects post-gastric bypass surgery. Obesity Research. 2003;11(8):919–924. [PubMed]
16. Morínigo R, Casamitjana R, Moizé V, et al. Short-term effects of gastric bypass surgery on circulating ghrelin levels. Obesity Research. 2004;12(7):1108–1116. [PubMed]
17. Leonetti F, Silecchia G, Iacobellis G, et al. Different plasma ghrelin levels after laparoscopic gastric bypass and adjustable gastric banding in morbid obese subjects. Journal of Clinical Endocrinology and Metabolism. 2003;88(9):4227–4231. [PubMed]
18. Lin E, Gletsu N, Fugate K, et al. The effects of gastric surgery on systemic ghrelin levels in the morbidly obese. Archives of Surgery. 2004;139(7):780–784. [PubMed]
19. Frühbeck G, Rotellar F, Hernández-Lizoain JL, et al. Fasting plasma ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia. Obesity Surgery. 2004;14(9):1208–1215. [PubMed]
20. Rodieux F, Giusti V, D’Alessio DA, Suter M, Tappy L. Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release. Obesity. 2008;16(2):298–305. [PubMed]
21. Foschi D, Corsi F, Colombo F, et al. Different effects of vertical banded gastroplasty and Roux-en-Y gastric bypass on meal inhibition of ghrelin secretion in morbidly obese patients. Journal of Investigative Surgery. 2008;21(2):77–81. [PubMed]
22. Le Roux CW, Aylwin SJB, Batterham RL, et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Annals of Surgery. 2006;243(1):108–114. [PubMed]
23. Le Roux CW, Welbourn R, Werling M, et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Annals of Surgery. 2007;246(5):780–785. [PubMed]
24. Faraj M, Havel PJ, Phélis S, Blank D, Sniderman AD, Cianflone K. Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. Journal of Clinical Endocrinology and Metabolism. 2003;88(4):1594–1602. [PubMed]
25. Stoeckli R, Clianda R, Langer I, Keller U. Changes of body weight and plasma ghrelin levels after gastric banding and gastric bypass. Obesity Research. 2004;12(2):346–350. [PubMed]
26. Korner J, Bessler M, Cirilo LJ, et al. Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. Journal of Clinical Endocrinology and Metabolism. 2005;90(1):359–365. [PubMed]
27. Couce ME, Cottam D, Esplen J, Schauer P, Burguera B. Is ghrelin the culprit for weight loss after gastric bypass surgery? A negative answer. Obesity Surgery. 2006;16(7):870–878. [PubMed]
28. Whitson BA, Leslie DB, Kellogg TA, et al. Entero-endocrine changes after gastric bypass in diabetic and nondiabetic patients: a preliminary study. Journal of Surgical Research. 2007;141(1):31–39. [PubMed]
29. Liou J-M, Lin J-T, Lee W-J, et al. The serial changes of ghrelin and leptin levels and their relations to weight loss after laparoscopic minigastric bypass surgery. Obesity Surgery. 2008;18(1):84–89. [PubMed]
30. Karamanakos SN, Vagenas K, Kalfarentzos F, Alexandrides TK. Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Annals of Surgery. 2008;247(3):401–407. [PubMed]
31. Oliván B, Teixeira J, Bose M, et al. Effect of weight loss by diet or gastric bypass surgery on peptide YY3-36 levels. Annals of Surgery. 2009;249(6):948–953. [PMC free article] [PubMed]
32. Korner J, Inabnet W, Febres G, et al. Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. International Journal of Obesity. 2009;33(7):786–795. [PMC free article] [PubMed]
33. Vendrell J, Broch M, Vilarrasa N, et al. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obesity Research. 2004;12(6):962–971. [PubMed]
34. Holdstock C, Engström BE, Öhrvall M, Lind L, Sundbom M, Karlsson FA. Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans. Journal of Clinical Endocrinology and Metabolism. 2003;88(7):3177–3183. [PubMed]
35. Sundbom M, Holdstock C, Engström BE, Karlsson FA. Early changes in ghrelin following Roux-en-Y gastric bypass: influence of vagal nerve functionality? Obesity Surgery. 2007;17(3):304–310. [PubMed]
36. Garcia-Fuentes E, Garrido-Sanchez L, Garcia-Almeida JM, et al. Different effect of laparoscopic Roux-en-Y gastric bypass and open biliopancreatic diversion of Scopinaro on serum PYY and ghrelin levels. Obesity Surgery. 2008;18(11):1424–1429. [PubMed]
37. Ybarra J, Bobbioni-Harsch E, Chassot G, et al. Persistent correlation of ghrelin plasma levels with body mass index both in stable weight conditions and during gastric-bypass-induced weight loss. Obesity Surgery. 2009;19(3):327–331. [PubMed]
38. Le Roux CW, Neary NM, Halsey TJ, et al. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. Journal of Clinical Endocrinology and Metabolism. 2005;90(8):4521–4524. [PubMed]
39. Pories WJ. Ghrelin? Yes, it is spelled correctly. Annals of Surgery. 2008;247(3):408–410. [PubMed]
40. McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cummings DE. Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive contrls. Journal of Clinical Endocrinology and Metabolism. 2004;89(4):1630–1635. [PubMed]
41. Adami GF, Cordera R, Marinari G, Lamerini G, Andraghetti G, Scopinaro N. Plasma ghrelin concentratin in the short-term following biliopancreatic diversion. Obesity Surgery. 2003;13(6):889–892. [PubMed]
42. Parker BA, Doran S, Wishart J, Horowitz M, Chapman IM. Effects of small intestinal and gastric glucose administration on the suppression of plasma ghrelin concentrations in healthy older men and women. Clinical Endocrinology. 2005;62(5):539–546. [PubMed]
43. Adami GF, Cordera R, Andraghetti G, Camerini GB, Marinari GM, Scopinaro N. Changes in serum ghrelin concentration following biliopancreatic diversion for obesity. Obesity Research. 2004;12(4):684–687. [PubMed]
44. García-Unzueta MT, Fernández-Santiago R, Domínguez-Díez A, Vazquez-Salví L, Fernández-Escalante JC, Amado JA. Fasting plasma ghrelin levels increase progressively after billiopancreatic diversion: one-year follow-up. Obesity Surgery. 2005;15(2):187–190. [PubMed]
45. Mingrone G, Granato L, Valera-Mora E, et al. Ultradian ghrelin pulsatility is disrupted in morbidly obese subjects after weight loss induced by malabsorptive bariatric surgery. American Journal of Clinical Nutrition. 2006;83(5):1017–1024. [PubMed]
46. Valera Mora ME, Manco M, Capristo E, et al. Growth hormone and ghrelin secretion in severely obese women before and after bariatric surgery. Obesity. 2007;15(8):2012–2018. [PubMed]
47. Frühbeck G, Diez-Caballero A, Gil MJ, et al. The decrease in plasma ghrelin concentrations following bariatric surgery depends on the functional integrity of the fundus. Obesity Surgery. 2004;14(5):606–612. [PubMed]
48. Kotidis EV, Koliakos G, Papavramidis TS, Papavramidis ST. The effect of biliopancreatic diversion with pylorus-preserving sleeve gastrectomy and duodenal switch on fasting serum ghrelin, leptin and adiponectin levels: is there a hormonal contribution to the weight-reducing effect of this procedure? Obesity Surgery. 2006;16(5):554–559. [PubMed]
49. Kotidis EV, Koliakos GG, Baltzopoulos VG, Ioannidis KN, Yovos JG, Papavramidis ST. Serum ghrelin, leptin and adiponectin levels before and after weight loss: comparison of three methods of treatment—a prospective study. Obesity Surgery. 2006;16(11):1425–1432. [PubMed]
50. Dixon AFR, Dixon JB, O’Brien PE. Laparoscopic adjustable gastric banding induces prolonged satiety: a randomized blind crossover study. Journal of Clinical Endocrinology and Metabolism. 2005;90(2):813–819. [PubMed]
51. Schindler K, Prager G, Ballaban T, et al. Impact of laparoscopic adjustable gastric banding on plasma ghrelin, eating behaviour and body weight. European Journal of Clinical Investigation. 2004;34(8):549–554. [PubMed]
52. Nijhuis J, van Dielen FMH, Buurman WA, Greve JWM. Ghrelin, leptin and insulin levels after restrictive surgery: a 2-year follow-up study. Obesity Surgery. 2004;14(6):783–787. [PubMed]
53. Hanusch-Enserer U, Cauza E, Brabant G, et al. Plasma ghrelin in obesity before and after weight loss after laparoscopical adjustable gastric banding. Journal of Clinical Endocrinology and Metabolism. 2004;89(7):3352–3358. [PubMed]
54. Wang Y, Liu J. Plasma ghrelin modulation in gastric band operation and sleeve gastrectomy. Obesity Surgery. 2009;19(3):357–362. [PubMed]
55. Shak JR, Roper J, Perez-Perez GI, et al. The effect of laparoscopic gastric banding surgery on plasma levels of appetite-control, insulinotropic, and digestive hormones. Obesity Surgery. 2008;18(9):1089–1096. [PMC free article] [PubMed]
56. Hanusch-Enserer U, Brabant G, Roden M. Ghrelin concentrations in morbidly obese patients after adjustable gastric banding. New England Journal of Medicine. 2003;348(21):2159–2160. [PubMed]
57. Langer FB, Hoda MAR, Bohdjalian A, et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Obesity Surgery. 2005;15(7):1024–1029. [PubMed]
58. Melissas J, Daskalakis M, Koukouraki S, et al. Sleeve gastrectomy—a “food limiting” operation. Obesity Surgery. 2008;18(10):1251–1256. [PubMed]
59. Bernstine H, Tzioni-Yehoshua R, Groshar D, et al. Gastric emptying is not affected by sleeve gastrectomy-scintigraphic evaluation of gastric emptying after sleeve gastrectomy without removal of the gastric antrum. Obesity Surgery. 2009;19(3):293–298. [PubMed]
60. Cohen R, Uzzan B, Bihan H, Khochtali I, Reach G, Catheline JM. Ghrelin levels and sleeve gastrectomy in super-super-obesity. Obesity Surgery. 2005;15(10):1501–1502. [PubMed]
61. Peterli R, Wölnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: a prospective randomized trial. Annals of Surgery. 2009;250(2):234–241. [PubMed]

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