Pathophysiology of Obesity: Why Surgery Remains the Most Effective Treatment Authors
First Online: 14 November 2007 Received: 26 March 2007 Accepted: 19 June 2007 DOI:
Cite this article as: Waseem, T., Mogensen, K.M., Lautz, D.B. et al. OBES SURG (2007) 17: 1389. doi:10.1007/s11695-007-9220-1
Obesity is a rapidly increasing, worldwide epidemic. Despite recent scientific advances, no currently recommended dietary program or medication results in long-term weight loss of more than 10% of body weight for the vast majority of people who attempt these interventions. Hence, surgical intervention is recommended for patients with a BMI ≥ kg/m
2. Although surgery is an effective, sustainable treatment of obesity, it can be associated with potentially significant perioperative risks and long-term complications. Current research is focused on developing a medical therapy, which produces more effective and sustainable weight loss, yet avoids the risks inherent in major surgery. With a reduced risk profile, such therapy could also be appropriately offered to those who are less obese and, in theory, help those who have BMIs as low as 27 kg/m 2. Toward that end, numerous scientists are working to both unravel the pathophysiology of obesity and to determine why surgical intervention is so effective. This review briefly examines the current status of obesity pathophysiology and management, the reasons for failure of conventional medical treatments, and the success of surgical intervention. Finally, future areas of research are discussed.
Roux-en-Y gastric bypass
Stubbs CO, Lee AJ. The obesity epidemic: both energy intake and physical activity contribute. Med J Aust 2004; 181: 489–91.
Brolin RE. Bariatric surgery and long-term control of morbid obesity. JAMA 2002; 288: 2793–6.
Prentice A, Jebb S. Energy intake/physical activity interactions in the homeostasis of body weight regulation. Nutr Rev 2004; 62: S98–S104.
Marti A, Moreno-Aliaga MJ, Hebebrand J et al. Genes, lifestyles and obesity. Int J Obes 2004; 28 (Suppl 3): S29–S36.
Kalra SP, Dube MG, Pu S et al. Interacting appetiteregulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68–100.
Williams G, Bing C, Cai XJ et al. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol Behav 2001; 74: 683–701.
Druce MR, Small CJ, Bloom SR. Minireview: Gut peptides regulating satiety. Endocrinology 2004; 145: 2660–5.
Dhillo WS, Bloom SR. Gastrointestinal hormones and regulation of food intake. Horm Metab Res 2004; 36: 846–51.
Strader AD, Woods SC. Gastrointestinal hormones and food intake. Gastroenterology 2005; 128: 175–91.
Mantzoros CS, Flier JS. Editorial: leptin as a therapeutic agent — trials and tribulations. J Clin Endocrinol Metab 2000; 85: 4000–2.
Gehlert DR. Role of hypothalamic neuropeptide Y in feeding and obesity. Neuropeptides 1999; 33: 329–38.
Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000; 106: 473–81.
Gumbs AA, Modlin IM, Ballantyne GH. Changes in insulin resistance following bariatric surgery: role of caloric restriction and weight loss. Obes Surg 2005; 15: 462–73.
Schwartz GJ. The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 2000; 16: 866–73.
Cummings DE, Purnell JQ, Frayo RS et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 1714–9.
Wren AM, Seal LJ, Cohen MA et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001; 86: 5992–6.
Asakawa A, Inui A, Kaga T et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 2003; 52: 947–52.
Shearman LP, Wang SP, Helmling S et al. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology 2006; 147: 1517–26.
Wortley KE, Del Rincon JP, Murray JD et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest 2005;115: 3573–8.
Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003; 23: 7973–81.
Zhang JV, Ren PG, Kretchmer OA et al. Obestatin, a peptide by the ghrelin gene, opposes ghrelin’s effects on food intake. Science 2005; 310: 996–9.
Tschop M, Castaneda TR, Joost HG et al. Physiology: does gut hormone PYY3-36 decrease food intake in rodents? Nature 2004; 430: 650–4.
Batterham RL, Cohen MA, Ellis SM et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003; 349: 941–8.
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. National Institutes of Health. Obes Res 1998; 6 (Suppl 2): 51S–209S.
Wadden TA, Foster GD, Letizia KA. One-year behavioral treatment of obesity: comparison of moderate and severe caloric restriction and the effects of weight maintenance therapy. J Consult Clin Psychol 1994; 62: 165–71.
Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res 2004; 12: 1197–211.
Lambert PD, Anderson KD, Sleeman MW et al. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 2001; 98: 4652–7.
Jbilo O, Ravinet-Trillou C, Arnone M et al. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J 2005; 19: 1567–9.
Bray GA, Hollander P, Klein S et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003; 11: 722–33.
Gadde KM, Franciscy DM, Wagner HR 2nd et al. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA 2003; 289:1820–5.
Anderson JW, Greenway FL, Fujioka K et al. Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obes Res 2002; 10: 633–41.
Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.
Della Zuana O, Sadlo M, Germain M et al. Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade. Int J Obes 2001; 25: 84–94.
Ishihara A, Tanaka T, Kanatani A et al. A potent neuropeptide Y antagonist, 1229U91, suppressed spontaneous food intake in Zucker fatty rats. Am J Physiol 1998; 274: R1500–4.
Kanatani A, Kanno T, Ishihara A et al. The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability. Biochem Biophys Res Commun 1999; 266: 88–91.
Shearman LP, Camacho RE, Sloan Stribling D et al. Chronic MCH-1 receptor modulation alters appetite, body weight and adiposity in rats. Eur J Pharmacol 2003; 475: 37–47.
Halatchev IG, Ellacott KL, Fan W et al. Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 2004; 145: 2585–90.
Mun EC, Blackburn GL, Matthews JB. Current status of medical and surgical therapy for obesity. Gastroenterology 2001; 120: 669–81.
Halmi KA, Mason E, Falk JR, et al. Appetitive behavior after gastric bypass for obesity. Int J Obes 1981; 5: 457–64.
Mason EE, Ito C. Gastric bypass. Ann Surg 1969; 170: 329–39.
Jones KB, Jr. Experience with the Roux-en-Y gastric bypass, and commentary on current trends. Obes Surg 2000; 10: 183–5.
Buchwald H, Buchwald JN. Evolution of operative procedures for the management of morbid obesity 1950–2000. Obes Surg 2002; 12: 705–17.
Dejardin DC, Pereffer FS, Gonzalez MH et al. The evolution of experimental surgery in the field of morbid obesity. Obes Surg 2004; 14: 1263–72.
Shikora SA. Implantable gastric stimulation for the treatment of severe obesity. Obes Surg 2004; 14: 545–8.
Cummings DE, Shannon MH. Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss? J Clin Endocrinol Metab 2003; 88: 2999–3002.
Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg 2004; 239: 1–11.
Kellum JM, Kuemmerle JF, O’Dorisio TM et al. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Ann Surg 1990; 211:763–70; discussion 770–1.
Frühbeck G, Diez Caballero A, Gil MJ. Fundus functionality and ghrelin concentrations after bariatric surgery. N Engl J Med 2004; 350: 308–9.
Naslund I. Gastric bypass versus gastroplasty. A prospective study of differences in two surgical procedures for morbid obesity. Acta Chir Scand 1987; 536 (Suppl): 1–60.
Pories WJ, Swanson MS, MacDonald KG et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995; 222: 339–50; discussion 350–2.
MacLean LD, Rhode BM, Nohr CW. Long- or shortlimb gastric bypass? J Gastrointest Surg 2001; 5: 525–30.
Cummings DE, Weigle DS, Frayo RS et al. Human plasma ghrelin levels after diet-induced weight loss and gastric bypass surgery. N Engl J Med 2002; 346: 1623–30.
Geloneze B, Tambascia M, Pilla VF et al. Ghrelin: a gut-brain hormone: effect of gastric bypass surgery. Obes Surg 2003; 13: 17–22.
Adami GF, Cordera R, Marinari G et al. Plasma ghrelin concentratin in the short-term following biliopancreatic diversion. Obes Surg 2003; 13: 889–92.
Tritos NA, Mun E, Bertkau A et al. Serum ghrelin levels in response to glucose load in obese subjects postgastric bypass surgery. Obes Res 2003; 11: 919–24.
Williams DL, Cummings DE, Grill HJ et al. Mealrelated ghrelin suppression requires postgastric feedback. Endocrinology 2003; 144: 2765–7.
Faraj M, Havel PJ, Phélis S et al. Plasma acylationstimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab 2003; 88: 1594–602.
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. Obes Surg 2004; 14: 606–12.
Nijhuis J, van Dielen FM, Buurman WA et al. Ghrelin, leptin and insulin levels after restrictive surgery: a 2-year follow-up study. Obes Surg 2004; 14: 783–7.
Frühbeck G, Rotellar F, Hernandez-Lizoain JL et al. Fasting plasma ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia. Obes Surg 2004; 14: 1208–15.
Overduin J, Frayo RS, Grill HJ et al. Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 2005;146: 845–50.
Garcia-Unzueta MT, Fernandez-Santiago R, Dominguez-Diez A et al. Fasting plasma ghrelin levels increase progressively after biliopancreatic diversion: one-year follow-up. Obes Surg 2005; 15: 187–90.
Mion F, Napoleon B, Roman S, et al. Effects of intragastric balloon on gastric emptying and plasma ghrelin levels in non-morbid obese patients. Obes Surg 2005; 15: 510–6.
Christou NV, Look D, McLean AP et al. Pre- and post-prandial plasma ghrelin levels do not correlate with satiety or failure to achieve a successful outcome after Roux-en-Y gastric bypass. Obes Surg 2005; 15: 1017–23.
Langer FB, Reza Hoda MA, Bohdjalian A et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Obes Surg 2005; 15: 1024–9.
Ram E, Vishne T, Diker D, et al. Impact of gastric banding on plasma ghrelin, growth hormone, cortisol, DHEA and DHEA-S levels. Obes Surg 2005; 15: 1118–23.
Foschi D, Corsi F, Rizzi A et al. Vertical banded gastroplasty modifies plasma ghrelin secretion in obese patients. Obes Surg 2005; 15: 1129–32.
Cohen R, Uzzan B, Bihan H et al. Ghrelin levels and sleeve gastrectomy in super-super-obesity. Obes Surg 2005; 15: 1501–2.
Takachi K, Doki Y, Ishikawa O et al. Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy. J Surg Res 2006; 130: 1–7.
Kotidis EV, Koliakos G, Papavramidis TS et al. 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? Obes Surg 2006; 16: 554–9.
Stratis C, Alexandrides T, Vagenas K et al. Ghrelin and peptide YY levels after a variant of biliopancreatic diversion with Roux-en-Y gastric bypass versus after colectomy: a prospective comparative study. Obes Surg 2006; 16: 752–8.
Holdstock C, Edén Engström B, Öhrvall M et al. Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans. J Clin Endocrinol Metab 2003; 88: 3177–83.
Meryn S, Stein D, Straus EW. Pancreatic polypeptide, pancreatic glucagon and enteroglucagon in morbid obesity and following gastric bypass operation. Int J Obes 1986; 10: 37–42.
Stoeckli R, Chanda R, Langer I et al. Changes of body weight and plasma ghrelin levels after gastric banding and gastric bypass. Obes Res 2004; 12: 346–50.
Christou NV, Look D, McLean AP. Pre- and post-prandial plasma ghrelin levels do not correlate with satiety or failure to achieve a successful outcome after Rouxen-Y gastric bypass. Obes Surg 2005; 15: 1017–23.
Couce ME, Cottam D, Esplen J et al. Is ghrelin the culprit for weight loss after gastric bypass surgery? A negative answer. Obes Surg 2006;16: 870–8.
Koopmans HS, Ferri GL, Sarson DL et al. The effects of ileal transposition and jejunoileal bypass on food intake and GI hormone levels in rats. Physiol Behav 1984; 33: 601–9.
Ueno T, Shibata C, Naito H et al. Ileojejunal transposition delays gastric emptying and decreases fecal water content in dogs with total colectomy. Dis Colon Rectum 2002; 45: 109–116; discussion 116–8.
Mason E. Ileal transposition and enteroglucagon in obesity (and diabetic) surgery. Obes Surg 1999; 9: 223–8.
Strader AD, Vahl TP, Jandacek RJ et al. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab 2005; 288: E447–E453.
Xu Y, Ramos EJ, Middleton F et al. Gene expression profiles post Roux-en-Y gastric bypass. Surgery 2004; 136:246–52.
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