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The ever-worsening problem of obesity has become so prevalent and is so strongly associated with medical comorbidities and mortality that it has begun to overtake infectious diseases as the most significant contributor to ill health worldwide.1–7 Despite the obvious public health benefits (and financial rewards) that would accrue from the development of truly effective pharmacotherapy for obesity, medical and behavioral approaches remain limited in their efficacy, facilitating no more than a 5–10% loss of body weight, and recidivism after even this modest weight loss is nearly universal.8–11 A principal reason for this is that body weight is regulated by a powerful homeostatic system that, in response to weight loss, triggers compensatory changes in appetite and energy expenditure to promote weight regain.12 Importantly, even minor weight loss confers disproportionate health benefits, in terms of ameliorating obesity-related comorbidities.7 Thus, obese individuals benefit greatly from the mild weight loss that can often be achieved with medical/behavioral approaches; however, more substantial and durable weight reduction would clearly be of even greater value. Fortunately, body-weight regulation researchers have made stunning recent advances,13 and it is widely hoped that these insights into the physiology of energy homeostasis will yield far more effective antiobesity pharmaceuticals in the future.

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At present, however, bariatric surgery is the only method that dependably produces major, long-lasting weight loss.14,15 In contrast to the transient 5–10% weight reduction typical of nonsurgical methods, modern bariatric operations can facilitate 35–40% loss of body weight, and most of this is maintained for at least 15 years.14–19 Not surprisingly, such massive weight loss is accompanied by improvements in virtually every obesity-related complication yet studied.10,15–18,20 This includes an almost miraculous resolution after certain procedures of diabetes mellitus (DM), which is traditionally considered a relentless, progressive disease. Selected operations completely reverse DM in over 80% of cases,16–18,21–24 by mechanisms that very likely extend beyond the effects of weight reduction alone.20,25

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The energy homeostasis system that normally constrains weight loss is evidently either overcome or circumvented by bariatric surgery, which improves body weight and glucose tolerance by mechanisms that are incompletely understood. Elucidating these mechanisms is a high priority, and as such knowledge should lead not only to the greater refinement of bariatric procedures but also, hopefully, to the ultimate harnessing of some of these capabilities into novel pharmaceuticals. Moreover, it is important to improve our understanding of bariatric surgery because the number of operations performed is increasing dramatically, e.g., in the United States the number increased from an estimated 29,000 in 1999 to over 100,000 in 2003.26 In this chapter, we review the known and hypothesized mechanisms that mediate some of the impressive effects of bariatric surgery on body weight and diabetes, focusing particularly on the Roux-en-Y gastric bypass (RYGB), which, in the United States, is considered to be the gold-standard operation.27

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Intestinal malabsorption and ...

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