Roles for Ghrelin in the Regulation of Appetite and Body Weight David E. Cummings, MD; Michael H. Shannon, MD O besity is a global epidemic that has proven daunting to prevent and treat. The preva- lences of obesity (body mass index [BMI] 30) and morbid obesity (BMI 40) among American adults are about 30% and 5%, respectively. 1 Obesity is so strongly associ- ated with medical comorbidities and mortality that it has begun to overtake infec- tious diseases as the most significant contributor to ill health worldwide. 2,3 Overweight persons are also frequently stigmatized and consequently suffer from low self-esteem. Their motivation to achieve and maintain weight loss is often Herculean. In 1 study of 47 patients who had durably lost 45 kg or more after bariatric surgery, 100% preferred to be deaf, dyslexic, diabetic, or have heart disease rather than be obese again; leg amputation and blindness were preferred by 91.5% and 89.4%, respectively. 4 The traditional treatment paradigm of diet, exercise, and medication gen- erally achieves no more than a 5% to 10% reduction in body weight, 5,6 and recidivism after such weight loss exceeds 90% within 5 years. 7,8 This failure arises because a robust homeostatic system of body weight regulation compensates for weight loss with increased hunger and decreased en- ergy expenditure. 9-11 The molecular mediators of these compensatory responses to weight loss are potential targets for antiobesity treatments. Ghrelin is a potent orexigenic (appetite-stimulating) peptide that seems to participate in the adaptive response to weight loss. Therefore, ghrelin holds promise as a target for both medical and surgical approaches to obesity. FUNDAMENTALS OF APPETITE AND BODY WEIGHT REGULATION Body weight is regulated within a nar- row, individualized range by a process known as “energy homeostasis.” 9,10,12 This process precisely matches overall energy intake and expenditure over long peri- ods—to within 1% of the more than 1 mil- lion kilocalories typically consumed per year—despite large daily caloric mis- matches. 13,14 Deviations from the de- fended level of body weight engage adap- tive, reciprocal alterations in appetite and energy expenditure that resist weight change, 11 rendering behavioral and me- dicinal interventions for obesity rela- tively ineffective. 5 Implicit in this regulatory system is a mechanism that communicates the sta- tus of energy stores in the body to the brain, which in turn coordinates adap- tive responses to energy imbalances. It has long been theorized that adipose tissue, the principal site of stored biological energy, produces neuroendocrine signals that inform the brain about the size of fat stores. The long-standing lipostatic model of en- ergy homeostasis proposes that periph- eral hormones reflecting adiposity exert negative feedback in the brain to de- crease food intake in conditions of en- ergy surplus and increase it in conditions of energy deficit. 15 The lipostatic theory was validated with the 1994 discovery of leptin. This adi- pocyte-derived peptide is the dominant hormone in a classic endocrine negative- feedback loop that dynamically regulates body weight (Figure 1). 16 Leptin circu- From the Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Veterans Affairs Puget Sound Health Care System, Seattle. SPECIAL ARTICLE (REPRINTED) ARCH SURG/ VOL 138, APR 2003 WWW.ARCHSURG.COM 389 ©2003 American Medical Association. All rights reserved. Downloaded From: http://archsurg.jamanetwork.com/ by a University of Washington Libraries User on 06/19/2015