GASTROENTEROLOGY 2007;132:2085–2086

Obesity: Much Silence Makes a Mighty Noise

REXFORD S. AHIMA

University of Pennsylvania School of Medicine, Department of Medicine, Division of , and Metabolism; and the Institute for Diabetes, and Metabolism, Philadelphia, Pennsylvania

Rexford S. Ahima, MD, PhD, Editor

In 2007, the majority of adults in the United States and physical activity has contributed prominently to the ris- many developed countries are overweight or obese. It is ing prevalence of obesity worldwide. estimated that 1.6 billion adults worldwide are over- This special issue of GASTROENTEROLOGY presents a weight (body mass index [BMI] Ͼ 25) and 400 million are series of review articles on the epidemiology of obesity, obese (BMI Ͼ 30). Obesity puts millions of people at risk pathophysiology, associated diseases, and management. for serious medical conditions such as type 2 diabetes, The contributors are leading experts drawn from a variety cardiovascular disease, musculoskeletal disorders, sleep of specialties, including epidemiology, endocrinology, apnea, and some forms of cancer. Children are also in- metabolism, gastroenterology, behavioral science, and creasingly overweight, with estimates as high as 20 mil- surgery. We emphasize that obesity is multidimensional lion globally. Alarmingly, type 2 diabetes and other dis- and requires an integrated approach to understanding eases thought to occur almost exclusively in adults are the extent of the problem, causation and health and now prevalent in children. Furthermore, developing socioeconomic consequences. Katherine Flegal (pages countries, which have dealt with the burden of infectious 2087–2102) reviews the epidemiology of obesity, high- disease and undernutrition for decades are now facing an lighting controversies surrounding adiposity measure- upsurge of obesity and its crippling health and economic ment, ethnic differences, childhood obesity, and diseases consequences. associated with obesity. Jeffrey Flier (pages 2103–2115) Why the silence about obesity until recently? Part of discusses how adipose tissue, the major energy store, the problem stems from societal notions of what consti- regulates energy balance via hormones that act in the tutes a “healthy weight” and whether obesity truly fits the brain and peripheral organs. The discovery of and definition of a “disease.” Attitudes about overweight and its neuronal targets in the hypothalamus marked the obesity range from acceptance of these conditions as beginning of concerted efforts to unravel how adipose indicative of prosperity and good health, to a negative tissue is coupled to feeding, energy expenditure, and perception of obese individuals as lacking self-control. regulation of hormones and immune and cardiovascular Many governments and institutions still consider obesity systems. Stephen Bloom (pages 2116–2130) reviews the a problem of personal choice that could be reversed role of gut hormones in appetite and weight regulation. simply by deciding to eat less and exercise more. In fact, Gut peptides serve as short-term signals to centers in the some have questioned whether obesity is truly “epi- hindbrain to control meal size and timing, as well as demic.” Attitudes are changing, however, due to the ris- gastrointestinal motility and secretions. Ultimately, these ing incidences of diabetes and other debilitating diseases functions impact energy storage in adipose tissue. Daniel attributable to obesity. Moreover, the negative impact of Drucker (pages 2131–2157) focuses on the of obesity on health care budgets and various sectors of the glucagon-like peptide (GLP)-1 and glucose-dependent in- economy is apparent. Scientific discoveries over the past sulinotropic polypeptide (GIP), both secreted within decade have also enlightened us about the physiologic minutes after eating. These incretin hormones facilitate processes that control weight and metabolism. The drive the disposal of nutrients and have profound effects on to eat and store energy mainly as fat is fundamental for glucose. Drugs based on potentiation of GLP-1 action maintaining metabolic demands and ensuring survival. For human societies, the amount of available food was Abbreviations used in this paper: BMI, body mass index; GIP, glu- limited over several generations. As a result of improve- cose-dependent insulinotropic polypeptide; GLP, glucagon-like pep- tide; mTOR, mammalian Target of Rapamycin. ments in agriculture which led to availability of cheap, © 2007 by the AGA Institute palatable, and energy dense foods, overconsumption of 0016-5085/07/$32.00 food is now the norm, and this coupled with minimal doi:10.1053/j.gastro.2007.03.060 2086 OBESITY: MUCH SILENCE MAKES A MIGHTY NOISE GASTROENTEROLOGY Vol. 132, No. 6

have been approved recently for the treatment of diabe- cusses the drug treatment of the overweight patient. tes. Randy Seeley (pages 2158–2168) discusses how nu- Currently, only 2 drugs are approved for chronic treat- trients act as signals to the brain and peripheral organs to ment of obesity in the United States, and 3 in Europe. regulate feeding and metabolism. AMP-activated protein However, new drugs are being developed based on new kinase plays a key role in integrating nutritional and insights into obesity pathophysiology. At present, bariat- hormonal signals and modulating feeding behavior and ric surgery is the most effective treatment for attaining energy balance. The mammalian Target of Rapamycin massive weight loss and ameliorating the complications (mTOR) also serves as a nutrient sensor in the hypothal- of morbid obesity. Bruce Wolfe discusses surgical proce- amus. Steven Shoelson (pages 2169–2180) discusses the dures for weight loss, criteria for patient selection, and relationship between obesity and inflammation. Factors outcomes. Lastly, the report of the AGA Institute Obesity produced by inflammatory cells in adipose tissue have Task Force, led by Lee Kaplan (pages 2272–2275) is pre- been linked to , and abnormal glucose sented. and lipid metabolism in obesity. Daniel Rader (pages Our hope is that this special issue will spur an interest 2181–2190) reviews how obesity affects the lipid profile in nutrition, metabolism, and obesity among physicians, in a manner that may predispose to atherogenesis. The health care providers, scientists, and the general public. A potential role of hyperinsulinemia in abnormal lipopro- better understanding of pathophysiology provides a tein metabolism is discussed. Frank Anania (pages 2191– framework for evidence-based treatment of obesity. How- 2207) discusses the pathophysiology of nonalcoholic ever, drugs and surgery alone cannot stem the tide of fatty liver disease, in particular the role of insulin resis- obesity. Ultimately, this requires changes in policies and tance and the relation to abnormal lipid and glucose societal practices pertaining to the “obesogenic” environ- metabolism. Putative mechanisms involved in hepatic ment. Population-wide interventions that promote inflammation and progression to fibrosis are discussed. healthier foods, reduce consumption, and increase activ- Edward Giovannucci (pages 2208–2225) reviews the evi- ity will lessen the burden of obesity and its cormorbidi- dence for and against a connection between obesity and ties. cancers of the colon, prostate and pancreas, and offers possible mechanisms based on animal experiments and epidemiological data. Thomas Wadden (pages 2226– Received February 13, 2007. Accepted February 20, 2007. 2238) discusses the importance and strategies for lifestyle Address correspondence to: Rexford S. Ahima, MD, PhD, Univer- sity of Pennsylvania School of Medicine, Division of Endocrinology, modification for the treatment of obesity. The efficacies Diabetes and Metabolism, 415 Curie Boulevard, 764 Clinical Re- of various diets, exercise and behavioral therapy are re- search Building, Philadelphia, Pennsylvania 19104. e-mail: viewed in detail. George Bray (pages 2239–2252) dis- [email protected]; fax: (215) 573-5809.