Journal of Clinical Endocrinology and Metabolism

Woods, Stephen C.; D'Alessio, David A.

doi: 10.1210/jc.2008-1630pmid: 18987269

ABSTRACTContextEnergy balance is critical for survival and health, and control of food intake is an integral part of this process. This report reviews hormonal signals that influence food intake and their clinical applications.Evidence AcquisitionA relatively novel insight is that satiation signals that control meal size and adiposity signals that signify the amount of body fat are distinct and interact in the hypothalamus and elsewhere to control energy homeostasis. This review focuses upon recent literature addressing the integration of satiation and adiposity signals and therapeutic implications for treatment of obesity.Evidence SynthesisDuring meals, signals such as cholecystokinin arise primarily from the GI tract to cause satiation and meal termination; signals secreted in proportion to body fat such as insulin and leptin interact with satiation signals and provide effective regulation by dictating meal size to amounts that are appropriate for body fatness, or stored energy. Although satiation and adiposity signals are myriad and redundant and reduce food intake, there are few known orexigenic signals; thus, initiation of meals is not subject to the degree of homeostatic regulation that cessation of eating is. There are now drugs available that act through receptors for satiation factors and which cause weight loss, demonstrating that this system is amenable to manipulation for therapeutic goals.ConclusionsAlthough progress on effective medical therapies for obesity has been relatively slow in coming, advances in understanding the central regulation of food intake may ultimately be turned into useful treatment options.

Rasouli, Neda; Kern, Philip A.

doi: 10.1210/jc.2008-1613pmid: 18987272

ABSTRACTContextAdipose tissue is increasingly recognized as an active endocrine organ with many secretory products and part of the innate immune system. With obesity, macrophages infiltrate adipose tissue, and numerous adipocytokines are released by both macrophages and adipocytes. Adipocytokines play important roles in the pathogenesis of insulin resistance and associated metabolic complications such as dyslipidemia, hypertension, and premature heart disease.Evidence AcquisitionPublished literature was analyzed with the intent of addressing the role of the major adipose secretory proteins in human obesity, insulin resistance, and type 2 diabetes.Evidence SynthesisThis review analyzes the characteristics of different adipocytokines, including leptin, adiponectin, pro-inflammatory cytokines, resistin, retinol binding protein 4, visfatin, and others, and their roles in the pathogenesis of insulin resistance.ConclusionsInflamed fat in obesity secretes an array of proteins implicated in the impairment of insulin signaling. Further studies are needed to understand the triggers that initiate inflammation in adipose tissue and the role of each adipokine in the pathogenesis of insulin resistance.

Bray, George A.

doi: 10.1210/jc.2008-1294pmid: 18987274

ABSTRACTContextObesity results from a prolonged small positive energy balance, and its treatment needs to reverse this imbalance.Evidence AcquisitionCitations retrieved from PubMed and The Handbook of Obesity 2008 were selected to illustrate the points.Evidence SynthesisMany different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that clearly supports a superiority of one macronutrient composition for diets used for weight loss. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Lifestyle strategies to modify eating behavior can be used in individual counseling sessions or in groups, both of which are important in helping patients modify their patterns of eating. Physical activity is particularly important in helping patients maintain a weight loss once achieved and is less valuable for weight loss itself. Food intake is controlled through many different mechanisms, but only a few drugs have been developed that tap these mechanisms. Orlistat, which blocks intestinal lipase, is one; sibutramine, a serotonin-norepinephrine reuptake inhibitor, is a second. Surgical approaches provide the most dramatic weight loss and have been demonstrated to reduce long-term mortality and reduce the incidence of diabetes.ConclusionsWeight loss can be achieved by many methods, but the surgical procedures appear to be the most durable.

Cali, Anna M. G.; Caprio, Sonia

doi: 10.1210/jc.2008-1363pmid: 18987268

ABSTRACTContextAlthough the prevalence rates of childhood obesity have seemingly been stable over the past few years, far too many children and adolescents are still obese. Childhood obesity, and its associated metabolic complications, is rapidly emerging as one of the greatest global challenges of the 21st century. About 110 million children are now classified as overweight or obese.Evidence AcquisitionIn this review we first describe the most recent data on the prevalence, severity, and racial/ethnic differences in childhood obesity. Obesity is associated with significant health problems in the pediatric age group and is an important early risk factor for much of adult morbidity and mortality.Evidence SynthesisWe review the metabolic complications associated with childhood obesity. Particular emphasis is given to the description of studies regarding the impact of varying degrees of obesity on the cardiometabolic risk factors in youth. We further describe studies in obese adolescents that have examined the importance of ectopic lipid deposition in the visceral abdominal depot and in insulin sensitive tissues in relation to the presence of insulin resistance. We end by describing studies that have examined β-cell function in obese adolescents with normal glucose tolerance.ConclusionsThe growing number of obese children and adolescents worldwide is of great concern. Many obese children and adolescents already manifest some metabolic complications, and these children are at high risk for the development of early morbidity. Understanding the underlying pathogenesis of this peculiar phenotype is of critical importance.

Jensen, Michael D.

doi: 10.1210/jc.2008-1585pmid: 18987271

ABSTRACTContextAn upper body/visceral fat distribution in obesity is closely linked with metabolic complications, whereas increased lower body fat is independently predictive of reduced cardiovascular risk.Evidence AcquisitionThe measured functions of different fat depots with regards to fatty acid storage and release in health and obesity were reviewed. The adverse effects of experimentally increasing free fatty acid (FFA) concentrations on liver, muscle, pancreatic β-cell, and endothelial function were noted.Evidence SynthesisThe most dramatic abnormality in FFA metabolism is failure to suppress FFA concentrations/adipose tissue lipolysis normally in response to postprandial hyperinsulinemia. Upper body sc fat delivers the majority of FFA to the systemic circulation under postabsorptive and postprandial conditions. In upper body obesity, portal FFA concentrations resulting from both systemic and visceral adipose tissue lipolysis may be significantly greater than arterial FFA concentrations, exposing the liver to even greater amounts of FFA. Visceral fat also releases sufficient IL-6 to increase portal vein IL-6 concentrations, which can affect hepatic metabolism as well.ConclusionsLower body, upper body sc, and visceral fat depots have unique characteristics with regards to fatty acid metabolism. Selective dysregulation of these depots probably plays an important role with the metabolic complications of obesity.

Marchesini, Giulio; Moscatiello, Simona; Di Domizio, Silvia; Forlani, Gabriele

doi: 10.1210/jc.2008-1399pmid: 18987273

ABSTRACTContextIn the last few years, several data have accumulated suggesting that obesity may be associated with liver disease and disease progression. Accordingly, the worldwide epidemic of obesity is likely to become a relevant source of morbidity and mortality in the general population.Evidence AcquisitionWe reviewed the literature on two main issues: 1) the evidence that obesity carries out an increased risk of liver disease, both in the general population and in selected cohorts; and 2) the evidence that obesity is a risk factor for nonalcoholic fatty liver disease and its progression in a series observed in liver units.Evidence SynthesisThe presence of obesity increases the risk of elevated liver enzymes by a factor of two to three, whereas the risk of steatosis at ultrasonography is increased by a factor of 3 in the presence of overweight and peaks at a factor of approximately 15 in the presence of obesity. Both cirrhosis (cryptogenic cirrhosis) and hepatocellular carcinoma are also associated with obesity in the general population. In patients with nonalcoholic fatty liver disease observed in liver units, obesity and weight gain are systematically associated with advanced fibrosis and fibrosis progression.Conclusion: Liver disease of metabolic origin, associated with obesity, is now recognized as the most prevalent liver disease in Western countries. Strategies are needed to approach obesity-associated liver disease by behavior programs, motivating people to adopt a healthier lifestyle. Such programs should be coupled with public policies at a societal level to obtain the maximum effects in lifestyle changes.

Pories, Walter J.

doi: 10.1210/jc.2008-1641pmid: 18987275

ABSTRACTContextOver 23 million Americans are afflicted with severe obesity, i.e. their body mass index (in kilograms per square meter) values exceed 35. Of even greater concern is the association of the adiposity with comorbidities such as diabetes, hypertension, cardiopulmonary failure, asthma, pseudotumor cerebri, infertility, and crippling arthritis.Objective: Diets, exercise, behavioral modification, and drugs are not effective in these individuals. This article examines the effect of surgery on the control of the weight and the comorbidities, as well as the safety of these operations.Interventions: Although the article focuses on the outcomes of the three most commonly performed operations, i.e. adjustable gastric banding, the gastric bypass, and the biliopancreatic bypass with duodenal switch, it aims for perspective with the inclusion of abandoned and current investigational procedures, a review of the complications, and an emphasis on the appropriate selection of patients.Positions: Ample evidence, including controlled randomized studies, now document that bariatric surgery produces durable weight loss exceeding 100 lb (46 kg), full and long-term remission of type 2 diabetes in over 80% with salutary effects on the other comorbidities as well with significant reductions in all-cause mortality. Although the severely obese present with serious surgical risks, bariatric surgery is performed safely with a 0.35% 90-d mortality in Centers of Excellence throughout the United States—similar to the complication rates after cholecystectomy.ConclusionsUntil better approaches become available, bariatric surgery is the therapy of choice for patients with severe obesity.

Blakemore, Alexandra I. F.; Froguel, Philippe

doi: 10.1210/jc.2008-1676pmid: 18987270

ABSTRACTContextTo design rational management regimes and identify novel therapeutic targets, it is essential to understand the biological drivers of the current epidemic of obesity. This review describes our current knowledge of genetic factors in obesity, drawing functional parallels in the underlying neuroendocrine mechanisms and suggesting promising new directions for research.Evidence AcquisitionPublished literature, addressing both the current knowledge of genetics of monogenic and syndromic forms of extreme obesity, and the emerging literature on genetic factors associated with more common forms of obesity are analyzed.Evidence SynthesisThe current genetic evidence in obesity underlines the importance of neuroendocrine mechanisms of appetite regulation. Monogenic forms of disease explain 6% of children with extreme obesity, having hyperphagia associated with defects in the leptin-melanocortin pathway, as a central feature. Candidate gene association studies indicate that more subtle variations of the same genes also contribute to common forms of obesity. Well-powered genome-wide association studies recently identified FTO as a strong contributor to both childhood and adult obesity, demonstrating the power of such hypothesis-free analysis to provide new insights into the underlying pathogenic mechanisms of a common complex disease.ConclusionsAlthough there has been some very heartening recent progress in elucidating genetic mechanisms underlying obesity, we are still a long way from explaining the high heritability of adiposity. Investigations of different forms of variation, such as copy number polymorphism, may extend our understanding of this condition.

Ford, Earl S.; Mokdad, Ali H.

doi: 10.1210/jc.2008-1356pmid: 18987267

ABSTRACTContextObesity has emerged as a global public health challenge. The objective of this review was to examine epidemiological aspects of obesity in the Western Hemisphere.Evidence AcquisitionUsing PubMed, we searched for publications about obesity (prevalence, trends, correlates, economic costs) in countries in North America, Central America, South America, and the Caribbean. To the extent possible, we focused on studies that were primarily population based in design and on four countries in the Western Hemisphere: Brazil, Canada, Mexico, and the United States.Evidence SynthesisData compiled by the International Obesity Task Force show a substantial level of obesity in all of or selected areas of the Bahamas, Barbados, Canada, Chile, Guyana, Mexico, Panama, Paraguay, Peru, St. Lucia, Trinidad and Tobago, the United States, and Venezuela. Furthermore, countries such as Brazil, Canada, Mexico, and the United States have experienced increases in the prevalence of obesity. In many countries, the prevalence of obesity is higher among women than men and in urban areas than in rural areas. The relationship between socioeconomic status and obesity depends on the stage of economic transition. Early in the transition, the prevalence of obesity is positively related to income whereas at some point during the transition the prevalence becomes inversely related to income.ConclusionsLike other countries in the Western Hemisphere, the four countries that we focused on have experienced a rising tide of obesity. The high and increasing prevalence of obesity and its attendant comorbidities are likely to pose a serious challenge to the public health and medical care systems in these countries.