Primary liver cancer, which consists predominantly of hepatocellular carcinoma (HCC), is the fifth most common cancer worldwide and the third most common cause of cancer mortality. HCC has several interesting epidemiologic features including dynamic temporal trends; marked variations among geographic regions, racial and ethnic groups, and between men and women; and the presence of several well-documented environmental potentially preventable risk factors. Moreover, there is a growing understanding on the molecular mechanisms inducing hepatocarcinogenesis, which almost never occurs in healthy liver, but the cancer risk increases sharply in response to chronic liver injury at the cirrhosis stage. A detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve our current concepts for screening and treatment of this disease.

Gastrojejunostomy (GJJ) is the most commonly used palliative treatment modality for malignant gastric outlet obstruction. Recently, stent placement has been introduced as an alternative treatment. We reviewed the available literature on stent placement and GJJ for gastric outlet obstruction, with regard to medical effects and costs.

The prevalence of obesity has increased in recent decades, and obesity is now one of the leading public health concerns on a worldwide scale. There is accumulating agreement that bariatric surgery is currently the most efficacious and enduring treatment for clinically severe obesity, and as a result, the number of bariatric surgery procedures performed has risen dramatically in recent years. This review will summarize historic and contemporary bariatric surgical techniques, including gastric bypass (open and laparoscopic), laparoscopic adjustable gastric banding, and biliopancreatic diversion (with or without duodenal switch). Data are presented on bariatric surgery outcomes, focusing on weight loss and obesity-related comorbidities. We also review possible complications from surgery. Bariatric surgery patients undergo many dramatic lifestyle changes, and comprehensive presurgical screening conducted by a multidisciplinary team is important to prepare patients for the numerous changes necessary for successful outcome. In addition, comprehensive presurgical screening can aid the treatment team in identifying patients who would benefit from additional services prior to or following surgery. Further research focused on presurgical variables that predict outcome-especially the longer term outcome-of bariatric surgery is needed. At present, approximately 1% of eligible individuals with morbid obesity receive bariatric surgery. In addition, there appears to be inequity in access to weight loss surgery. Given the accumulating evidence that bariatric surgery is efficacious in producing significant and durable weight loss, improving obesity-related comorbidities, and extending survival, the U.S. healthcare system should examine ways to improve access to this treatment for obesity.

Three medications with approval for long-term use in the treatment of obesity are currently available in the United States. Sibutramine (U.S. Food and Drug Administration [FDA] approved in 1997), orlistat (FDA approved in 1999), and rimonabant (available in Europe and given FDA approvable status in 2006 and expected to be marketed in 2007) represent modern approaches to medications used adjunctively for weight management. As demonstrated in large clinical trials of 2 to 4 years' duration, these medications significantly increase weight loss compared with placebo; weight loss with these drugs reaches a nadir between 20 and 28 weeks; weight loss, averaged 8%-10%, with the placebo contributing 4%-6% of that. Weight maintenance is demonstrated as long as adherence to medication continues. All medications have side effects that need to be considered. For sibutramine, there is a rise in blood pressure and heart rate that may require discontinuation of the drug in a small percent of patients. For orlistat, steatorrhea produces the principal gastrointestinal side effects. Rimonabant appears to have a favorable safety and tolerability profile. Nausea and gastrointestinal symptoms are the chief tolerability issue, but they are usually self-limited. In addition there are several drugs and drug combinations in phase 2 or phase 2 trials that will be reported on in the coming years.

Several expert panels have recommended that obese individuals attempt to lose 10% of their initial body weight through a combination of diet, physical activity, and behavior therapy (frequently referred to as lifestyle modification). This article reviews the short-and long-term results of lifestyle modification and methods to improve them. Randomized controlled trials were examined that compared different diet and activity interventions for inducing and maintaining weight loss. Studies that compared different methods of providing lifestyle modification, including on-site vs. Internet-based delivery, also were examined. A comprehensive lifestyle modification program was found to induce a loss of approximately 10% of initial weight in 16 to 26 weeks of group or individual treatment, delivered on-site. Comprehensive Internet-based programs induced a loss of approximately half this size. Patients' consumption of portion-controlled diets, including liquid meal replacements, was associated with significantly greater short-term weight loss than was the consumption of isocaloric diets comprised of conventional foods. Factors associated with long-term weight control included continued patient-practitioner contact (whether on-site or by e-mail), high levels of physical activity, and the long-term use of pharmacotherapy combined with lifestyle modification. In summary, lifestyle modification induces clinically significant weight loss that is associated with the prevention or amelioration of cardiovascular risk factors.

Recent evidence indicates that obesity and related metabolic abnormalities are associated with increased incidence or mortality for a number of cancers, including those of the colon, prostate, and pancreas. Obesity, physical inactivity, visceral adiposity, hyperglycemia, and hyperinsulinemia are relatively consistent risk factors for colon cancer and adenoma. Also, patients with type 2 diabetes mellitus have a higher risk of colon cancer. For prostate cancer, the relationship to obesity appears more complex. Obesity seems to contribute to a greater risk of aggressive or fatal prostate cancer but perhaps to a lower risk of nonaggressive prostate cancer. Furthermore, men with type 2 diabetes mellitus are at lower risk of developing prostate cancer. Long-standing type 2 diabetes increases the risk of pancreatic cancer by approximately 50%. Furthermore, over the past 6 years, a large number of cohort studies have reported positive associations between obesity and pancreatic cancer. Together with data from prediagnostic blood specimens showing positive associations between glucose levels and pancreatic cancer up to 25 years later, sufficient evidence now supports a strong role for diabetes and obesity in pancreatic cancer etiology. The mechanisms for these associations, however, remain speculative and deserve further study. Hyperinsulinemia may be important, but the role of oxidative stress initiated by hyperglycemia also deserves further attention.

Nonalcoholic fatty liver disease represents a spectrum of histopathologic abnormalities, the prevalence of which may be as high as 24% of the population of the United States. Nonalcoholic fatty liver disease will play a major role in the science and practice of gastroenterology in the near future. The fundamental derangement in nonalcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, hypertriglyceridemia, essential hypertension, low circulating high-density lipoprotein, and obesity. The natural history of fatty liver disease is not always benign, and causality for cirrhosis and chronic liver disease is well-founded in the literature. Treatment strategies are limited and, at present, are primarily focused on weight loss and use of insulin sensitizing agents, including the thiazolidenediones. Recent data clearly implicate hepatic insulin resistance as a culprit in accumulation of free fatty acids as triglycerides in hepatocytes. Hepatic insulin resistance is clearly exacerbated by systemic insulin resistance and impaired handling by skeletal muscle and adipose tissue of both glucose and free fatty acids. The key consequence of hepatic insulin resistance, impaired hepatocyte insulin signal transduction, results in adverse cellular and molecular changes exacerbating hepatocyte triglyceride storage. Cytokines secreted by white adipose tissue, adipokines, have emerged as key players in glucose and fat metabolism previously thought controlled largely by insulin. Modulation of adipokines may aid in further understanding of the pathophysiology and treatment of nonalcoholic fatty liver disease.

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.

Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus.

Individual cells must carefully regulate their energy flux to ensure nutrient levels are adequate to maintain normal cellular activity. The same principle holds in multicellular organisms. Thus, for mammals to perform necessary physiological functions, sufficient nutrients need to be available. It is more complex, however, to understand how the energy status of different cells impacts on the overall energy balance of the entire organism. We propose that the central nervous system is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organismal level. In particular, we suggest that in specific hypothalamic neurons, evolutionarily conserved fuel sensors, such as adenosine monophosphate-activated protein kinase and mammalian target of rapamycin (mTOR), integrate sensory input from nutrients, including those derived from recently ingested food or those that are stored in adipose tissue, to regulate effector pathways responsible for fuel intake and utilization. The corollary to this hypothesis is that dysregulation of these fuel-sensing mechanisms in the brain may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes.

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.

Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut-brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity.

Obesity is responsible for the mounting incidence of metabolic disease in adult and pediatric populations. Understanding of the pathogenesis and maintenance of the obese state has advanced rapidly over the past 10 years. Bodily energy reserves are managed actively by complex systems that regulate food intake, substrate partitioning, and energy expenditure. An underlying assumption that circulating factors released from storage organs were able to signal bodily energy reserves was confirmed with the discovery of the leptin system. This proof of concept has spurred on the discovery of a multitude of other adipocyte-generated factors. These circulating factors signal to the brain and other organs of metabolic importance, including adipose tissue, liver, muscle, and the immune system. Adipose-derived factors have numerous implications for the basic biology of obesity and provide prospective targets for the amelioration of obesity and its adverse metabolic consequences. In this review we detail the current understanding of leptin as a prototypical adipose tissue-derived hormone related to appetite and obesity. We also describe other important adipose-derived factors in relation to their metabolic effect.

In the United States, obesity among adults and overweight among children and adolescents have increased markedly since 1980. Among adults, obesity is defined as a body mass index of 30 or greater. Among children and adolescents, overweight is defined as a body mass index for age at or above the 95th percentile of a specified reference population. In 2003-2004, 32.9% of adults 20-74 years old were obese and more than 17% of teenagers (age, 12-19 y) were overweight. Obesity varies by age and sex, and by race-ethnic group among adult women. A higher body weight is associated with an increased incidence of a number of conditions, including diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease, and with an increased risk of disability. Obesity is associated with a modestly increased risk of all-cause mortality. However, the net effect of overweight and obesity on morbidity and mortality is difficult to quantify. It is likely that a gene-environment interaction, in which genetically susceptible individuals respond to an environment with increased availability of palatable energy-dense foods and reduced opportunities for energy expenditure, contributes to the current high prevalence of obesity. Evidence suggests that even without reaching an ideal weight, a moderate amount of weight loss can be beneficial in terms of reducing levels of some risk factors, such as blood pressure. Many studies of dietary and behavioral treatments, however, have shown that maintenance of weight loss is difficult. The social and economic costs of obesity and of attempts to prevent or to treat obesity are high.