Kathleen E. Corey, MD, MPHa and Lee M. Kaplan, MD, PhDb∗LMKaplan@partners.org,     aGastrointestinal Unit, Weight Center, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA; bGastrointestinal Unit, Weight Center, Obesity, Metabolism and Nutrition Institute, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Room 8219, Charlestown, MA 02129, USA

∗Corresponding author.

Obesity is a rapidly growing health problem that is associated with more than 65 comorbidities and results in substantially increased all-cause mortality. The increase of obesity has played an important role in the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease in the United States. Understanding the prevalence, comorbidities, and pathogenesis of obesity provides an essential foundation for clinicians who care for individuals with NAFLD.

Keywords

Obesity

Nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis

Cirrhosis

Weight loss

Fat mass

Energy balance

Key points

Introduction

Obesity, defined as the state of having excess body fat, is an epidemic and still-growing health problem across the world. Data from the 2009–2010 National Health and Nutrition Examination Survey reveal that 36% of Americans have obesity.1 Globally, more than 400 million people have this disorder.2 Obesity is associated with more than 65 demonstrated comorbidities, including diabetes mellitus, cardiovascular disease, and several forms of cancer; because of these sequelae, it is associated with a substantially increased all-cause mortality.3,4 Moreover, obesity accounts for an estimated $163 to $300 billion in additional health care costs annually, accounting for up to 10% of overall health care costs in this country.5

Despite studies that correlate obesity with numerous societal changes and individual behaviors, full understanding of its pathogenesis and rising prevalence remains elusive. Countless shifts in our environment over the past century likely contribute to obesity development.6 These shifts include alterations in routine physical activity and muscle function, the chemical composition of our diets, and a variety of external stressors, each of which likely plays an important contributing role. Furthermore, obesity seems to be a symptom of multiple related disorders, each with distinct phenotypes, clinical characteristics, and proximate causes. This heterogeneity likely contributes to the difficulty in identifying broadly effective preventative and long-term treatment strategies and suggests that treatment plans individualized to disease subtypes will be required.

The recent increase in the prevalence of nonalcoholic fatty liver disease (NAFLD), now the most common cause of liver disease in the United States, is in large part a result of the obesity epidemic. This issue of Clinics in Liver Disease is devoted to addressing all aspects of NAFLD. To frame this important discussion, the authors begin with a review of the prevalence, comorbid conditions, and pathogenesis of obesity, a major underlying cause of NAFLD. The authors conclude their discussion with a review of the therapeutic options that can serve to treat obesity and, thereby, contribute to the effective treatment of NAFLD.

Challenges in obesity

Obesity treatment is challenging for myriad reasons. First, although obesity is largely considered one disease, the term obesity actually encompasses multiple disorders with distinct causes and treatments. The regulation of energy balance and body fat storage is complex, involving multiple central and peripheral, biochemical, metabolic, and signaling pathways; a disturbance in any of these pathways can disrupt normal physiologic regulation. Obesity can, thus, be viewed as analogous to cancer. No single pathway is responsible for the development of the many different types and subtypes of cancer, and no single therapy is successful in treating all cancers. Obesity can similarly be viewed as a heterogeneous disease, with varying mechanisms that contribute to its development, requiring individually tailored treatment after a thorough clinical evaluation.

Additional challenges to the effective treatment of obesity are the powerful and widespread environmental influences inherent to modern society that promote the development and maintenance of the obese state (Table 1). These environmental influences include profound changes in the chemical composition of ingested nutrients, including an increased prevalence of calorie-dense, highly processed, and often homogeneous foods. Our service-based economy, labor-saving devices, the increased speed and volume of communication and decision making, frequent disruption of sleep and circadian rhythms, and a variety of other cultural and economic factors add to the obesogenic environment. These forces act on a genetically and developmentally determined human biology that is frequently unable to resist these powerful influences. Added to these forces is the increasingly widespread use of medications that promote weight gain, including for complications of obesity itself (eg, diabetes, hypertension) and other diseases of modern society, such as psychological and inflammatory disorders. Obesity, thus, reflects the perfect storm of numerous cooperative changes in the environment acting on a biology that evolved in a different era.

Prevalence of obesity

More than a third of Americans currently suffer from obesity; an equal number are overweight, a designation that, although indicating a weight disorder of lesser intensity, is still associated with a significantly increased risk of potentially debilitating metabolic disease.1 After increasing 2- to 3-fold over the past 40 years, the rate of growth seems to have abated in the past decade. Although the prevalence of obesity overall has begun to stabilize, however, the average weight of the population continues to increase; the prevalence of the most severe classes of obesity continues to increase rapidly (Fig. 1).7 Thus, despite early signs of hope, it is difficult to argue that we have yet made substantial progress in tackling this disease.

Obesity-related morbidity and mortality

Obesity results in a wide variety of health-related complications and affects nearly all organ systems. Obesity-related complications can be conveniently considered in 6 categories, including metabolic, structural (anatomic), inflammatory, degenerative, neoplastic, and psychological (Table 2). Metabolic complications include diabetes mellitus, NAFLD, dyslipidemia, gallstones, thrombogenesis (from plasminogen activator inhibitor-1 deficiency), and various forms of infertility. Structural effects of obesity include gastroesophageal reflux disease, pseudotumor cerebri, arthritis in weight-bearing joints, obstructive sleep apnea (OSA), and injuries resulting from mechanical falls.8 Obesity also contributes to the development of autoimmune and inflammatory disease, including asthma, hypothyroidism, psoriasis, arthritis in non–weight-bearing joints, pancreatitis, and nonalcoholic steatohepatitis (NASH).9 Obesity-associated degenerative disorders include several longer-term sequelae of acute manifestations, such as atherosclerotic cardiovascular disease, other complications of type 2 diabetes, pulmonary hypertension from OSA, and NASH-associated...