Obesity is a world-wide pandemic and its incidence is on the rise along with associated comorbidities. Currently, there are few effective therapies to combat obesity. The use of lifestyle modification therapy, namely, improvements in diet and exercise, is preferable over bariatric surgery or pharmacotherapy due to surgical risks and issues with drug efficacy and safety. Although they are initially successful in producing weight loss, such lifestyle intervention strategies are generally unsuccessful in achieving long-term weight maintenance, with the vast majority of obese patients regaining their lost weight during followup. Recently, various compensatory mechanisms have been elucidated by which the body may oppose new weight loss, and this compensation may result in weight regain back to the obese baseline. The present review summarizes the available evidence on these compensatory mechanisms, with a focus on weight loss-induced changes in energy expenditure, neuroendocrine pathways, nutrient metabolism, and gut physiology. These findings have added a major focus to the field of antiobesity research. In addition to investigating pathways that induce weight loss, the present work also focuses on pathways that may instead prevent weight regain. Such strategies will be necessary for improving long-term weight loss maintenance and outcomes for patients who struggle with obesity. 1. Introduction Obesity is a global public health crisis. Its incidence continues to rise, and the prevalence of overweight has outstripped that of underfed [1]. The prevalence of overweight and obesity has increased over the past three decades [2]. Wang et al. predict that if rates continue in this fashion, by the year 2030, 86.3% of adults will be overweight or obese and 51.1% will be obese [2]. According to the 2009-2010 National Health and Nutrition Examination Survey (NHANES), 78 million (35.7%) US adults and 12.5 million (16.9%) US children and adolescents were obese [3]. In addition to being a widespread health problem on its own, obesity is a risk factor for the development of chronic diseases such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemias, stroke, and cancer [4–6]. In fact, the deleterious effects of obesity are greater than both smoking and drinking in terms of overall health conditions and health-related costs [7]. In 2008, costs to treat obesity totaled $147 billion in the US [8]. The etiology of obesity is believed to be multifactorial, with both genetic and environmental contributions. A key determinant of obesity is the balance between
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