Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity

Abstract

Context: Obesity has emerged as one of the leading medical challenges of the 21st century. The resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority is to delineate how mechanisms governing food intake and body fat content are altered in an obesogenic environment.

Evidence acquisition: We considered all relevant published research and cited references that represented the highest quality evidence available. Where space permitted, primary references were cited.

Evidence synthesis: The increase of energy intake that has fueled the U.S. obesity epidemic is linked to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in genetically susceptible individuals and involves the biological defense of an elevated body fat mass, which may result in part from interactions between brain reward and homeostatic circuits. Inflammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypothalamic neurons may also contribute to the development of obesity and offer a plausible mechanism to explain the biological defense of elevated body fat mass.

Conclusions: Despite steady research progress, mechanisms underlying the resistance to fat loss once obesity is established remain incompletely understood. Breakthroughs in this area may be required for the development of effective new obesity prevention and treatment strategies.

Figures

Fig. 1.

Per capita energy intake in the United States, 1970–2009. According to U.S. Department of Agriculture (USDA) food disappearance data (corrected for waste), per capita daily energy intake in the United States has increased 20% since 1970 (133). The increase began shortly after 1980, closely paralleling the rapid increment in obesity prevalence. Although USDA data are calculated from food disappearance measurements, this recent increase is broadly consistent with estimates calculated via other methods.

Fig. 2.

Model for CNS regulation of food intake and body fat mass. The CNS is hypothesized to regulate body fat mass via coordinated adjustments of both food intake and energy expenditure in response to afferent long-term and short-term signals of energy status. Environmental factors (e.g. the availability of highly palatable/rewarding foods, food composition, physical activity, etc.), genetic and developmental factors, hypothalamic inflammation, and neuron injury collectively determine the biologically defended level of body fat mass. Brain image: Patrick J. Lynch.

Fig. 3.

Homeostatic regulation of body fat mass. A, Return of fat mass to baseline after short-term underfeeding or overfeeding. B, Gradual increase in the defended level of fat mass with age in an obese individual. The homeostatic response to fat loss induced by calorie restriction (CR) occurs in obese as well as lean individuals, resulting in the recovery of lost fat.