Review
The Dichotomous Effect of Chronic Stress on Obesity

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Trends

Chronic stress and socioeconomic status have been associated with metabolic diseases.

A beneficial metabolic potential of BAT has been identified in humans. Recent data suggest that psychological stress is a natural stimulus for BAT function, together with classically recognized cold- and diet-induced thermogenesis.

Recent data also demonstrate that the dichotomous metabolic outcome of social stress can be related to differential levels of basal BAT activity and stress-induced recruitment and activation of BAT.

We propose a bidirectional relation between stress and energy balance, whereby stress promotes obesity in the presence of hyperphagia and unchanged BAT function, but results in weight loss and/or obesity resistance in the presence of hypophagia or when hyperphagia is associated with enhanced BAT recruitment and/or thermogenesis.

Obesity and metabolic diseases are linked to chronic stress and low socioeconomic status. The mechanistic link between stress and obesity has not been clarified, partly due to the inherent complexity exemplified by the bidirectional effect of stress on eating and body weight. Recent studies focusing on adaptive thermogenesis and brown adipose tissue (BAT) function support a dichotomous relation to explain the impact of stress on obesity: stress promotes obesity in the presence of hyperphagia and unchanged BAT function; stress results in weight loss and/or obesity resistance in the presence of hypophagia, or when hyperphagia is associated with BAT recruitment and enhanced thermogenesis. Mechanistically dissecting the bidirectional effects of stress on metabolic outcomes might open new avenues for innovative pharmacotherapies for the treatment of obesity-associated diseases.

Section snippets

The Dichotomous Consequences of Stress on Energy Balance

Over the past few decades, obesity-associated metabolic diseases have become a pandemic, seemingly due to the widespread consumption of a Western-type diet combined with sedentary lifestyle and increased psychoemotional stress [1]. However, industrialized societies also suffer from stress-associated eating disorders that can negatively impact energy balance, such as anorexia nervosa, characterized by self-starvation and excessive weight loss, and bulimia, characterized by periods of excessive

Central Mechanisms of Stress-Induced Positive Energy Balance

Laboratory rodents can respond with hyperphagic behavior to several psychological and physical stress models. For example, chronic mild stress and chronic social stress (see Glossary) have been linked to sustained hyperphagia and binge eating-like disorders 17, 18, 19. During chronic stress and the corresponding hyperactivation of the HPA axis, glucocorticoids and insulin increase craving for calorie-rich meals [20]. The preference for palatable food ingestion has been proposed to reduce the

Adaptive Thermogenesis and BAT Function at the Core of the Stress-Induced Regulation of Obesity

A major factor hindering the understanding of the dichotomous metabolic responses to stress reviewed above is the intrinsic complexity of the physiologic regulation of metabolism [67]. In this context, the CNS has a key role by exerting efferent control on adipose depot functions. The autonomic innervation of WAT is fundamental in the regulation of adipogenesis and lipolysis [48] and, under certain conditions, thermogenesis [68]. Sympathectomy causes the increased accumulation of lipids in WAT

The Dichotomous Effect of Stress on Obesity: An Energy Balance Perspective

The main components of energy balance are food intake, nutrients absorption, and energy expenditure. Energy expenditure is classically subdivided into three main components: basal thermogenesis, physical activity-related thermogenesis, and adaptive thermogenesis [13]. We propose that there are two main factors promoting stress-induced vulnerability versus resilience to obesity: (i) changes in food intake; and (ii) recruitment and/or activation of BAT and its impact on nutrient clearance and

Concluding Remarks and Future Perspectives

The metabolic effects of chronic stress in rodents are heterogeneous and reminiscent of human data. While progress has been made on the identification of the mediators of stress-induced metabolic effects using classical neuroendocrine approaches, the mechanistic understanding of how stress affects energy balance is still at an early stage (see Outstanding Questions). Accumulated evidence now supports a major role for sympathetically derived factors in brown adipocyte function. Classically,

Acknowledgments

We would like to thank past and current members of the laboratory as well as colleagues and collaborators for help generating the experimental data discussed in the review and for helpful discussions. We apologize to those authors whose papers could not be cited owing to space constraints. A.B. is supported by NIH/NIDDK R01DK102496, NIH/NIA R01AG043972.

Glossary

Chronic mild stress
sequential exposure of experimental animals to a variety of mild stressors (e.g., overnight illumination; periods of food and/or water deprivation; cage tilt; or change of cage mate).
Chronic social stress
two male mice are paired and allowed to aggressively interact for a short period of time daily; they are thereafter in sensory contact allowed by a perforated partition in the housing cage for up to 6 weeks. A dominant mouse and a subordinate mouse are identified by

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