Abstract
Obesity and being overweight have become a worldwide epidemic affecting more than 1.9 billion adults and 340 million children. Efforts to curb this global health burden by developing effective long-term non-surgical weight loss interventions continue to fail due to weight regain after weight loss. Weight cycling, often referred to as Yoyo dieting, is driven by physiological counter-regulatory mechanisms that aim at preserving energy, i.e. decreased energy expenditure, increased energy intake, and impaired brain-periphery communication. Models based on genetically determined set points explained some of the weight control mechanisms, but exact molecular underpinnings remained elusive. Today, gene–environment interactions begin to emerge as likely drivers for the obesogenic memory effect associated with weight cycling. Here, epigenetic mechanisms, including histone modifications and DNA methylation, appear as likely factors that underpin long-lasting deleterious adaptations or an imprinted obesogenic memory to prevent weight loss maintenance. The first part summarizes our current knowledge on the physiology of weight cycling by discussing human and murine studies on the Yoyo-dieting phenomenon and physiological adaptations associated with weight loss and weight re-gain. The second part provides an overview on known associations between obesity and epigenetic modifications. We further interrogate the roles of epigenetic mechanisms in the CNS control of cognitive functions as well as reward and addictive behaviors, and subsequently discuss whether such mechanisms play a role in weight control. The final two parts describe major opportunities and challenges associated with studying epigenetic mechanisms in the CNS with its highly heterogenous cell populations, and provide a summary of recent technological advances that will help to delineate whether an obese memory is based upon epigenetic mechanisms.
Highlights
The CNS with homeostatic control centers within the hypothalamus and hindbrain appears to be key for the maintenance of body weight
Of similar importance are hedonic control centers and reward circuitry within the limbic system, which orchestrate behavioral and biological responses such as food seeking, food reward and food perception behaviors, memory formation and cognition. These brain regions are susceptible to epigenetic reprogramming (Alsiö et al., 2010; Miller et al., 2010; Gupta-Agarwal et al., 2014; Jayanthi et al., 2018), and are likely targets for epigenetic modifications induced by obesity
Future studies should unravel whether an epigenetic memory for obesity exists within these CNS centers, and whether it is functionally linked to the regulation of body weight or weight re-gain after weight loss
Summary
Obesity and being overweight have become a worldwide epidemic affecting more than 1.9 billion adults and 340 million children. Efforts to curb this global health burden by developing effective long-term non-surgical weight loss interventions continue to fail due to weight regain after weight loss. Epigenetic mechanisms, including histone modifications and DNA methylation, appear as likely factors that underpin longlasting deleterious adaptations or an imprinted obesogenic memory to prevent weight loss maintenance. The final two parts describe major opportunities and challenges associated with studying epigenetic mechanisms in the CNS with its highly heterogenous cell populations, and provide a summary of recent technological advances that will help to delineate whether an obese memory is based upon epigenetic mechanisms
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