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Abstract Background Obese subjects undergoing weight loss often fear the Yoyo dieting effect, which involves regaining or even surpassing their initial weight. To date, our understanding of such long-term obesity and weight cycling effects is still limited and often based on only short-term murine weight gain and loss studies. This study aimed to investigate the long-term impacts of weight cycling on glycemic control and metabolic health, focusing on adipose tissue, liver, and hypothalamus. Methods Chow-fed mice and mice subjected to prolonged high-fat diet (HFD) consumption for 20 weeks, followed by 24 weeks of dietary interventions to either induce weight gain, weight loss, or weight cycling were monitored for perturbations in feeding efficiency and glucose homeostasis. Post-mortem analyses included qPCR, Western Blotting, biochemical and microscopical assessments for hepatic steatosis and insulin resistance, hypothalamic and adipose tissue inflammation, and circulating lipid, leptin and IL-6 levels. Results Weight cycling led to hyperphagia and rapid weight regain, matching the weights of mice continuously on HFD. Despite weight loss, adipose tissue inflammation persisted with elevated pro-inflammatory markers, macrophage infiltration, and impaired Glut4 expression. HFD-induced dysregulation in hypothalamic expression of orexigenic peptides and synaptic plasticity markers persisted also after weight normalization suggesting long-lasting neural alterations. Weight-cycled mice exhibited higher circulating IL-6 and leptin levels, increased hepatic lipid storage, and dysregulated glucose metabolism compared to those with consistent diets, indicating worsened metabolic effects by Yoyo dieting. Conclusion In sum, our study highlights significant metabolic risks associated with weight cycling, particularly following prolonged obesity. Persistent adipose tissue inflammation, perturbed neural peptide and plasticity markers and impaired glucose tolerance emphasize the need for effective and sustainable weight loss strategies to mitigate the adverse outcomes of weight regain and improve long-term metabolic health.

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.