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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., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: PTP received speaker honoraria by Novo Nordisk. All other authors declare that they have no conflict of interest related to this study., (© 2025. The Author(s).)

Background: Obesity is associated with structural deterioration in the gut. Yoyo dieting, which refers to repeated phases of dieting and non-dieting periods leading to cyclic weight loss and regain, is a common occurrence in individuals with obesity. However, there is limited evidence on how gut structures are affected in yoyo dieting. There is good evidence suggesting that increased intake of resistant starch (RS) may be beneficial in promoting structural improvements in the gut. This investigation aimed to explore the effect of yoyo dieting on gastrointestinal structure and whether RS has beneficial effects in improving obesity-related gastrointestinal damage., Method: In this study, male and female C57BL/6 mice were assigned to six different diets for 20 weeks: (1) control diet, (2) high fat diet (HF), (3) yoyo diet (alternating HF and control diets every 5 weeks), (4) control diet with RS, (5) HF with RS, and (6) yoyo diet with RS. Distal colon was collected for epithelial barrier integrity measurement. The small and large intestines were collected for histological assessment., Results: After 20 weeks, yoyo dieting resulted in increased colonic inflammation and exacerbated mucosal damage in comparison with continuous HF diet feeding. RS supplemented in HF and yoyo diets reduced mucosal damage in comparison to diets without RS. However, RS supplementation in a control diet significantly increased inflammation, crypt length, and goblet cell density. There were no significant differences in epithelial change and epithelial barrier integrity across diet groups., Conclusions: This study suggests that yoyo dieting worsens gut damage, and incorporating high levels of RS may be detrimental in the absence of dietary challenge.

Cyclic weight loss and subsequent regain after dieting and non-dieting periods, a phenomenon termed yoyo dieting, places individuals at greater risk of metabolic complications and alters gut microbiome composition. Resistant starch (RS) improves gut health and systemic metabolism. This study aimed to investigate the effect of yoyo dieting and RS on the metabolism and gut microbiome. C57BL/6 mice were assigned to 6 diets for 20 weeks, including control, high fat (HF), yoyo (alternating HF and control diets every 5 weeks), control with RS, HF with RS, and yoyo with RS. Metabolic outcomes and microbiota profiling using 16S rRNA sequencing were examined. Yoyo dieting resulted in short-term weight loss, which led to improved liver health and insulin tolerance but also a greater rate of weight gain compared to continuous HF feeding, as well as a different microbiota profile that was in an intermediate configuration between the control and HF states. Mice fed HF and yoyo diets supplemented with RS gained less weight than those fed without RS. RS supplementation in yoyo mice appeared to shift the gut microbiota composition closer to the control state. In conclusion, yoyo dieting leads to obesity relapse, and increased RS intake reduces weight gain and might help prevent rapid weight regain via gut microbiome restoration.