Experimental Models of Weight Cycling: A Narrative Review of Protocol Design and Metabolic Outcomes

Weight cycling (WC), characterized by repeated weight loss and regain, has been associated with adverse health effects, though evidence remains inconsistent. The aim of this review is evaluating WC protocols used in rodent studies, with a particular focus on how variations in experimental design and cycle periodization influence metabolic outcomes. All included studies were conducted in C57BL/6 mice, with protocols alternating between normocaloric and hypercaloric diets, in a variety of protocols, mainly in the periodization of cycles, diet composition, and sex of the animals. Despite evidence suggesting greater resistance to metabolic disorders associated with WC, studies in females are still scarce. Frequent cycling was associated with worsened metabolic outcomes, whereas prolonged weight-loss phases did not reverse obesity-induced alterations. Common findings included increased feed efficiency, loss of lean mass, persistent insulin resistance, and impaired glucose tolerance, alongside adipose tissue remodeling and low-grade inflammation. Divergent results appeared in relation to inflammation and lipid deposition in peripheral tissues. Collectively, the need for more standardized, sex-inclusive experimental designs will improve mechanistic insight and translational relevance.