Continuous caloric restriction and diet replacement but not alternate-day fasting may enhance susceptibility to glucose intolerance, dyslipidemia and cell stress under renewed high-fat diet

Background Weight regain affects most individuals attempting to treat obesity and its comorbidities, and it is associated with increased risk of metabolic and cardiovascular diseases. Several strategies have been proposed to induce weight loss, including caloric restriction (CCR), diet replacement (DR) and alternate-day fasting (ADF). Aim To compare these approaches in terms of weight maintenance and metabolic, oxidative, and inflammatory outcomes. Methods Male Wistar rats underwent a three-phase protocol. First, animals received a high-fat diet (HFD) for eight weeks to induce obesity. Second, they were divided into four groups: ad lib -HFD (continued HFD), R-HFD (30% reduction of HFD w/w), ADF-HFD (24 h fasting alternating with 24 h ad libitum HFD), and ad lib- LFD (DR via ad libitum access to low-fat chow) for six weeks. Finally, all groups returned to free access to HFD for four weeks. Results All interventions delayed weight gain; however, discontinuation led to rapid weight regain. Under renewed HFD ad libitum exposure, CCR and DR induced higher susceptibility to dyslipidemia, as shown by the temporal analysis. These strategies also impaired hepatic and adipose antioxidant and anti-inflammatory responses and heightened lymph node stress upon return to unlimited offer of obesogenic diet. In contrast, ADF appeared to confer partial protection against the metabolic complications of weight rebound. Conclusions Despite similar weight-loss efficacy, ADF may better preserve metabolic homeostasis during weight regain.