Alternate-day fasting alleviates lipid metabolism disorder induced by high-fat diet: role of ketogenesis

Abstract

Alternate day fasting (ADF), a diet regimen that involves 24-h fasting followed by 24-h ad libitum (AL) food and liquids consumption, induces body weight loss in rodents and humans. However, it is not clear whether the benefits of ADF are due to reduced overall calorie intake or 24-h fasting period. Therefore, in this study, we aimed to compare the effects of both interventions on the markers of health including body weight, adiposity, lean mass, liver health, and lipid metabolic pathways in high-fat (45% calories from fat) diet-induced obese C57BL/6NTac male mice. After 8-weeks of obesity induction, mice were divided into three groups: (1) High-fat diet (HFD-AL): free access to high-fat diet at all times (n = 10), (2) ADF: free access to high-fat diet on alternate days (n = 10), and (3) PF (pair-fed): high-fat diet isocaloric consumption to ADF without fasting (n = 10). An additional non-obese group (ND-AL) maintained on a normal chow diet was used as a control (n = 10). After 8 weeks of intervention, ADF demonstrated a significant reduction in body weight and adiposity with showing improvements in lean mass. Moreover, ADF exhibited a significant reduction in lipid accumulation compared to its isocaloric counterpart. We also demonstrate that ADF and PF equally improve the glucose homeostasis. Furthermore, plasma biochemical analysis revealed elevated ketogenesis in ADF; however, lipid profile analysis demonstrated similar improvements between ADF and PF as compared to HFD. Metabolic phenotype analysis showed a significantly high expression levels of proteins associated with white adipose tissue (WAT) lipolysis in ADF as compared to HFD-AL and PF. Both ADF and PF showed comparable stimulation of thermogenesis in WAT. These data suggest that fasting in ADF could be the reason for the improvements observed on lean mass, adiposity, and lipid metabolism-related markers. Keywords: Alternate day fasting, obesity, ketogenesis, lipid metabolism