Dapagliflozin-intermittent fasting combination maximizes weight and metabolic regulation through AMPK/sirtuins/clock genes and gut microbiota signaling in high-fat diet-induced obesity: a novel anti-obesity approach

Gut microbes follow a daily rhythm, and prolonged periods without food are necessary for them to carry out repair processes in the lining of the intestine.

In rats fed a high-fat diet, combining dapagliflozin with 16:8 intermittent fasting changes the gut microbiome by normalizing the Firmicutes-to-Bacteroidetes ratio and increasing microbial diversity, which is linked to lower body fat and better metabolic health markers.

In rats on a high-fat diet, taking dapagliflozin and following a 16:8 fasting schedule for eight weeks reduces body weight by 29.5% and body mass index by 30.7% compared to rats on the same diet without these interventions, and more effectively restores normal levels of fat tissue, liver size, and blood glucose through increased energy use and decreased fat accumulation.

In rats fed a high-fat diet, combining the drug dapagliflozin with 16:8 intermittent fasting increases levels of p-AMPK and SIRT1 proteins in fat tissue while decreasing SIRT7 levels, which corresponds to changes in molecular pathways linked to reduced fat storage and increased fat breakdown.

In rats fed a high-fat diet, combining the drug dapagliflozin with a 16:8 intermittent fasting schedule reduces the activity levels of three circadian clock genes—BMAL1, CLOCK, and CRY1—in fat tissue by 72.3%, 61.2%, and 61.8%, respectively, compared to rats fed a high-fat diet without this intervention.

In rats fed a high-fat diet, combining the drug dapagliflozin with 16:8 intermittent fasting restores normal levels of acetate and propionate in the blood and reduces GPR43 receptor expression in fat tissue by 56.1% compared to rats on a high-fat diet alone, resulting in increased satiety hormone production and reduced appetite.