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.

Innovative and affordable treatment options are required to combat obesity and its detrimental impact on health economics. Dapagliflozin (Dapa), an antidiabetic medication, promotes weight loss; however, the extent of weight reduction may be limited. Intermittent fasting (IF) is a dietary approach regarded as a cost-effective and readily accessible regimen. This study investigated the beneficial effects of Dapa, IF, and their combination on weight loss and metabolic derangements in high-fat diet (HFD)-induced obesity in rats. Male Sprague-Dawley rats were allocated into 6 groups: groups 1 (normal control) and 2 (drug control) were administered a normal chow diet, while the obesity groups 3, 4, 5, and 6 were subjected to HFD for 8 weeks. Rats in groups 4, 5, and 6 underwent a further 8-week treatment with Dapa (5 mg/kg, p.o) daily, IF (16/8), or a combination of both, respectively. The HFD group exhibited elevated anthropometric measurements and adiposity index. Upon histopathological examination, the HFD group showed adipocyte hypertrophy, hypercellularity, and possible necrosis, along with hepatic fat accumulation and elevated serum liver enzymes. The HFD group showed a downregulation of p-AMPK/SIRT1 and an upregulation of SIRT7, GPR43, and clock genes BMAL1, CLOCK, and CRY1 expression in adipose tissue, along with a drop in the gut microbiome diversity, serum short-chain fatty acids (SCFAs), POMC, and PYY levels. Dapa and IF combination demonstrated favorable outcomes over monotherapy, as evidenced by normalized anthropometric measurements, improved histopathological and biochemical derangements, regulated p-AMPK/SIRT1, SIRT7, and clock genes expression, and restored gut microbiome and SCFA levels. Conclusively, this study suggests the concurrent administration of Dapa and IF as a new, beneficial, cost-effective anti-obesity strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-026-01557-4.