Time-Restricted Feeding Associated with Resistance Training Ameliorates MAFLD and Improves Insulin Sensitivity in Obese Male and Female Mice

Introduction and Objective: Metabolic-associated fatty liver disease (MAFLD), characterized by hepatic fat accumulation, is one of the most prevalent liver diseases globally. Obesity and insulin resistance are major risk factors, and weight loss has been associated with improvements in this condition. This study investigated the effects of time-restricted feeding (TRF) and resistance training (RT) on obesity, insulin resistance, and MAFLD in male and female mice fed a high-fat diet (HFD). Methods: During the diurnal cycle, the TRF was 12 hours, while the TR consisted of training sessions (Weight Pulling) on ​​ alternate days. Results: TRF with RT attenuated body weight gain, improved insulin sensitivity, and, reduced liver lipid content in male and female mice. The combination of TRF and RT yielded complementary benefits, including reduced adipocyte area, enhanced liver cholesterol regulation, and improved liver mitochondrial respiration. Moreover, liver transcriptomic analyses revealed elevated expression of lipogenic genes (Srebp1c, Klf15, Fasn, and Scd1) and protein levels (SREBP-1c, KLF15, and FAS) in HFD-fed mice, with sex-specific regulation of KLF15. TRF combined with RT significantly reduced KLF15 levels in males, suggesting its potential as a therapeutic target for lipogenesis modulation. Analysis of liver transcriptomic data from obese humans undergoing caloric restriction (GSE15679) showed increased PPARα and reduced SREBF1 expression in males and CHREBP1 downregulation in females, further supporting sex-specific regulation of fatty acid metabolism. Conclusion: In conclusion, the combined interventions of TRF and RT produced superior effects on obesity, insulin resistance, and MAFLD compared to isolated interventions, underscoring the efficacy of TRF+RT in metabolic modulation with sex-specific responses. Disclosure: G.D. Brisque: None. A.P.A. Macêdo: None. G. Erlich: None. G. Iasniswski: None. V.R. Muñoz: None. D. Brunelli: None. G. Antonio: None. L. Dias: None. E.R. Ropelle: None. D.E. Cintra: None. A. Silva: None. J.R. Pauli: None. Funding: This study was financed, in part, by the Sao Paulo Research Foundation (FAPESP; process numbers 19/11820-5 and 23/08357-7) and by the National Council for Scientific and Technological Development (CNPq; process number 309268/2023-0).