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Development and Validation of a Methodology for Establishing Obese Rat Models with Typical Fatty Pancreas
Published on: November 11, 2025
Early Time-Restricted Feeding Mitigates Insulin Resistance and Proteinuria in Prepubertal Obese Dahl Salt-Sensitive
Sautan Mandal1, Ubong S Ekperikpe, Anukool A Bhopatkar
1Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS.
Background:
Previous studies from our laboratory have shown that hyperinsulinemia and insulin resistance (IR) are elevated in obese Dahl salt-sensitive (SS) leptin receptor mutant (SSLepRmutant) rats compared to SS rats before puberty. Clinical studies suggest that time-restricted feeding improves insulin sensitivity and is considered beneficial in obese patients. Therefore, the current study examined whether time-restricted feeding improves IR and reduces renal injury in obese SSLepRmutant rats prior to puberty.
Methods:
Four-week-old SS and SSLepRmutant rats were given either ad libitum access to food for 24 hours (control) or 8 hours each day during their active phase time-restricted feeding for 4 weeks. Metabolic parameters, insulin sensitivity, renal function and injury, proximal tubular SGLT2 expression, inflammation, and mitochondrial bioenergetics were assessed at the end of the study.
Results:
Body weight and food intake were significantly elevated in SSLepRmutant compared to SS rats, and time-restricted feeding did not affect either parameter. Fasting blood glucose levels were normal (≤120 mg/dL) in all groups. HOMA-IR (marker of IR) was significantly elevated in SSLepRmutant rats versus SS rats, and time-restricted feeding significantly reduced HOMA-IR only in SSLepRmutant rats. Proteinuria was significantly higher in SSLepRmutant rats vs SS rats (361±32 vs. 17±4 mg/day, respectively), and time-restricted feeding markedly reduced proteinuria in SSLepRmutant rats (144±19 mg/day). We observed a 2-fold increase in GFR in SSLepRmutant rats compared to SS rats indicating renal hyperfiltration. Time-restricted feeding prevented renal hyperfiltration in SSLepRmutant rats. Renal tubular sodium-glucose cotransporter 2 (SGLT2) expression was markedly increased in SSLepRmutant rats relative to SS rats and was notably reduced by time-restricted feeding in the SSLepRmutant rats. When measuring mitochondrial function, there was a tendency of OCR to be reduced in SSLepRmutant rats compared to SD rats, indicating impaired mitochondrial function, but time-restricted feeding significantly increased baseline OCR in SSLepRmutant rats.
Conclusions:
Overall, these data suggest that time-restricted feeding reduces proteinuria by potentially improving insulin sensitivity and tubular mitochondrial function indicating TRF could be of great potential in obese children with early signs of renal injury.
