Early Time-Restricted Feeding Mitigates Insulin Resistance and Proteinuria in Prepubertal Obese Dahl Salt-Sensitive Rats

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. 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. 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. 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.