SUN-718 - Intermittent Fasting Reduces Kidney Injury Markers in Obese Mice Independent of Weight

Background: Obesity is an independent risk factor for chronic kidney disease (CKD) and ectopic lipid accumulation in the kidney is a major contributor to renal injury. Current therapies for CKD which target blood pressure and diabetes control are incompletely effective at preventing obesity-related kidney injury, indicating the need for novel therapeutic approaches. Intermittent fasting has recently been shown to improve other obesity comorbidities such as hepatic steatosis, but its effects on the kidney and renal lipid metabolism are relatively unknown. We hypothesized that intermittent fasting reduces renal lipid accumulation and urinary markers of kidney injury in the setting of diet-induced obesity.

Methods: C57BL/6J mice were fed either a normal diet (ND) (12% fat) or a high fat diet (HFD) (60% fat) for 12 weeks. Following this, one group of HFD fed mice (n=3) were intermittently fasted overnight for 16 hours twice per week for an additional 6 weeks (HFD IF group) while the remaining HFD fed (n=3) and ND fed mice were allowed to continue ad libitum feeding for the same period (HFD AL and ND AL groups respectively). Urinary albumin-creatinine ratio, Neutrophil Gelatinase-Associated Lipocalin (NGAL), and Kidney Injury Molecule-1 (KIM-1) were measured to assess renal injury. Renal lipid accumulation was measured via organic lipid extraction from kidney tissue, and insulin resistance was determined by an insulin tolerance test.

Results: While HFD AL mice had significantly greater weight than ND AL mice (57.97g ± 1.22 vs. 34.33g ± 1.43) (p < 0.05), there was no significant difference in weight between HFD AL and HFD IF (54.63g ± 1.71). Insulin tolerance testing demonstrated that HFD AL mice were insulin-resistant compared to ND AL mice whereas HFD IF mice were significantly more responsive to insulin than HFD AL mice. Renal triglycerides in HFD AL mice were 33% greater than in ND AL mice (11.74 ± 2.08 mg/g vs. 8.83 ± 1.43 mg/g) but decreased 57% in HFD IF mice (4.79 ± 1.36 mg/g) compared to HFD AL(p < 0.05). Compared to ND AL, urinary KIM-1 increased by 157% in HFD AL compared to ND AL (p < 0.01) and decreased 81% in HFD IF compared to HFD AL (p < 0.01). Similarly, Urinary NGAL increased 167% in HFD AL mice compared to ND AL (p < 0.05). Compared to HFD AL, urinary NGAL decreased 29% (p=0.28). Although HFD AL mice demonstrated a three-fold increase in urine albumin-creatinine ratio compared to ND AL (p < 0.05), intermittent fasting had no significant effect on albuminuria.

Conclusions: Despite having no significant effect on overall weight, intermittent fasting reduced insulin resistance, renal lipid accumulation and urinary markers of renal injury. These findings demonstrate the potential benefit of intermittent fasting in reducing obesity-related kidney injury.

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