Abstract Body: Introduction: Obesity-related renal lipotoxicity, is attributed to renal lipid accumulation due to increased renal lipogenesis and reduced fatty acid β-oxidation (FAO). Fasting in lean mice increases renal FAO and decreases lipogenesis. While recent evidence suggests that the effects of fasting on renal lipogenesis are decreased in obesity, the effects of fasting on renal FAO are less understood.

Hypothesis: We hypothesized that obesity reduces the upregulation of FAO enzymes in the kidney in response to fasting.

Methods: Male C57BL/6 mice were fed normal diet (ND, 12% fat) or high fat diet (HFD, 60% fat) for 16 weeks. Mice from each group underwent either ad libitum (AL) feeding or a 16hr overnight fast followed by kidney tissue harvest for transcriptomic analysis and biochemical assessment of lipid content.

Results: HFD AL mice demonstrated a 64% increase in body weight compared to ND AL mice (p<0.01). Fasting raised kidney triglyceride content 8-fold in ND mice (p<0.01) and HFD AL mice had 7-fold greater triglyceride content compared to ND AL mice (p<0.01). There was no significant change in triglyceride content between HFD AL and HFD fasted mice. Enrichment analysis of RNA sequencing data demonstrated that fatty acid metabolism pathways were significantly enriched by fasting under both ND and HFD conditions compared to their respective AL controls (q values 0.00001 and 0.004 respectively). However, fatty acid metabolism pathways were also significantly enriched in ND fasted mice compared to HFD fasted mice (q =1.56x10^-10). Multiple genes responsible for FAO including EHHADH, HMGCS2, ACSM3, CYP4A10, ACOX1, and ACSL1 had significantly higher renal expression in ND fasted mice than HFD fasted mice (q<0.05, log2fold change>0.58). Of these genes, EHHADH, ACOX1, and ASCL1 had significantly increased expression with ND fasting compared to ND AL mice but were not significantly affected by fasting in HFD mice. Conversely, expression of CIDEA, a gene which promotes triglyceride and lipid droplet formation, was significantly greater in HFD fasting than ND fasting mice.

Conclusion: Lean mice demonstrated greater transcriptional upregulation of renal FAO genes during fasting compared to mice with diet-induced obesity. Further investigation is needed into whether this reduction in metabolic flexibility contributes to the kidney’s susceptibility to injury in the setting of obesity.