EXERCISE-INDUCED LIPOKINE 13-HDHA REGULATES RENAL FATTY ACID METABOLISM AND SUPPRESSES FIBROTIC PROGRAMMING IN DIABETIC KIDNEY DISEASE

White adipose tissue (WAT) is the primary depot of free fatty acids (FFAs) and a key energy source during exercise. Lipolysis in subcutaneous WAT (scWAT) supplies ~90–95% of circulating FFAs used by skeletal muscle. These findings suggest that fatty acids released from adipose tissue during exercise may influence metabolism in organs such as the kidney.

The kidney relies predominantly on fatty acid oxidation to sustain its function. Impaired lipid metabolism causes lipid accumulation, inflammation, and fibrosis in renal tubular cells. Epithelial–mesenchymal transition (EMT) is a key process driving renal fibrosis and can be triggered by metabolic disturbances such as impaired lipid oxidation. Sex differences exist in renal lipid metabolism: male kidneys are more prone to lipid deposition and fibrosis, whereas estrogen enhances fatty acid oxidation and provides protection. We aimed to clarify how exercise-induced lipid metabolism affects renal pathology, focusing on sex differences, the degree of fibrosis, and the role of an exercise-induced lipokine.

Four-week-old male and female C57BL/6 mice were fed a 30% high-fat diet (HFD) for six weeks to induce metabolic abnormalities, and sex differences in renal expression of lipid metabolism–related genes were examined. To assess links between lipid metabolism and fibrosis, we performed single-cell RNA sequencing (scRNA-seq) on two male db/db strains: the standard BKS db/db, a model of obesity and diabetes with mild renal fibrosis, and the CD-1 db/db strain generated by backcrossing the Lepr^db mutation onto the CD-1 background as previously reported by our group, which develops severe fibrosis. Finally, HFD-fed C57BL/6 mice underwent two weeks of voluntary wheel running (VWR) to test whether exercise mitigates renal fibrosis. Lipidomic analysis of scWAT identified exercise-induced lipokines with potential renoprotective effects.

First, in HFD-fed C57BL/6 mice, female kidneys showed higher expression of peroxisome proliferator–activated receptor delta (Ppard) and other β-oxidation–related genes than males, suggesting that enhanced fatty acid utilization in females may underlie sex dimorphism in renal phenotypes. Next, scRNA-seq of db/db mice showed that the CD-1 strain, which develops pronounced renal fibrosis, had lower expression of lipid uptake (Cd36, Fabp3) and β-oxidation enzymes (Acad, Acaa2, Hadha, Hadhb) in proximal tubular cells compared with the BKS strain, indicating that reduced lipid oxidation capacity is associated with fibrosis progression. Finally, two weeks of VWR in HFD-fed C57BL/6 mice partially suppressed the renal fibrotic program, reflected by increased E-cadherin and decreased α-SMA expression, reflecting inhibition of EMT. Lipidomics identified 13-hydroxydocosahexaenoic acid (13-HDHA), an ω-3–derived oxidized DHA metabolite, as markedly elevated in scWAT after exercise. In HK2 proximal tubular cells, 13-HDHA attenuated palmitic acid–induced EMT, preserving epithelial phenotype and enhancing expression of fatty acid oxidation–related genes.

This study revealed that renal lipid metabolism shows clear sex dimorphism, with females exhibiting greater fatty acid oxidation capacity. Impaired lipid uptake and β-oxidation in diabetic models were associated with fibrosis progression. Exercise training alleviated renal fibrotic programming and elevated 13-hydroxydocosahexaenoic acid (13-HDHA) in adipose tissue, which directly modulated tubular metabolism by suppressing lipid-induced EMT and promoting fatty acid oxidation. These findings highlight an adipose–renal metabolic axis mediated by exercise-induced lipokines such as 13-HDHA, linking lipid metabolism to renal protection in diabetic kidney disease.