Role of H3K36me2 in Palmitate Induced Metabolic Memory in Human Podocytes

Palmitate has been found to induce insulin resistance in various cell types including podocytes. Hyperglycemia has a delayed damaging effect on glucose metabolism, termed “metabolic memory”. Increased plasma saturated fatty acids are associated with insulin resistance and hyperglycemia but their effect on metabolic memory is largely unknown. Therefore, we investigated the molecular mechanisms behind the persistent metabolic memory by palmitate in human podocytes. Palmitate treatment in podocytes prevented insulin induced phosphorylation of IR‐beta, AKT and GSK 3‐beta. This inhibitory effect of palmitate was found to be persistent even after 48 hours of palmitate removal. Further, Palmitate treatment prevented insulin induced degradation of FOXO 1 and increased mRNA levels of well‐defined FOXO 1 target genes such as PDK4, p21, G‐6‐Pc and IGFBP1. The mRNA levels of these genes were found to be persistent even after 48 hrs of palmitate removal. In addition, palmitate treatment also prevented insulin induced H3K36me2 demethylation. Interestingly, this inhibition of insulin action was persistent after 48 hrs of palmitate removal. Chromatin immune‐precipitation (ChIP) assay showed reduced H3k36me2 enrichment on FOXO 1 promoter after insulin stimulation and this effect of insulin was blunted by palmitate and remained persistent even after 48 hrs of palmitate removal. In summary, our data demonstrate that palmitate induced metabolic memory involves persistent FOXO 1 activation through increased H3K36me2 on FOXO 1 promoter. Out data suggest that manipulation of H3K36 di‐methylation and FOXO 1 expression may be a useful strategy to prevent palmitate induced metabolic memory in human podocytes.