Nardilysin in adipocyte regulates insulin sensitivity via HIF1α and PPARγ

Obesity is a critical global health issue and a major risk factor for type 2 diabetes mellitus (T2DM). However, molecular mechanism by which obesity leads to T2DM has not been fully elucidated. Here, we investigated the role of adipocyte nardilysin (NRDC) in insulin sensitivity using adipocyte-specific NRDC-knockout mice (Adipo-KO). Despite no difference in body weight, Adipo-KO demonstrated enhanced glucose tolerance and insulin sensitivity exclusively under high fat diet (HFD) conditions. Epididymal white adipose tissue (eWAT) in Adipo-KO showed the decreased crown-like structures and F4/80-positive cells. Consistently, insulin-stimulated Akt phosphorylation was elevated in the eWAT of HFD-fed Adipo-KO and 3T3-L1 adipocytes with NRDC knockdown. In addition, NRDC knockdown led to a decrease in cellular oxygen consumption rate and hypoxia-induced HIF1α expression in 3T3-L1 adipocytes. The augmented Akt phosphorylation by NRDC knockdown was reversed by daprodustat, which stabilizes HIF1α, suggesting that the effect of NRDC on insulin sensitivity is mediated by HIF1α. Upstream analysis of the differentially expressed genes (DEGs) in NRDC knockdown 3T3-L1 adipocytes revealed that PPARγ is enriched in the promoters of the DEGs. We also confirmed the complex formation of NRDC and PPARγ. In conclusion, NRDC in adipocyte regulates insulin sensitivity through HIF1α and PPARγ.