Hypoxia‑inducible factor‑1α regulates Lipin1 differently in pre‑adipocytes and mature adipocytes.

Hypoxia-inducible factor (HIF)-1 alpha is a transcription factor that is activated in low oxygen conditions. Adipose tissues are poorly oxygenated in patients with obesity. The low oxygen conditions in obese adipose tissues induce HIF-1 alpha in adipocytes. Previous studies using genetically modified mice suggest that HIF-1 alpha contributes to dysfunction in adipocytes. Lipin1 is a bifunctional protein that works as a phosphatidate phosphatase and transcriptional coactivator, which regulates lipid metabolism and adipogenesis, respectively. HIF-1 alpha directly regulates Lipin1 in hepatocytes. However, the regulation of Lipin1 by HIF-1 alpha in adipocytes is not well determined. Therefore, the present study investigated the regulation of Lipin1 by HIF-1 alpha in adipocytes. Expression levels of Lipin1 were reduced in epididymal adipose tissues of adipocyte-specific HIF-1 alpha knockout mice, indicating that HIF-1 alpha regulates Lipin1 in adipocytes. In differentiated mature adipocytes, a HIF-1 alpha activator, dimethyloxallyl glycine (DMOG), was demonstrated to increase Lipin1, and a HIF-1 alpha inhibitor, 3-(5 '-hydroxymethyl-2 '-furyl)-1-benzylindazole (YC-1), reversed this increase, indicating that HIF-1 alpha regulates Lipin1 in differentiated adipocytes. However, during differentiation of pre-adipocytes into adipocytes, YC-1 increased Lipin1 even though HIF-1 alpha was decreased. The differentiation efficiency increased with YC-1 treatment. In addition, DMOG reduced Lipin1 expression levels during differentiation despite increased HIF-1 alpha. Under these conditions, differentiation efficiency was reduced. These results suggest that Lipin1 is negatively regulated by HIF-1 alpha in pre-adipocytes. Our results show that regulation of Lipin1 by HIF-1 alpha is different in adipocytes and pre-adipocytes.