Inhibition of hypoxia inducible factor 1 alpha (HIF‐1a) improves the metabolic phenotype in C57BL/6J mice with diet induced obesity (DIO)

Abstract

Obesity has been associated with tissue hypoxia. Hypoxia inducible factor 1 (HIF‐1) is a master‐regulator of metabolic responses to hypoxia, but its role in obesity is unknown. DIO mice were treated with antisense oligonucleotides (ASO) against an O2‐ sensitive α subunit of HIF‐1 or control ASO (25 mg/kg, i.p., twice a week) for 8 weeks and compared with an unhandled group. HIF‐ 1α ASO suppressed HIF‐1α gene expression by 95% in liver and epididymal fat and by 72% in brown fat, whereas inguinal, mesenteric fat and muscle were unaffected. By Day 28th, HIF‐1a ASO mice started losing weight and by the end of the experiment they were 10% lighter then mice in the control ASO and unhandled groups (41 ± 3.9 vs 46 ± 3.1 and 47 ± 2.8 g respectively, p < 0.001). There was no change in food intake, but there was a significant increase in the energy expenditure (13.3 ± 0.6 vs 12 ± 0.1 and 11.9 ± 0.4 kcal/kg/hr in control ASO and unhandled groups, p < 0.001) and activity. HIF‐1α ASO mice showed a significant decreases in fasting blood glucose (195.5 ± 8.4 mg/dl vs 239 ± 7.8 mg/dl and 222 ± 8.2 mg/dl, p < 0.01), fasting plasma insulin (0.29 ± 0.04 vs 0.53± 0.09 and 0.77 ± 0.18 ng/ml, p < 0.05), liver fat content (15.32 ± 1.7 μg/mg vs 23.07 ± 1.5 μg/mg and 22.87 ± 21.1 μg/mg, p < 0.05), and increased liver glycogen content (12.1 ± 0.8 % wt/wt vs 8.9 ± 0.9, p < 0.05, and 7.4 ± 1.2 % wt/wt, p < 0.01), compared to control ASO and unhandled mice, respectively. In conclusion, in DIO mice, depletion of HIF‐1α results in increased energy expenditure, weight loss, improved insulin resistance and glucose tolerance.