Metabolic Consequences of High-Fat Diet Are Attenuated by Suppression of HIF-1a

Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alpha (HIF-1a). Prior studies in transgenic mice have shown that HIF-1a plays a role in the metabolic dysfunction associated with obesity. Therefore, we hypothesized that, after the development of diet-induced obesity (DIO), metabolic function could be improved by administration of HIF-1a antisense oligonucleotides (ASO). DIO mice were treated with HIF-1a ASO or with control ASO for 8 weeks and compared with an untreated group. We found that HIF-1a ASO markedly suppressed Hif-1a gene expression in adipose tissue and the liver. HIF-1a ASO administration induced weight loss. Final body weight was 41.661.4 g in the HIF-1a ASO group vs 46.760.9 g in the control ASO group and 47.960.8 g in untreated mice (p,0.001). HIF-1a ASO increased energy expenditure (13.360.6 vs 1260.1 and 11.960.4 kcal/kg/hr, respectively, p,0.001) and decreased the respiratory exchange ratio (0.7160.01 vs 0.7560.01 and 0.7660.01, respectively, p,0.001), which suggested switching metabolism to fat oxidation. In contrast, HIF-1a ASO had no effect on food intake or activity. HIF-1a ASO treatment decreased fasting blood glucose (195.568.4 mg/dl vs 23967.8 mg/dl in the control ASO group and 22268.2 mg/dl in untreated mice, p,0.01), plasma insulin, hepatic glucose output, and liver fat content. These findings demonstrate that the metabolic consequence