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

Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alpha (HIF-1 alpha). Prior studies in transgenic mice have shown that HIF-1 alpha 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-1 alpha antisense oligonucleotides (ASO). DIO mice were treated with HIF-1 alpha ASO or with control ASO for 8 weeks and compared with an untreated group. We found that HIF-1 alpha ASO markedly suppressed Hif-1 alpha gene expression in adipose tissue and the liver. HIF-1 alpha ASO administration induced weight loss. Final body weight was 41.6 +/- 1.4 g in the HIF-1 alpha ASO group vs 46.7 +/- 0.9 g in the control ASO group and 47.9 +/- 0.8 g in untreated mice (p<0.001). HIF-1 alpha ASO increased energy expenditure (13.3 +/- 0.6 vs 12 +/- 0.1 and 11.9 +/- 0.4 kcal/kg/hr, respectively, p<0.001) and decreased the respiratory exchange ratio (0.71 +/- 0.01 vs 0.75 +/- 0.01 and 0.76 +/- 0.01, 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-1 alpha ASO treatment decreased fasting blood glucose (195.5 +/- 8.4 mg/dl vs 239 +/- 7.8 mg/dl in the control ASO group and 222 +/- 8.2 mg/dl in untreated mice, p<0.01), plasma insulin, hepatic glucose output, and liver fat content. These findings demonstrate that the metabolic consequences of DIO are attenuated by HIF-1 alpha ASO treatment.