Metabolic consequences of high-fat diet are attenuated by suppression of HIF-1α.

Abstract

Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alpha (HIF-1α). Prior studies in transgenic mice have shown that HIF-1α 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-1α antisense oligonucleotides (ASO). DIO mice were treated with HIF-1α ASO or with control ASO for 8 weeks and compared with an untreated group. We found that HIF-1α ASO markedly suppressed Hif-1α gene expression in adipose tissue and the liver. HIF-1α ASO administration induced weight loss. Final body weight was 41.6 ± 1.4 g in the HIF-1α 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-1α 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-1α 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-1α ASO treatment.

• Authors: Mi-Kyung Shin, Luciano F Drager, Qiaoling Yao, Shannon Bevans-Fonti, Doo-Young Yoo, Jonathan C Jun, Susan Aja, Sanjay Bhanot, Vsevolod Y Polotsky
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e46562 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23049707 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Insulin
• Oligonucleotides, Antisense

Topics

• Adipose Tissue (metabolism)
• Animals
• Blood Glucose (drug effects)
• Blotting, Western
• Body Weight (drug effects)
• Diet, High-Fat (adverse effects)
• Energy Metabolism (drug effects)
• Gene Expression Regulation (drug effects)
• Histological Techniques
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors)
• Insulin (blood)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (etiology, physiopathology)
• Oligonucleotides, Antisense (genetics, pharmacology)
• Real-Time Polymerase Chain Reaction