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
|