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-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.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Mi-Kyung
MK
Shin
Luciano F
LF
Drager
Qiaoling
Q
Yao
Shannon
S
Bevans-Fonti
Doo-Young
DY
Yoo
Jonathan C
JC
Jun
Susan
S
Aja
Sanjay
S
Bhanot
Vsevolod Y
VY
Polotsky
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006652:Histological Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
D001786:Blood Glucose; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D016376:Oligonucleotides, Antisense