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

PLoS One

Susan Aja¹  Mi-Kyung Shin²  Qiaoling Yao²  Doo-Young Yoo²  Jonathan C. Jun²  Vsevolod Y. Polotsky²  Shannon Bevans-Fonti²  Luciano F. Drager³  Sanjay Bhanot⁴ 

[1] Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America;Hypertension Unit, Heart Institute (InCor), University of Saõ Paulo Medical School, Saõ Paulo, Brazil;Isis Pharmaceuticals, Inc., Carlsbad, California, United States of America

关键词: Fatty liver;    Fats;    Glucose;    Glycogens;    Insulin;    Brown adipose tissue;    Insulin resistance;    Glucose metabolism;   

DOI  :  10.1371/journal.pone.0046562

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY