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.
Highlights
HIF-1 is a transcription factor that controls multiple metabolic pathways related to cellular hypoxia [1,2,3,4,5]
Effect of antisense oligonucleotides (ASO) on body weight and adiposity hypoxia inducible factor 1 alpha (HIF-1a) ASO treatment led to significant weight loss, observed by the 33rd day of treatment (Figure 3) and the weight curves continued to diverge thereafter
The novelty of our study is that we have shown that therapeutic depletion of HIF-1a in severe obesity induces a metabolic switch to fat oxidation resulting in lower metabolic efficiency, energy wasting and weight loss
Summary
HIF-1 is a transcription factor that controls multiple metabolic pathways related to cellular hypoxia [1,2,3,4,5]. Recent studies demonstrated that obesity is associated with adipose tissue hypoxia in humans and rodents [13,14,15,16,17,18]. Adipose tissue hypoxia leads to upregulation of HIF-1a [16,17,18,19,20]. Transgenic mice with constitutive activation of adipose HIF-1a develop mild obesity, insulin resistance and glucose intolerance [19], while mice with tissuespecific knockout of adipose HIF-1a are protected against diet induced obesity (DIO) and metabolic dysfunction [21]. Nonalcoholic and alcohol-induced fatty livers were associated with HIF-1a up-regulation [23,24,25,26]. Adipose and liver HIF-1a may be an important target to address the metabolic dysfunction of obesity. We treated DIO mice with HIF-1a anti-sense oligonucleotides (ASO) and examined the impact of this treatment on lipid and glucose metabolism
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