Disruption of Hypoxia-Inducible Factor 1 in Adipocytes Improves Insulin Sensitivity and Decreases Adiposity in High-Fat Diet–Fed Mice
Changtao Jiang,Aijuan Qu,Tsutomu Matsubara,Tatyana Chanturiya,William Jou,Oksana Gavrilova,Yatrik M. Shah,Frank J. Gonzalez +7 more
TLDR
Inhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance, and is revealed to provide a novel potential therapeutic target for obesity and type 2 diabetes.Abstract:
OBJECTIVE Obesity, insulin resistance, and type 2 diabetes form a tightly correlated cluster of metabolic disorders in which adipose is one of the first affected tissues. The role of hypoxia and hypoxia-inducible factor 1 (HIF1) in the development of high-fat diet (HFD)–induced obesity and insulin resistance was investigated using animal models.
RESEARCH DESIGN AND METHODS Mice with adipocyte-specific targeted disruption of the genes encoding the HIF1 obligatory subunits Hif1α or Arnt (Hif1β) were generated using an aP2-Cre transgene with the Cre/LoxP system. The mice were fed an HFD for 12 weeks and their metabolic phenotypes were determined. Gene expression patterns in adipose tissues were also determined by microarray and quantitative PCR.
RESULTS On an HFD, adipocyte-specific ARNT knockout mice and adipocyte-specific HIF1α knockout mice exhibit similar metabolic phenotypes, including reduced fat formation, protection from HFD-induced obesity, and insulin resistance compared with similarly fed wild-type controls. The cumulative food intake remained similar; however, the metabolic efficiency was lower in adipocyte-specific HIF1α knockout mice. Moreover, indirect calorimetry revealed respiratory exchange ratios were reduced in adipocyte-specific HIF1α knockout mice. Hyperinsulinemic-euglycemic clamp studies demonstrated that targeted disruption of HIF1α in adipocytes enhanced whole-body insulin sensitivity. The improvement of insulin resistance is associated with decreased expression of Socs3 and induction of adiponectin.
CONCLUSIONS Inhibition of HIF1 in adipose tissue ameliorates obesity and insulin resistance. This study reveals that HIF1 could provide a novel potential therapeutic target for obesity and type 2 diabetes.read more
Citations
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The cellular and signaling networks linking the immune system and metabolism in disease
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Fibrosis and adipose tissue dysfunction.
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DNA methylation and body-mass index: a genome-wide analysis
Katherine J. Dick,Katherine J. Dick,Christopher P. Nelson,Christopher P. Nelson,Loukia Tsaprouni,Johanna K. Sandling,Johanna K. Sandling,Dylan Aïssi,Dylan Aïssi,Dylan Aïssi,Simone Wahl,Eshwar Meduri,Pierre-Emmanuel Morange,Harald Grallert,Melanie Waldenberger,Annette Peters,Jeanette Erdmann,Christian Hengstenberg,François Cambien,François Cambien,François Cambien,Alison H. Goodall,Alison H. Goodall,Willem H. Ouwehand,Willem H. Ouwehand,Willem H. Ouwehand,Heribert Schunkert,John R. Thompson,Tim D. Spector,Christian Gieger,David-Alexandre Trégouët,David-Alexandre Trégouët,David-Alexandre Trégouët,Panos Deloukas,Panos Deloukas,Panos Deloukas,Nilesh J. Samani,Nilesh J. Samani +37 more
TL;DR: Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue, and perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people.
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Adipokines: a link between obesity and cardiovascular disease.
TL;DR: The adipose tissue microenvironment and the role of adipokines in modulating systemic inflammatory responses that contribute to cardiovascular disease are focused on.
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Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity
Yun Sok Lee,Jung Whan Kim,Olivia Osborne,Da Young Oh,Roman Sasik,Simon Schenk,Ai Chen,Heekyung Chung,Anne N. Murphy,Steven M. Watkins,Oswald Quehenberger,Randall S. Johnson,Randall S. Johnson,Randall S. Johnson,Jerrold M. Olefsky +14 more
TL;DR: Early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia, which triggers HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity.
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