Disruption of Hypoxia-Inducible Factor 1 in Adipocytes Improves Insulin Sensitivity and Decreases Adiposity in High-Fat Diet–Fed Mice

Jiang, Changtao; Qu, Aijuan; Matsubara, Tsutomu; Chanturiya, Tatyana; Jou, William; Гаврилова, Оксана; Shah, Yatrik M.; Gonzalez, Frank J.

doi:10.2337/db11-0174

Cited by 241 publications

(239 citation statements)

References 42 publications

(49 reference statements)

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“…2). This finding is consistent with several recent reports demonstrating that the efficiency of aP2-Cre recombination in macrophages is much less efficient than in adipocytes [39][40][41].…”

Section: Resultssupporting

confidence: 93%

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

et al. 2012

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Aims/hypothesis Inflammation in obesity increases the levels of the suppressor of cytokine signalling-3 (SOCS3) protein in adipose tissue, but the physiological importance of this protein in regulating whole-body insulin sensitivity in obesity is not known. Methods We generated Socs3 floxed (wild-type, WT) and Socs3 aP2 (also known as Fabp4)-Cre null (Socs3 AKO) mice. Mice were maintained on either a regular chow or a high-fat diet (HFD) for 16 weeks during which time body mass, adiposity, glucose homeostasis and insulin sensitivity were assessed. Results The HFD increased SOCS3 levels in adipose tissue of WT but not Socs3 AKO mice. WT and Socs3 AKO mice had similar body mass and adiposity, assessed using computed tomography (CT) imaging, irrespective of diet or sex. On a control chow diet there were no differences in insulin sensitivity or glucose tolerance. When fed a HFD, female but not male Socs3 AKO mice had improved glucose tolerance as well as lower fasting glucose and insulin levels compared with WT littermates. Hyperinsulinaemic-euglycaemic clamps and positron emission tomography (PET) imaging demonstrated that improved insulin sensitivity was due to elevated adipose tissue glucose uptake. Increased insulin-stimulated glucose uptake in adipose tissue was associated with enhanced levels and activating phosphorylation of insulin receptor substrate-1 (IRS1). Conclusions/interpretation These data demonstrate that inhibiting SOCS3 production in adipose tissue of female mice is effective for improving whole-body insulin sensitivity in obesity.

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Section: Resultssupporting

confidence: 93%

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

et al. 2012

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“…Inhibition of Hif-1a by disruption of its gene in adipocytes (30) or administration of its inhibitor (31) or antisense oligonucleotides (32) attenuates the consequences of an HFD in mice. Currently, no explanation is available for the discrepancy between those data and the beneficial effects of Hif-a stabilization by Hif-p4h-2 deficiency, but the additional stabilization of Hif-2a has been suggested to possibly play an important role (25).…”

Section: Discussionmentioning

confidence: 99%

HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

et al. 2014

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Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4-hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2–deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipocytes, and less adipose tissue inflammation than their littermates. They also had improved glucose tolerance and insulin sensitivity. Furthermore, the mRNA levels of the HIF-1 targets glucose transporters, glycolytic enzymes, and pyruvate dehydrogenase kinase-1 were increased in their tissues, whereas acetyl-CoA concentration was decreased. The hepatic mRNA level of the HIF-2 target insulin receptor substrate-2 was higher, whereas that of two key enzymes of fatty acid synthesis was lower. Serum cholesterol levels and de novo lipid synthesis were decreased, and the mice were protected against hepatic steatosis. Oral administration of an HIF-P4H inhibitor, FG-4497, to wild-type mice with metabolic dysfunction phenocopied these beneficial effects. HIF-P4H-2 inhibition may be a novel therapy that not only protects against the development of obesity and its consequences but also reverses these conditions.

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“…Hypoxia-inducible factor (HIF)-1a and HIF-2a are key transcription factors to mediate hypoxic responses such as angiogenesis, glycolysis, adhesion, and infiltration. Most studies of adipose tissue HIFs have focused on HIF-1a (14)(15)(16)(17). For instance, activation of HIF-1a has been implicated in adipose tissue inflammation, fibrosis, and adipocyte dysfunction.…”

mentioning

confidence: 99%

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Choe

Shin

et al. 2014

Diabetes

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In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α–overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fed Hif-2α heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.

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Disruption of Hypoxia-Inducible Factor 1 in Adipocytes Improves Insulin Sensitivity and Decreases Adiposity in High-Fat Diet–Fed Mice

Cited by 241 publications

References 42 publications

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

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