Selective Inhibition of Hypoxia-Inducible Factor 1α Ameliorates Adipose Tissue Dysfunction

Sun, Kai; Halberg, Nils; Khan, Mahmood; Magalang, Ulysses J.; Scherer, Philipp E.

doi:10.1128/mcb.00951-12

Cited by 200 publications

(195 citation statements)

References 62 publications

Supporting

Mentioning

188

Contrasting

Order By: Relevance

“…PX-478 has been shown to decrease Hif1α both in vitro and in vivo by decreasing Hif1α mRNA levels and blocking Hif1α mRNA translation (27,30,31). Constitutive VEGF signaling abrogates the effect of PX-478 on downstream angiogenic signaling, confirming that its effect is upstream of VEGF.…”

Section: Discussionsupporting

confidence: 53%

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Agarwal

Loder

Brownley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

193

223

View full text Add to dashboard Cite

Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1α fl:fl ) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.is the pathologic formation of extraskeletal bone in soft tissues. This process occurs in two separate patient populations: those with severe trauma, including large surface-area burns, musculoskeletal injury, orthopedic operations, and even spinal cord injury; and those with a genetic disease known as fibrodysplasia ossificans progressiva (FOP) (1-4). FOP is caused by a hyperactivating mutation in the type I bone morphogenetic protein (BMP) receptor ACVR1 (Activin type 1 receptor), and patients with FOP develop ectopic bone lesions in the absence of any substantial trauma. The clinical sequela of these pathologic ectopic bone formations, whether in the setting of trauma or genetic mutations, include nonhealing wounds, chronic pain, and joint immobility. In the case of FOP, progressive ossification may lead to death as a result of loss of thoracic cage compliance.Treatment options for HO are limited because bone often recurs following surgical resection, and some patients may have nonresectable HO because of its sensitive location. The risk of an operation may outweigh the benefits of excision, especially in the face of recurrence (5). Therefore, there is a need to identify therapeutic options ...

show abstract

Section: Discussionsupporting

confidence: 53%

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Agarwal

Loder

Brownley

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

193

223

View full text Add to dashboard Cite

show abstract

“…Consistently, several studies point to the role of macrophages in promoting fibroblastic phenotype and ECM production in human preadipocytes [33][34][35] . Taken together with recent observations that activation of hypoxia-inducible factor-1 in adipocytes contributes to interstitial fibrosis in adipose tissue 8 , Mincle in macrophages may link obesity-induced adipocyte damages with myofibroblast formation.…”

Section: Discussionmentioning

confidence: 88%

“…In this regard, Khan et al 6 reported that mice lacking collagen VI, which is expressed abundantly in adipose tissue, exhibit the uninhibited adipose tissue expansion and substantial improvement in insulin sensitivity on a high-fat diet (HFD). Although recent evidence suggests a role for obesity-induced hypoxic state 7,8 , the molecular mechanisms underlying adipose tissue fibrosis are still largely unknown.…”

mentioning

confidence: 99%

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

et al. 2014

View full text Add to dashboard Cite

“…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

View full text Add to dashboard Cite

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.

show abstract

Selective Inhibition of Hypoxia-Inducible Factor 1α Ameliorates Adipose Tissue Dysfunction

Cited by 200 publications

References 62 publications

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

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

Contact Info

Product

Resources

About