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

Choe, Sung Sik; Shin, Kyung Cheul; Ka, Sojeong; Lee, Yun Kyung; Chun, Jang‐Soo; Kim, Jae Bum

doi:10.2337/db13-1965

Cited by 90 publications

(91 citation statements)

References 45 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Examining the role of HIF in ATMs has shown that in vitro exposure to hypoxia increased the expression of IL-6 and IL-1␤ but not TNF-␣, which strongly supports our findings (18). Additionally, Choe et al (47) have shown that knocking down HIF-2␣ enhanced palmitate-induced IL-6 expression, which is also in agreement with our findings. Collectively, although HIFs modulate various pro-inflammatory pathways, including IL1␤ expression, our data indicate that, during acute exposure to 1% O 2 , HIFs are not primarily responsible for potentiating the production of palmitate-induced, pro-inflammatory cytokines in macrophages.…”

Section: Discussionsupporting

confidence: 83%

See 1 more Smart Citation

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O 2 ) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate-induced mRNA expression and protein secretion of IL-6 and IL-1␤. Although palmitate-induced endoplasmic reticulum stress and nuclear factor B pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1␣ and HIF-2␣ alone or in combination failed to reduce IL-6 and only modestly reduced IL-1␤ gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1␤ and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage-mediated inflammation.

show abstract

Section: Discussionsupporting

confidence: 83%

“…HIFs have been implicated in adipose tissue inflammation and insulin resistance (9,47). For this reason, we speculated that the potentiation of palmitate-induced, pro-inflammatory cytokines in hypoxic macrophages may be mediated by HIF-1␣ and HIF-2␣.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Snodgrass¹,

Boß²,

Zezina³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Interestingly, HIF-2a haplodeficiency in mice on a normal chow diet also did not report any differences in glucose tolerance or insulin sensitivity. 25 These findings are consistent with our study in the HIF-2a OE mice on chow diet. However, upon HFD feeding, HIF-2a heterozygous-null mice exhibited more aggravated glucose intolerance and insulin resistance compared to WT mice.…”

Section: Pancreas Specific Overexpression Of Hif-2a Does Not Alter Glsupporting

confidence: 83%

“…24 In macrophages, overexpression of HIF-2a improved insulin resistance in adipocytes. 25 To our knowledge the specific in vivo role of HIF-2a overexpression in b cells has not been identified to date. In the present study, we used a tissue specific approach to overexpress HIF-2a in pancreatic b cells to determine its role in glucose homeostasis under basal conditions and during metabolic challenge by high fat diet (HFD) feeding.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Brunt

Shi

Schroer

et al. 2014

Islets

View full text Add to dashboard Cite

Keywords: Hypoxia inducible factor b cell glucose homeostasis diabetes mellitus pancreas Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; EPAS1, endothelial PAS domain protein 1; GLUT1 glucose transporter 1; GTT, glucose tolerance test; HFD, high fat diet; HIF, hypoxia inducible factor; HIF-1a, hypoxia inducible factor-1 a; HIF-1b, hypoxia inducible factor-1 b; HIF-2a, hypoxia inducible factor-2 a; i.p., intraperitoneal; ITT, insulin tolerance test; OE, overexpression; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; WT, wild-type.Both type 1 and type 2 diabetes are associated with insufficient functional b-cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions. Activation of this pathway increases expression of numerous genes involved in multiple cellular processes and has been shown to impact the regulation of b-cell function. Previously, deletion of HIF-1a or HIF-1b in pancreatic b-cells, as well as constitutive activation of the HIF pathway in b-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2a overexpression in pancreatic b-cells in vivo. We overexpressed HIF-2a in pancreatic b-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2a overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or b-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2a in the pancreatic b-cells does not play a significant role in b-cell function and glucose homeostasis.

show abstract

“…M2 polarization also can be advantageous in adipose tissue macrophages because hypoxia-inducible factor-2a, expressed mainly in M2-like adipose tissue macrophages, ameliorates adipose tissue inflammation and insulin resistance in obesity (2).…”

mentioning

confidence: 99%

Comment on Lee et al. Diabetes 2015;64:2836–2846. Comment on Roberts et al. Diabetes 2015;64:471–484

Kruszelnicka

Surdacki

2016

Diabetes

View full text Add to dashboard Cite

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

Cited by 90 publications

References 45 publications

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Comment on Lee et al. Diabetes 2015;64:2836–2846. Comment on Roberts et al. Diabetes 2015;64:471–484

Contact Info

Product

Resources

About