title: Myeloid heme oxygenase-1 haploinsufficiency reduces high fat diet-induced insulin resistance by affecting adipose macrophage infiltration in mice.
abstract: Increased adipose tissue macrophages contribute to obesity-induced metabolic syndrome. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory and proangiogenic activities in macrophages. However, the role of macrophage HO-1 on obesity-induced adipose inflammation and metabolic syndrome remains unclear. Here we show that high-fat diet (HFD) feeding in C57BL/6J mice induced HO-1 expression in the visceral adipose tissue, particularly the stromal vascular fraction. When the irradiated C57BL/6J mice reconstituted with wild-type or HO-1(+/-) bone marrow were fed with HFD for over 24 weeks, the HO-1(+/-) chimeras were protected from HFD-induced insulin resistance and this was associated with reduced adipose macrophage infiltration and angiogenesis, suggesting that HO-1 affects myeloid cell migration toward adipose tissue during obesity. In vivo and in vitro migration assays revealed that HO-1(+/-) macrophages exhibited an impaired migration response. Chemoattractant-induced phosphorylation of p38 and focal adhesion kinase (FAK) declined faster in HO-1(+/-) macrophages. Further experiments demonstrated that carbon monoxide and bilirubin, the byproducts derived from heme degradation by HO-1, enhanced macrophage migration by increasing phosphorylation of p38 and FAK, respectively. These data disclose a novel role of hematopoietic cell HO-1 in promoting adipose macrophage infiltration and the development of insulin resistance during obesity.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors: Jun-Yuan
authors: JY
authors: Huang
authors: Ming-Tsai
authors: MT
authors: Chiang
authors: Shaw-Fang
authors: SF
authors: Yet
authors: Lee-Young
authors: LY
authors: Chau
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001663:Bilirubin / Q000494:pharmacology; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000494:pharmacology; D002465:Cell Movement; D059305:Diet, High-Fat / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D057895:Haploinsufficiency; D051547:Heme Oxygenase-1 / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology* / Q000473:pathology; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D001663:Bilirubin