title: Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.
abstract: Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.
authors: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Naomi
authors: N
authors: Hosogai
authors: Atsunori
authors: A
authors: Fukuhara
authors: Kazuya
authors: K
authors: Oshima
authors: Yugo
authors: Y
authors: Miyata
authors: Sachiyo
authors: S
authors: Tanaka
authors: Katsumori
authors: K
authors: Segawa
authors: Shigetada
authors: S
authors: Furukawa
authors: Yoshihiro
authors: Y
authors: Tochino
authors: Ryutaro
authors: R
authors: Komuro
authors: Morihiro
authors: M
authors: Matsuda
authors: Iichiro
authors: I
authors: Shimomura
mesh_terms: D016475:3T3 Cells; D000273:Adipose Tissue / Q000503:physiopathology*; D000821:Animal Feed; D000818:Animals; D016207:Cytokines / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D004041:Dietary Fats; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors
chemical_list: D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors