Abstract
Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for insulin resistance. Recently, IH is considered to independently cause adipose tissue inflammation/dysfunction, leading to worsening insulin resistance; however, the detailed mechanism remains unknown. We exposed mouse 3T3-L1 and human SW872 adipocytes to experimental IH or normoxia for 24 h, and analyzed mRNA expression of several adipokines. We found that the mRNA levels of RETN, TNFα, and CCL2 in SW872 and 3T3-L1 adipocytes were significantly increased by IH, whereas the promoter activities of these genes were not increased. A target mRNA search of microRNA (miR)s revealed that all human mRNAs have a potential target sequence for miR-452. The miR-452 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-452 mimic and non-specific control RNA (miR-452 mimic NC) were introduced into SW872 cells, and the IH-induced up-regulation of the genes was abolished by introduction of the miR-452 mimic but not by the miR-452 mimic NC. These results indicate that IH stress down-regulates the miR-452 in adipocytes, resulting in increased levels of RETN, TNFα, and CCL2 mRNAs, leading to insulin resistance in SAS patients.
Highlights
Sleep apnea syndrome (SAS) is a highly prevalent disease characterized by repetitive episodes of pharyngeal airway narrowing or obstruction during sleep, leading to apnea and hypopnea, often accompanied by a decrease in oxygen saturation [1]
We measured the mRNA levels of several adipokines (leptin [Lep], adiponectin [Adip], Retn, interleukin-6 (IL-6), TNFα, and C motif chemokine ligand 2 (CCL2)) by real-time reverse transcription polymerase chain reaction (RT-PCR)
We demonstrated that intermittent hypoxia (IH) exposure induced increases of RETN, TNFα, and CCL2 mRNIAn tlheviseslstu. dWye, fwuertdheemr sotnusdtireadtetdhatht atht eIHmeexchpaonsuisrme sinbdyuwcehdicihncIrHeauseps-roefgRuElaTteNs,tThNe FmαR, NanAd lCevCeLl2s mofRaNdAipolekvineless
Summary
Sleep apnea syndrome (SAS) is a highly prevalent disease characterized by repetitive episodes of pharyngeal airway narrowing or obstruction during sleep, leading to apnea and hypopnea, often accompanied by a decrease in oxygen saturation [1]. Accumulating evidence suggests that recurrent short cycles of oxygen desaturation followed by rapid reoxygenation (intermittent hypoxia [IH]), which are typical features of SAS, contribute to the development of impaired glucose tolerance/insulin resistance [4,5,6]. This relationship is considered to be irrelevant to the degree of obesity [7,8,9]. We have reported that IH stress influences pancreatic β cell proliferation/dysfunction, hepatocytes proliferation/dysfunction, and synthesis of anorexigenic peptides in neuronal cells, which may lead to aggravate insulin resistance/type 2 diabetes [1,11,12]
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