Analysis of In Vitro Insulin-Resistance Models and Their Physiological Relevance to In Vivo Diet-Induced Adipose Insulin Resistance

•In vitro models capture different aspects of in vivo insulin resistance•Cotreatment with TNF-α and hypoxia is most able to mimic in vivo changes in mice•C/EBPβ is likely to mediate TNF-α-induced adipose insulin resistance•AdipoSight is a web-based tool for exploring adipocyte transcription regulation

SummaryDiet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-α, hypoxia, dexamethasone, high insulin, and a combination of TNF-α and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice. We found that different in vitro models capture distinct features of DIO adipose insulin resistance, and a combined treatment of TNF-α and hypoxia is most able to mimic the in vivo changes. Using genome-wide DNase I hypersensitivity followed by sequencing, we further examined the transcriptional regulation of TNF-α-induced insulin resistance, and we found that C/EPBβ is a potential key regulator of adipose insulin resistance.

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