Regulation of obesity and insulin resistance by hypoxia-inducible factors

In obesity, dysregulated metabolism and aberrant expansion of adipose tissue lead to the development of tissue hypoxia that plays an important role in contributing to obesity-associated metabolic disorders. Recent studies utilizing adipocyte-specific hypoxia-inducible factor-α (HIF-α) gain- or loss-of-function animal models highlight the pivotal involvement of hypoxic responses in the pathogenesis of obesity-associated inflammation and insulin resistance. HIF-1α, a master transcription factor of oxygen homeostasis, induces inflammation and insulin resistance in obesity, whereas its isoform, HIF-2α, exerts opposing functions in these obesity-associated metabolic phenotypes. In this review, recent evidence elucidating functional implications of adipocyte HIFs in obesity and, more importantly, how these regulate obesity-associated inflammation, fibrosis, and insulin resistance will be discussed. Further, we propose that modulation of HIF-1 could be a potential novel therapeutic strategy for antidiabetic treatment.