Role for hypoxia-inducible factor-1a in Oncostatin-induced adaptations in adipocytes during normoxia

Obesity is characterized by chronic, low-grade inflammation that leads to insulin resistance and metabolic syndrome. It is well accepted that the expansion of adipose tissue leads to a state of relative hypoxia that is associated with inflammation and adipocyte dysfunction. While numerous studies have established hypoxia-inducible factor-1??(HIF-1?) as a critical transcription factor for metabolic adaptation during low oxygen conditions, less is known about the regulation and functionality of HIF-1?induced by inflammation under normoxic conditions. Data presented in this dissertation demonstrated that HIF-1??is induced by the inflammatory cytokine Oncostatin M (OSM) in 3T3-L1 adipocytes during normoxia. The induction of HIF-1??by OSM was regulated at the level of transcription and dependent on ERK and AKT signaling pathways. Furthermore, data show that HIF-1??was responsible for metabolic and vasculature adaptations, such as increased glycolytic gene expression, glucose uptake, lactate production and angiogenic gene expression induced by OSM. We further demonstrated that OSM contributes to adipose tissue remodeling by reducing cell growth and inhibiting adipogenesis. Specifically, OSM inhibited differentiation during mitotic clonal expansion (MCE) and prevented the induction of peroxisome proliferator-activated receptor ??(PPAR?), CCAAT/enhancer-binding protein ??(C/EBP?), adipocyte protein 2 (aP2) and adiponectin (ADPN). As MCE is characterized by several rounds of cell cycle, examination of cyclins revealed that OSM dramatically reduced cyclin D1. Furthermore, HIF-1??knockdown partially restored PPAR?, C/EBP?, aP2 and cyclin D1, suggesting that HIF-1??is a mediator of the inhibition of cell growth and differentiation by OSM. Data also show that the addition of hypoxia-mimetic, CoCl2 and OSM led to a synergistic effect on HIF-1?, which suggests that the hypoxia and inflammation implicated during obesity may magnify the effect on downstream targets of HIF-1?. These data demonstrate an essential role for HIF-1??in the effect of OSM on adaptations in adipocytes during normoxia. Collectively, the findings presented here provide insight into the molecular mechanisms by which hypoxia and inflammation contribute to metabolic adaptation and adipose tissue remodeling