Abstract 466: Role of Janus Kinases and Signal Transducers and Activators of Transcription in Interferon-gamma--Induced Insulin Resistance in Human Adipocytes

Abstract

Obesity induces chronic low-grade inflammation of the adipose tissue, accompanied by an infiltration of cytokine-secreting immune cells, driving adipose and systemic insulin resistance. Circulating levels of interferon-gamma (IFNγ) in obesity correlate with increased adiposity and insulin resistance. Furthermore, IFNγ inhibits insulin signaling in adipocytes. IFNγ receptors signal via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, but the specific molecules involved with IFNγ signaling in adipocytes have not been determined. Based on pharmacological data, we hypothesized that JAK1 and STAT1, but not JAK2 and STAT3 would mediate IFNγ signaling in human adipocytes. To test this hypothesis we developed lentivirus-delivered shRNA against JAK1, JAK2, STAT1, and STAT3. Knockdown of JAK1, JAK2, and STAT1 in adipocytes with shRNA significantly inhibited IFNγ-induced suppressor of cytokine signaling (SOCS)1 and SOCS3 expression. IFNγ downregulated insulin-signaling related gene (insulin receptor substrate-1, insulin receptor, and glucose transporter-4), and adipogenic gene (adiponectin, fatty acid synthase, lipoprotein lipase, perilipin, and peroxisome proliferator-activated receptor gamma) expression. JAK1, JAK2, and STAT1 shRNA attenuated IFNγ-induced downregulation of insulin signaling related and adipogenic gene expression, whereas STAT3 shRNA had no significant effect. These findings suggest that, in adipocytes, JAK1 and JAK2 as well as STAT1, but not STAT3, contribute to IFNγ signaling and the subsequent decrease in insulin sensitivity. Understanding the molecular mechanisms by which inflammation induces adipose insulin resistance may identify pathways for therapeutic treatment or prevention of obesity induced insulin resistance and diabetes.