Type 1 diabetes (T1D) is characterized by loss of blood glucose control due to autoimmune attack of insulin secreting [beta] cells within the pancreatic islet. During the immunologic response, proinflammatory cytokines are secreted by immune cells and contribute to [beta] cell loss. Interferon gamma (IFN[gamma]) is an anti-viral cytokine with proinflammatory and immunomodulatory effects, and elicits pleiotropic impacts on [beta] cell function. Current studies have demonstrated a novel role of fatty acid (FA) and cholesterol metabolism in host cell defense against infection. In addition, IFNs have been shown to alter immune cell lipid metabolism that is directly link to activation of immune responses. Currently, there is a lack of understanding of the role of IFN[gamma] on [beta] cell lipid metabolism and whether it is associated with IFN[gamma]-mediated effects on [beta] cell function. Here, in vivo study in a T1D-susceptible model (LEW.1WR1 rats) showed that induction of islets autoimmunity with viral mimetic resulted in elevated and sustained IFN[gamma] signaling, concomitant with a significant increase of triacylglyceride (TAG) levels in pancreatic islets. The effects of IFN[gamma] on lipid metabolism therefore was examined in [beta] cell line INS-1. Treatment of INS-1 cells with IFN[gamma] led to a dynamic change in TAG levels and lipid droplets (LD): a decrease at 6 h and an increase at 24 h in TAG levels and LD numbers. Gene expression results suggested that IFN[gamma] transiently induces lipolysis, followed by upregulation of de novo lipogenesis (DNL). Importantly, IFN[gamma] potentiated anti-viral gene expression stimulated by viral mimetic, and pharmacological inhibition of DNL abrogated this priming effect by IFN[gamma], suggesting that IFN[gamma]-induced DNL is important for host defense against infection. Intracellular TAG/FA cycling plays a central role in [beta] cell insulin secretion, mitochondrial and endoplasmic reticulum (ER) homeostasis. Consistent with transient lipolysis and late DNL, IFN[gamma] upregulated mitochondrial FA oxidation genes, however 24 h exposure to IFN[gamma] led to accumulation of acyl carnitines, suggesting FA overload and limited FA oxidation. IFN[gamma] had minimal impact on glucose oxidation, mitochondrial biogenesis and glucose-stimulated insulin secretion. The IFN[gamma]-induced TAG accumulation at 24 h was insufficient to cause unfolded protein response but increased susceptibility to ER stress induced by interleukin-1[beta] (IL-1[beta]) or tumor necrosis factor [alpha] (TNF[alpha]). These data suggest that IFN[gamma] enhances DNL for host cell defense in the expense of decreased FA oxidation, and increased risk of cellular stress. Many cytokines exert their classical biological effects via activation of Janus kinases (JAK) and phosphorylation of Signal Transducer and Activator of Transcription (STAT). IFN[gamma] was shown to regulate lipid metabolism genes in a unique manner compared to type 1 IFN and other inflammatory cytokines, and dependent on signaling through JAK1/2. STAT3 was shown to mediate IFN[gamma]-induced transient lipolysis, however, multiple JAKs/STATs and unphosphorylated STATs could be involved in the constitutive and IFN[gamma]-stimulated expression of genes involved in lipid metabolism in [beta] cells. In conclusion, this work demonstrates that IFN[gamma] regulates pancreatic [beta] cell lipid metabolism in a dynamic manner that is intimately linked to host defense and cellular function. These findings indicate complex physiological and pathological roles of IFN[gamma] in modulating [beta] cell function, and provide better insight into the mechanism of actions of proinflammatory cytokines in T1D. Targeting lipid metabolism may thus be potential to modulate the effects of proinflammatory cytokines for the prevention and treatment of T1D as well as other inflammatory diseases.
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