In summary, we show that normalization of IL-1Ra improves insulin sensitivity in obese, insulin resistant mice. This mechanism is independent of the classical IL-1R1 Betaxolol HCl signaling and we hypothesize that at high concentrations, as observed in chronic obesity, IL-1Ra also binds to another, yet to be identified, receptor and drives the development of hepatic insulin resistance. These findings have important consequences in current and future antiinflammatory approaches in the treatment of Type 2 diabetes. Tumor Necrosis Factor alpha is a pleiotropic cytokine extensively studied for its role in the pathogenesis of a variety of disease conditions, which is known to have a wide range of beneficial and deleterious effects in humans. TNFa is Bitopertin produced by a variety of cells which include: macrophages, monocytes, lymphocytes, NK cells, eosinophils, keratinocytes, langerhan cells, kupffer cells, glial cells, adipocytes and fibroblasts. This cytokine is known to be produced in response to a wide range of stimuli such as, bacterial toxins ; infections ; antigen-antibody complexes; injury; host inflammatory agents ; as well as toxic and non-toxic environmental challenges. TNFa elicits a wide spectrum of cellular responses which mediates inflammation, regulates immune response and also induces apoptosis in certain types of cancer cells. Appropriate levels of TNFa are necessary for homeostatic functions like protection from infection, haematopoiesis, immune response regulation, cellular growth in wound healing, tumor regression and immune surveillance. In contrast, dysregulation in TNFa production or signaling has been associated with a wide range of inflammatory disorders, ranging from sepsis to anaphylaxis to autoimmune diseases. TNFa mediates its inflammatory functions by inducing the production of various proinflammatory cytokines and chemokines, activation of leukocytes and lymphocytes, inducing vascular permeability, enhancing the expression of adhesion molecules in immune cells as well as in the vascular endothelium, and promoting inflammatory cell migration, proliferation and differentiation.