Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance.

S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of IRS-1 function. This effect can be triggered directly by nutrients such as amino acids or by insulin through a homeostatic negative-feedback loop. However, the role of S6K1 in mediating IRS-1 phosphorylation in a physiological setting of nutrient overload is unresolved. Here we show that S6K1 directly phosphorylates IRS-1 Ser-1101 in vitro in the C-terminal domain of the protein and that mutation of this site largely blocks the ability of amino acids to suppress IRS-1 tyrosine and Akt phosphorylation. Consistent with this finding, phosphorylation of IRS-1 Ser-1101 is increased in the liver of obese db/db and wild-type, but not S6K1(-/-), mice maintained on a high-fat diet and is blocked by siRNA knockdown of S6K1 protein. Finally, infusion of amino acids in humans leads to the concomitant activation of S6K1, phosphorylation of IRS-1 Ser-1101, a reduction in IRS-1 function, and insulin resistance in skeletal muscle. These findings indicate that nutrient- and hormonal-dependent activation of S6K1 causes insulin resistance in mice and humans, in part, by mediating IRS-1 Ser-1101 phosphorylation.

Immune alterations in mice exposed to the herbicide simazine.

Simazine, a triazine herbicide, was investigated for its in vivo immunomodulatory properties. Male C57Bl/6 mice were treated with vehicle or 300 or 600 mg/kg body weight (bw) simazine daily orally for 4 wk. The immune system was evaluated by the antibody response to sheep red blood cells (SRBC; plaque assay and serum immunoglobulin G), natural killer (NK) and macro-phage activities, lymphocyte subpopulations in the spleen and thymus, and concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated lymphocyte proliferation using splenocytes. Body weight and spleen and thymus weight decreased generally in simazine-treated mice, while the weight of adrenal glands was higher than in the control. Simazine treatment (600 mg/kg) induced an increase in the percentage of CD4(+) cells in spleen and CD8 + in thymus. Simazine inhibited the IgM plaque-forming cell numbers and lowered the level of IgG and the proliferation of mitogen-stimulated B cells and T cells. In addition, splenic NK and peritoneal macrophage activities in exposed mice were significantly decreased. Exposure to simazine also decreased cytokine production by macrophages, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Taken together, data indicate that the immune system was suppressed by oral simazine exposure.