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Insulin resistance contributes importantly to the pathophysiology of type 2 diabetes mellitus. One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor B kinase (IKK) complex. However, the precise molecular mechanisms by which IKK may contribute to the development of insulin resistance are not well understood. In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser 307 (equivalent to Ser 312 in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-␣ or calyculin A treatment that paralleled surrogate markers for IKK activation. The phosphorylation of human IRS-1 at Ser 312 in response to tumor necrosis factor-␣ was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J 2 as well as in cells derived from IKK knock-out mice. We observed interactions between endogenous IRS-1 and IKK in intact cells using a co-immunoprecipitation approach. Moreover, this interaction between IRS-1 and IKK in the basal state was reduced upon IKK activation and increased serine phosphorylation of IRS-1. Data from in vitro kinase assays using recombinant IRS-1 as a substrate were consistent with the ability of IRS-1 to function as a direct substrate for IKK with multiple serine phosphorylation sites in addition to Ser 312 . Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser 312 (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.Many factors implicated in the development of insulin resistance such as TNF-␣ 1 (1, 2), free fatty acids (3, 4), and serine phosphatase inhibitors (5, 6) are able to activate the inhibitor B kinase (IKK) complex and its downstream effector, NFB (7-10). Interestingly, insulin-sensitizing drugs such as thiazolidinediones inhibit NFB activity (11). Adiponectin, a cytokine secreted by adipose cells whose plasma levels are negatively correlated with insulin resistance (12), inhibits IKK activity in cells (13). Moreover, diet-induced insulin resistance is ameliorated in IKK2-deficient mice (14). Because IKK and NFB are major components of the intracellular inflammatory pathway, a cross-talk between metabolic and inflammatory signaling pathways may play an important role in the development of insulin resistance and the pathophysiology of major public health problems such as diabetes and obesity. However, molecular mechanisms by which IKK may specifically interact with metabolic insulin signaling pathways are not well understood. IKK is a serine kinase that controls the activation of NFB, a ubiquitous transcription factor closely associated with inflammation (15-18). In addition to inflammation, NF...

of exercise. Obesity. 2006;14:345-356. Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.

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