We show that NF-κB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-κB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-β in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1β and TNF-α, was increased in LIKK mice to a similar extent as induced by HFD in in wildtype mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-β. Hepatic expression of the IκBα superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-κB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.Obesity is increasingly prevalent and strongly associated with the development of insulin resistance 1 , an underlying feature of both type 2 diabetes (T2D) and the metabolic syndrome 2 . Although epidemiological correlations are established, the cellular and molecular mechanisms that link obesity and insulin resistance are unknown. Increased adiposity is associated with lipid accumulation in other tissues, including muscle (intramyocellular lipid) and liver (hepatic steatosis), which has made it that much more difficult to pinpoint the primary sites responsible for initiating insulin resistance 3 . Fat accumulation in the visceral depot and liver are strongly correlated, and both are highly correlated with the development and severity of insulin resistance 4-6 .Growing evidence links a chronic, subacute inflammatory state to the development of obesity and the coexisting conditions of insulin resistance, T2D and the metabolic syndrome. Epidemiologists have consistently found elevations in markers and potential mediators of inflammation and the acute-phase response 7,8 , suggesting that low-grade inflammation precedes and predicts the development of T2D 9 . Proinflammatory cytokines can cause insulin resistance 10,11 and anti-inflammatory medications may reverse it 12,13 , suggesting that inflammation may be directly involved in its pathogenesis. Markers and mediators of inflammation that are biosynthesized in liver include CRP, PAI-1, fibrinogen and IL-6, suggesting that 'subacute inflammation' in liver, secondary to steatosis, might be involved in the development of insulin resistance, T2D and the metabolic syndrome. Because visceral adiposity and hepatic steatosis are etiologically and functionally intertwined, and both might be associated with subacute inflammation, we took a transgenic approa...

Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.