This study investigates the role of hepatic inflammation in the development of insulin resistance, a key feature of type 2 diabetes (T2D) and metabolic syndrome. The authors show that obesity and high-fat diet (HFD) activate NF-κB and its transcriptional targets in the liver, leading to chronic, subacute inflammation. To mimic this state without obesity or steatosis, they created transgenic mice (LIKK) with constitutively active IKK-β expressed in hepatocytes. These mice exhibit severe hepatic insulin resistance and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, is increased in LIKK mice, similar to the effects of HFD in wild-type mice. Insulin resistance in LIKK mice can be improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-β. Additionally, expressing the IκBα superrepressor in the liver (LISR) reversed the insulin resistance phenotype in both LIKK mice and wild-type mice fed an HFD. These findings suggest that lipid accumulation in the liver leads to subacute hepatic inflammation through NF-κB activation and downstream cytokine production, causing both local hepatic and systemic insulin resistance. The study provides insights into the molecular mechanisms linking obesity and insulin resistance and identifies potential therapeutic targets.This study investigates the role of hepatic inflammation in the development of insulin resistance, a key feature of type 2 diabetes (T2D) and metabolic syndrome. The authors show that obesity and high-fat diet (HFD) activate NF-κB and its transcriptional targets in the liver, leading to chronic, subacute inflammation. To mimic this state without obesity or steatosis, they created transgenic mice (LIKK) with constitutively active IKK-β expressed in hepatocytes. These mice exhibit severe hepatic insulin resistance and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, is increased in LIKK mice, similar to the effects of HFD in wild-type mice. Insulin resistance in LIKK mice can be improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-β. Additionally, expressing the IκBα superrepressor in the liver (LISR) reversed the insulin resistance phenotype in both LIKK mice and wild-type mice fed an HFD. These findings suggest that lipid accumulation in the liver leads to subacute hepatic inflammation through NF-κB activation and downstream cytokine production, causing both local hepatic and systemic insulin resistance. The study provides insights into the molecular mechanisms linking obesity and insulin resistance and identifies potential therapeutic targets.