Uncoupling of Inflammation and Insulin Resistance by NF-κB in Transgenic Mice through Elevated Energy Expenditure

Abstract

To study the metabolic activity of NF-B, we investigated phenotypes of two different mouse models with elevated NF-B activities. The transcriptional activity of NF-B is enhanced either by overexpression of NF-B p65 (RelA) in aP2-p65 mice or inactivation of NF-B p50 (NF-B1) through gene knock-out. In these models, energy expenditure was elevated in day and night time without a change in locomotion. The mice were resistant to adulthood obesity and diet-induced obesity without reduction in food intake. The adipose tissue growth and adipogenesis were inhibited by the elevated NF-B activity. Peroxisome proliferator-activator receptor ␥ expression was reduced by NF-B at the transcriptional level. The two models exhibited elevated inflammatory cytokines (tumor necrosis factor-␣ and interleukin-6) in adipose tissue and serum. However, insulin sensitivity was not reduced by the inflammation in the mice on a chow diet. On a high fat diet, the mice were protected from insulin resistance. The glucose infusion rate was increased more than 30% in the hyperinsulinemic-euglycemic clamp test. Our data suggest that the transcription factor NF-B promotes energy expenditure and inhibits adipose tissue growth. The two effects lead to prevention of adulthood obesity and dietary obesity. The energy expenditure may lead to disassociation of inflammation with insulin resistance. The study indicates that inflammation may prevent insulin resistance by eliminating lipid accumulation.The IKK␤ 2 /NF-B signaling pathway plays an important role in the control of inflammation, apoptosis, carcinogenesis, and oxidative stress (1). In this pathway, the serine kinase IKK␤ (IKK2) activates the transcription factor NF-B through phosphorylation of NF-B inhibitor (IB␣). In obesity research, the metabolic activity of IKK␤ was tested in the control of insulin sensitivity (2-4) or food intake in transgenic mice (5). In these studies, the IKK␤ activity was modified either globally or tissuespecifically in several major tissues/organs, such as the liver (3, 4), skeletal muscle (6), and brain (5). In these studies, the role of IKK␤ in the regulation of energy expenditure and adipose tissue growth was not examined. Although IKK␤ and NF-B activities are parallel in most cases, their activities are not identical (7). IKK␤ has NF-B-independent activities (7, 8). We investigated the metabolic activity of NF-B using the NF-B transgenic mice in the current study.NF-B activation is associated with energy expenditure in cachexia (9, 10). However, the cause/effect relationship has not been tested for NF-B/energy expenditure in transgenic models. NF-B is a transcription factor that regulates expression of a broad spectrum of genes. Its activity is found in many types of cells, including adipocytes and macrophages (1, 11). The common form of NF-B contains two subunits: p65 (RelA) and p50 (NF-B1). p65 contains the transactivation domain and mediates transcriptional activation of target genes. p50 usually inhibits the transcriptional activity of p65 (12), and the inhibiti...

Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway

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Regulation of energy balance by inflammation: Common theme in physiology and pathology

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