P65 inactivation in adipocytes and macrophages attenuates adipose inflammatory response in lean but not in obese mice

Abstract

NF-κB induces transcriptional expression of proinflammatory genes and antiapoptotic genes. The two activities of NF-κB remain to be characterized in the mechanism of chronic inflammation in obesity. To address this issue, we inactivated NF-κB in adipose tissue by knocking out p65 (RelA) in mice (F-p65-KO) and examined the inflammation in lean and obese conditions. In the lean condition, KO mice exhibited a reduced inflammation in adipose tissue with a decrease in macrophage infiltration, M1 polarization, and proinflammatory cytokine expression. In the obese condition, KO mice had elevated inflammation with more macrophage infiltration, M1 polarization, and cytokine expression. In the mechanism of enhanced inflammation, adipocytes and macrophages exhibited an increase in cellular apoptosis, which was observed with more formation of crown-like structures (CLS) in fat tissue of KO mice. Body weight, glucose metabolism, and insulin sensitivity were not significantly altered in KO mice under the lean and obese conditions. A modest but significant reduction in body fat mass was observed in KO mice on HFD with an elevation in energy expenditure. The data suggest that in the control of adipose inflammation, NF-κB exhibits different activities in the lean vs. obese condition. NF-κB is required for expression of proinflammatory genes in the lean but not in the obese condition. NF-κB is required for inhibition of apoptosis in the obese condition, in which proinflammation is enhanced by NF-κB inactivation.

IRF3 promotes adipose inflammation and insulin resistance and represses browning

“…Ablation of p65, the major active subunit of NF-κB, using an aP2-driven Cre transgene causes reduced adipose inflammation in the lean state, but greater inflammatory markers upon high-fat feeding. No change in insulin sensitivity was noted between these knockout mice and controls on high-fat diet (13). Similarly, p65 overexpression in adipocytes induces browning of white fat, which promotes insulin sensitivity, not insulin resistance (15).…”

“…Upon phosphorylation by IKK-β, IκB is degraded, allowing NF-κB to translocate to the nucleus and bind to its target genes. On the basis of inference from studies in immune cells, NF-κB has been supposed to be the major transcriptional driver of inflammation in the adipocyte, although this has never been directly proven, and is in fact controverted by several studies (11)(12)(13)(14)(15). We thus raise the question: how are proinflammatory signals transduced into altered gene expression of inflammatory markers, and which transcription factors mediate the enhanced inflammatory state of adipose tissue in the setting of obesity?…”

Quercus infectoria inhibits Set7/NF-κB inflammatory pathway in macrophages exposed to a diabetic environment

“…The NF-κB pathway plays crucial roles in inflammatory responses by regulating transcription of inflammatory genes [22]. Since Qi extract reduced expression of inflammatory cytokines, we tested whether Qi also inhibited the NF-κB pathway.…”

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

“…LoxP p65 mice were generated on a C57BL/6 gene background as described elsewhere (10). Alb-cre mice on the C57BL/6 genetic background (stock number 003574) were purchased from The Jackson Laboratory (Bar Harbor, ME).…”