The Protein Kinase IKKɛ Regulates Energy Balance in Obese Mice

Abstract

Summary Obesity is associated with chronic low-grade inflammation that negatively impacts insulin sensitivity. Here we show that high fat diet can increase NFκB activation in mice, which leads to a sustained elevation in level of IκB kinase ε (IKKε) in liver, adipocytes and adipose tissue macrophages. IKKε knockout mice are protected from high fat diet-induced obesity, chronic inflammation in liver and fat, hepatic steatosis and whole-body insulin resistance. These mice show increased energy expenditure and thermogenesis via enhanced expression of the uncoupling protein UCP-1. They maintain insulin sensitivity in liver and fat, without activation of the proinflammatory JNK pathway. Gene expression analyses indicate that IKKε knockout reduces expression of inflammatory cytokines, and changes expression of certain regulatory proteins and enzymes involved in glucose and lipid metabolism. Thus, IKKε may represent an attractive new therapeutic target for obesity, insulin resistance, diabetes and other complications associated with these disorders.

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

“…There is growing evidence that the acquisition of brown-like fat cells in WAT protects against both genetic and diet-induced obesity through increased metabolic activity, and this "browning" phenomenon has become a subject of considerable interest for possible treatment of obesity and metabolic syndrome (68 -70). Browning of WAT has been shown to occur in mouse models of prolactin receptor deficiency, IkB kinase ⑀ deficiency, COXII overexpression, and increased prostaglandin synthesis (71)(72)(73)(74). In these instances, mice displayed a protection against diet-induced obesity as well as increased oxygen consumption.…”

IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity

“…To explore this observation further, we examined the expression of NF-κB target genes in WAT because decrease in adipose tissue inflammation has been shown to increase energy expenditure and decrease weight gain on a HFD (31). Consistent with the antiinflammatory effects of IL-4 in WAT macrophages (21), expression of IκB kinase ε (Ikbke), Rela and other NF-κB target genes, such as Tnf, Nos2, and Ccl2, was reduced by 50% to 80% in WAT of IL-4-treated mice (Fig.…”

Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet

“…Animal models of type 2 diabetes also show increased expression of inflammatory markers specific for cytokines, chemokines and immune cells in both insulin-responsive tissues (liver, muscle, adipose tissue) and pancreatic islets [3,[8][9][10][11]. This local tissue inflammation has now been causally linked to insulin resistance and beta cell function in a number of genetic knockout models and therapeutic intervention studies [3,11].…”