Beneficial effects of IKKε-deficiency on body weight and insulin sensitivity are lost in high fat diet-induced obesity in mice.

Activation of the classical IκB kinases (IKKα and IKKß) was previously shown to contribute to obesity-induced inflammation and insulin resistance. Using knockout mice, we investigated whether the related isoform IKKε plays a similar metabolic role. IKKε(-/-) mice had reduced body weight, leptin levels, as well as higher insulin sensitivity when kept on chow diet. However, inflammatory parameters, measured in liver, adipose tissue and plasma, were either unaltered or showed a trend toward up-regulation (liver NF-κB activity, TNFα and IL-1ß expression). Chronic feeding of a high fat diet induced equal obesity and insulin resistance, and similarly induced inflammatory markers, in IKKε(-/-) and wild-type mice, indicating that under high caloric conditions the inflammatory and metabolic effects of IKKε deficiency were overridden. Taken together, our data indicate that IKKε does not have general pro-inflammatory properties in liver and adipose tissue, and suggest that reduced adiposity is the primary mechanism for improved insulin sensitivity in IKKε(-/-) mice on chow diet.

Acute-phase serum amyloid A as a marker of insulin resistance in mice.

Acute-phase serum amyloid A (A-SAA) was shown recently to correlate with obesity and insulin resistance in humans. However, the mechanisms linking obesity-associated inflammation and elevated plasma A-SAA to insulin resistance are poorly understood. Using high-fat diet- (HFD-) fed mice, we found that plasma A-SAA was increased early upon HFD feeding and was tightly associated with systemic insulin resistance. Plasma A-SAA elevation was due to induction of Saa1 and Saa2 expression in liver but not in adipose tissue. In adipose tissue Saa3 was the predominant isoform and the earliest inflammatory marker induced, suggesting it is important for initiation of adipose tissue inflammation. To assess the potential impact of A-SAA on adipose tissue insulin resistance, we treated 3T3-L1 adipocytes with recombinant A-SAA. Intriguingly, physiological levels of A-SAA caused alterations in gene expression closely resembling those observed in HFD-fed mice. Proinflammatory genes (Ccl2, Saa3) were induced while genes critical for insulin sensitivity (Irs1, Adipoq, Glut4) were down-regulated. Our data identify HFD-fed mice as a suitable model to study A-SAA as a biomarker and a novel possible mediator of insulin resistance.