Abstract 15348: CD40 Deficiency Aggravates Diet-Induced Obesity, Adipose Tissue Inflammation, and Insulin Resistance in Mice
Background: Infiltration of immune cells, such as T-cell subsets, is a hallmark of adipose tissue inflammation and the metabolic syndrome. T-cell functioning potently depends on co-stimulatory pathways, such as the CD40L-CD40 dyad. CD40 has recently been shown to be associated with obesity and insulin resistance. Here, we tested the hypothesis that genetic deficiency of CD40 directly modulates diet-induced obesity (DIO) in vivo.
Methods and Results: WT or CD40-/- mice consumed either a low fat diet (LFD) or a high fat diet (HFD) for 20 weeks (n>15 per group). Surprisingly, CD40-/- mice consuming HFD exhibited an aggravated metabolic phenotype with increased weight gain and enhanced fat depositions as assessed by MRI. CD40 deficiency increased accumulation of inflammatory cells in adipose tissue particularily of adipose tissue M1 macrophages and CD8+ T-cells. Gene expression analysis revealed upregulation of >350 genes in visceral fat pads of CD40-/- mice, including pro-inflammatory gene sets, such as matrix-metalloproteases, chemokines, and macrophage and T-cell signaling adapters. Moreover, CD40-deficient mice developed aggravated systemic and peripheral insulin resistance as shown by euglycemic-hyperinsulinemic clamp analysis. Also, CD40-/- mice had increased levels of low density lipoproteins (LDL) and accumulated cholesterol in the liver. Additionally, histological analysis revealed signs of worsened liver steatosis, such as increased vacuole formation and lipid depositions. Systemically, plasma levels of the adipokines IL-6 and TNFα showed no regulation in HFD-consuming animals while being reduced in CD40-/- mice consuming LFD. Interestingly, CD40 deficiency in mice consuming standard diet protected from DIO, adipose tissue inflammation, and liver steatosis, suggesting a switch in the inflammatory and metabolic properties of CD40-signaling induced by DIO.
Conclusion: We present the surprising finding that CD40 deficiency aggravates adipose tissue inflammation and the metabolic syndrome in vivo while inducing a protective phenotype in CD40-/- mice consuming standard diet. These findings identify co-stimulatory signaling cascades, such as CD40, as potential link between inflammation and metabolic disease.
- © 2011 by American Heart Association, Inc.