96 - Monocytic Glutaredoxin 1 Protects Mice against Obesity, Hyperglycemia and Atherosclerosis

Abstract

We previously reported that glutaredoxin 1 (Grx1) protects monocytes from metabolic-stress induced priming, dysregulation and hypersensitization to chemokines. To address the role of monocytic Grx1 in mice and in the development of atherogenesis and obesity, we transplanted bone marrow (BM) from either wild-type (WT) or Grx1-/- (Grx1Leuko -/-) donor mice into atherosclerosis-prone LDLR-/- mice and fed these mice a high-fat diet (HFD) for up to 20 weeks. Grx1Leuko -/- mice showed accelerated weight gain after 9 weeks followed by early onset of hyperglycemia. After 6 weeks on HFD, atherosclerotic lesions were slightly larger in Grx1Leuko -/- mice than in WT, but the differences did not reach statistical significance. However, after 20 weeks, Grx1Leuko -/- mice showed 36% larger lesions than WT-BM recipients, and monocyte chemotaxis in vivo was increased 1.6-fold. Furthermore, compared to WT-BM recipients, adipose tissues and livers of Grx1Leuko -/- mice also showed increased macrophage content and elevated tissue inflammation as determined by IHC and qRT-PCR. Adipose tissue in particular, showed significant increases in the expression of proinflammatory genes in addition to an increased abundance proinflammatory “crown-like” structures. Gene expression analysis by qRT-PCR of peritoneal macrophages revealed that macrophages isolated from Grx1-/- mice also have increased expression of pro-inflammatory M1-associated genes and decreased M2-associated genes after activation with INFγ+TNFα and IL-4 respectively. Additionally, macrophages from Grx1-/- mice exposed to metabolic stress also display increased protein-S-glutathionylation, enhanced hypersensitization to chemokine, and impaired autophagy compared to wild-type cells. Taken together, our data show that loss of monocytic Grx1 worsens monocyte priming and accelerates the infiltration of dysfunctional monocyte-derived macrophages into tissues, such as aorta, liver and adipose tissues. We conclude that monocytic Grx1 is critical for maintaining metabolic homeostasis in mice and protects against obesity and atherosclerosis.