Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-α in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice

Abstract

Deficiency of ACE2 in macrophages has been suggested to promote the development of an inflammatory M1 macrophage phenotype. We evaluated effects of ACE2 deficiency in bone-marrow-derived stem cells on adipose inflammation and glucose tolerance in C57BL/6 mice fed a high fat (HF) diet. ACE2 activity was increased in the stromal vascular fraction (SVF) isolated from visceral, but not subcutaneous adipose tissue of HF-fed mice. Deficiency of ACE2 in bone marrow cells significantly increased mRNA abundance of F4/80 and TNF-α in the SVF isolated from visceral adipose tissue of HF-fed chimeric mice, supporting increased presence of inflammatory macrophages in adipose tissue. Moreover, deficiency of ACE2 in bone marrow cells modestly augmented glucose intolerance in HF-fed chimeric mice and increased blood levels of glycosylated hemoglobin. In summary, ACE2 deficiency in bone marrow cells promotes inflammation in adipose tissue and augments obesity-induced glucose intolerance.

Figure 1

ACE2 activity is increased in the stromal vascular fraction (SVF) isolated from visceral adipose tissue of HF-fed C57BL/6 mice. ACE2 activity was quantified in mouse peritoneal macrophages (MPMs), bone marrow (BM), and SVF isolated from epididymal (EF), retroperitoneal (RPF) or subcutaneous (SubQ) adipose tissue from LF or HF-fed mice. Data are mean ± SEM from N = 3-4 mice/diet group. *: P < 0.05 compared to LF.

Figure 2

Bone marrow deficiency of ACE2 increases F4/80 and TNF-α mRNA abundance in the stromal vascular fraction (SVF) isolated from visceral adipose tissue of HF-fed C57BL/6 mice. Quantification of mRNA abundance in the SVF isolated from epididymal adipose (EF, a), retroperitoneal adipose (RPF, b), or subcutaneous fat (SubQ, c) of chimeric mice transplanted with Ace2^+/y (depicted on the x-axis as +) or ^−/y (depicted on the x-axis as−) bone marrow. Data are mean ±  SEM from N = 3–11 mice/donor genotype. *: P < 0.05 compared to +.

Figure 3

Bone marrow deficiency of ACE2 augments glucose intolerance at specific time points following glucose injection in HF-fed C57BL/6 mice. (a) Glucose tolerance tests (GTT) in HF-fed chimeric mice transplanted with bone marrow from Ace2^+/y or ^−/y mice. (b) Percent glycosylated hemoglobin levels and plasma insulin concentrations (c) in Ace2^+/y and ^−/y chimeric mice. Data are mean ± SEM from N = 8–15  mice/donor genotype. *: P < 0.05 compared to Ace2^+/y.