Visceral adipose tissue inflammation accelerates atherosclerosis in apolipoprotein E-deficient mice

Abstract

Background: Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis.

Methods and results: To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient (Lep(ob/ob)) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lep(ob/ob) mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E-deficient ApoE(-/-) mice. Plasma from ApoE(-/-) mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE(-/-) mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE(-/-) mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation.

Conclusions: Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.

Figure 1

Transplanted adipose tissue displays signs of inflammation. A, Macrophages surrounding adipocyte (arrow). B, Macrophages have formed multinucleated giant cells (arrow). Staining with Mac-3; magnification ×40; scale bar=20 µm.

Figure 2

Effect of inflammatory fat on atherosclerosis in ApoE^−/− mice. Representative en face view of aortic tree stained with Oil Red O of sham-operated (A) and fat-transplanted (B) ApoE^−/− mouse. C, Fat-transplanted ApoE^−/− mice (n=6, black bar) had significantly more atherosclerotic lesions than sham-operated (n=6, white bar) mice (P=0.03). All the mice were 46 to 48 weeks old at euthanasia.

Figure 3

Effect of pioglitazone on MCP-1, fat inflammation, atherosclerosis, and IL-10 in transplanted and control mice. A, Plasma MCP-1 levels in control (n=4, white bar) and pioglitazone-treated (n=3, black bar) mice 10 weeks postoperatively (P=0.03). All values were normalized to the average of pioglitazone-treated mice. B, IL-10 levels in transplanted fat of control (n=4, white bar) and pioglitazone-treated (n=3, black bar) ApoE^−/− mice (P=0.003). C, Macrophage content of transplanted fat in control (n=4, white bar) and pioglitazone-treated (n=3, black bar) ApoE^−/− mice (P=0.03). D, Atherosclerotic lesion area in control (n=4, white bar) and pioglitazone-treated (n=3, black bar) ApoE^−/− mice (P=0.02). All the mice were 20 weeks old at euthanasia.

Figure 4

Subcutaneous adipose tissue transplants displayed signs of chronic inflammation such as crown-like structures (arrow) similar to those of visceral transplants. Staining with Mac-3; magnification ×40; scale bar=20 µm.