Why Browning of White Adipocytes in Fat Grafts Correspond to Increased Inflammation

With great interest we read the article by Liu et al entitled “Browning of White Adipocytes in Fat Grafts Associated With Higher Level of Necrosis and Type 2 Macrophages Recruitment.” ¹ This in vivo study with a murine model for fat grafting was performed to confirm the browning of white adipocytes in fat grafts and its association with inflammation and necrosis. Qiu et al showed in their study the evidence of a switch from white to beige fat after fat grafting in an animal model, and this study by Liu et al expands on previous knowledge from the point of inflammation.² The authors found the browning process of white adipocytes after fat grafting with a large volume, which was associated with increased M2 inflammatory response and fat necrosis.

In Figure 1, we could see UCP1+ beige cells with multiple lipid drops located in the center of fat graft, whereas Qiu et al found beige adipocytes in the peripheral region of the grafts, with more CD31+ endothelial cells compared with the central zone.² The mechanism of browning may be different in these 2 studies, and further study is needed.

In this study, 0.1 mL and 0.5 mL of fat grafts were injected subcutaneously on the back of mice in bolus, because the 0.5-mL group was considered a large volume. The authors found more browning adipocytes and higher levels of inflammation and necrosis in the 0.5-mL group compared with the 0.1-mL group. However, 0.5 mL of fat injection in bolus is rarely employed clinically because the “3-zone” theory indicated that adipocytes in the surviving zone were located 100 to 300 μm from the surface and those in the regenerating zone were 300 to 1500 μm from the periphery, whereas adipocytes far from the distance died eventually.³ Khouri and Khouri recommended that 1 mL of fat injection should be performed at the length of 10 cm along a retraction cylinder for enough contact area with the recipient site.⁴ For the animal study, Kokai et al⁵ recommended a volume of 0.3 mL in bolus for the optimization and standardization of assessing fat grafting outcomes in the murine model. Therefore, the clinical transformation of this study is doubtful.

In the Results section, the authors stated that increased beige adipocytes of grafts origin were correlated with necrosis in fat grafts. Based on the authors’ description, we tend to speculate that the browner compositions lead to increased inflammation and necrosis of the graft. However, the authors did not provide the volume retention and the level of vascularization in the grafts of the 2 groups. Moreover, the authors mentioned PLN1 immunostaining in the Methods section, but we did not find the corresponding results. Although there were more necrotic components in the 0.5-mL group than in the 0.1-mL group, we did not know whether the 0.5-mL group also survived more than the 0.1-mL group. Beige adipocytes are regenerated components that did not exist in the fat particles before grafting. Thus, the presence of beige adipocytes may also promote graft survival and volume retention. We tend to think that a larger volume of fat injection leads to higher volume retention, because we can infer that beige adipocytes are associated with higher volume retention. The authors evaluated the graft quality only from levels of browning and inflammation and necrosis, which is incomplete and not rigorous.

In the Results and Discussion sections, the authors focused on the relationship of Type 2 macrophages and browning in the grafted adipose, but they did not explain the phenomenon of increased cytokines secreted by Type 1 macrophages in 4 weeks.

The authors stated that beige adipocytes are in an exhausted status because of their elevated energy expenditure. However, the recipient site is in an extremely hypoxic state after fat grafting. From common sense, the pathophysiology of the graft should be changed to adapt to the environment, that is, the cell state with reduced oxygen demand. Thus, further investigations with more specific mechanisms on high metabolic beige adipocytes would advance our understanding of the outcome of fat graft.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Funding

The authors received no financial support for the research, authorship, and publication of this article.

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