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Fat Grafting Can Induce Browning of White Adipose Tissue

Hoppela, Erika, MD*,†; Grönroos, Tove J., PhD†,‡; Saarikko, Anne M., MD, PhD§; Tervala, Tomi V., MD; Kauhanen, Susanna, MD, PhD§; Nuutila, Pirjo, MD, PhD; Kivinen, Katri, MD, PhD; Hartiala, Pauliina, MD, PhD*,**

Plastic and Reconstructive Surgery – Global Open: June 2018 - Volume 6 - Issue 6 - p e1804
doi: 10.1097/GOX.0000000000001804
Experimental
Finland

Background: Fat grafting is commonly used when treating soft-tissue defects. However, much of the basic biology behind fat transfer is still uncovered. Adipocytes can be divided into energy storing white and energy burning brown adipose cells. It is now well known, that also adult humans have metabolically active brown adipose tissue (BAT) within white adipose tissue (WAT). Previously our group showed that transfer of metabolically inactive WAT into a new environment increased the metabolic activity of the fat grafts to resemble the activity in the recipient site and that different WAT depots have variation in the metabolic activity. This led us to speculate, whether the metabolic increase of the graft is a result of “browning” of the transferred WAT toward beige adipose tissue.

Methods: We investigated the metabolic and histological characteristics and BAT marker Ucp1 gene expression in different types of WAT grafts placed either in subcutaneous or muscle tissue in mice. Metabolic activity of the grafts was investigated by FDG-PET/CT at 4- and 12-week time-points.

Results: The glucose uptake of all transferred fat types was increased when compared with respective control WAT regardless of transfer location. Ucp1 gene and protein expression was increased in 4 of 15 intramuscularly placed fat graft samples and showed histological resemblance to BAT with multilocular cells.

Conclusions: Grafting of metabolically inactive fat intramuscularly may induce browning of fat grafts toward more active beige adipose tissue. This opens up new research areas in exploiting fat grafting in metabolic diseases.

From the *Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland

Turku PET Centre, University of Turku, Turku, Finland

Medicity Research Laboratory, University of Turku, Turku, Finland

§Department of Plastic Surgery, Helsinki University Hospital, Helsinki, Finland

Department of Plastic Surgery, Kuopio University Hospital, Kuopio, Finland

Department of Medical Genetics, Turku University Hospital, Turku, Finland

**Institute of Biomedicine, University of Turku, Turku, Finland.

Published online 19 June 2018.

Received for publication February 20, 2018; accepted April 11, 2018.

Supported by The Finnish Medical Foundation, The Turku University Foundation and Special Governmental Funding (EVO grant) allocated to Turku University Hospital.

Presented at EURAPS (European Association of Plastic Surgeons), May 2016, Brussels, Belgium (presented by Pauliina Hartiala); Operative Days (Annual Meeting of the National Surgical Society, plastic surgery section), November 2016, Helsinki, Finland (presented by Erika Hoppela); EASAPS (European Association of Societies of Aesthetic Plastic Surgery), October 2017, Bucharest, Romania (presented by Erika Hoppela).

Disclosure: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors.

Supplemental digital content is available for this article. Clickable URL citations appear in the text.

Erika Hoppela, MD, Department of Plastic and General Surgery, Turku University Hospital, P.O Box 52, FI 20251, Turku, Finland, E-mail: erika.hoppela@utu.fi

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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INTRODUCTION

Autologous free white adipose tissue (WAT) grafts are commonly used in plastic surgery for reconstruction of soft-tissue defects.1 Novel experimental therapies include softening and contour of scars and other fibrotic conditions.2–4 However, the basic biology of fat transfer surgery and the antifibrotic effects are still poorly understood. Many of the effects are thought to be mediated by the immunomodulatory properties of adipose-derived stem cells, which are present in the transferred adipose tissue.5 They have been shown to reduce proinflammatory cytokine (IL-1, IL-17) levels and increase anti-inflammatory protein (IL-10) levels in mice.6 Only a few experimental reports describe the effects of fat grafting in muscle tissue7 , 8 although fat grafting is routinely performed in large volumes for example in pectoralis and latissimus dorsi muscles in breast reconstruction and augmentation.9 , 10

The type of adipose tissue plays a great role in obesity and metabolic disorders such as type 2 diabetes. It is known that there are 2 types of adipose tissue in mammals: thermogenically active brown adipose tissue (BAT) and WAT, which is mainly involved in storing excess energy.11 Typically BAT contains adipocytes with small multilocular lipid droplets, and numerous mitochondria with uncoupling protein 1 (UCP1), the protein responsible for regulation of thermogenesis and characteristic feature for BAT.12 , 13 Previously, BAT was thought to exist only in small mammals and infants, but during the past decade, several studies have demonstrated significant amounts of functional BAT also in adults.14 Interestingly, also adult humans have inducible brown-like adipocytes called beige (or brite) adipose tissue, which consists of brown-like adipocytes among WAT bringing about similar characteristics in energy metabolism as BAT.15–17 Recent evidence suggest that beige adipocytes derive from the same mesenchymal stem cells but different precursor cells as WAT18 and begin to differentiate due to environmental stimuli, such as changes in temperature and nutrition.19

We have previously used an experimental model to evaluate the vascularization, survival, and metabolic changes after free fat transfer using18F-fluorodeoxyglucose (FDG) PET/CT imaging described by Tervala et al.20 Results showed that transfer of the metabolically inactive (epididymal) fat into a new environment modulates the metabolic activity of the fat grafts to resemble the situation in the recipient site. We also noted metabolic differences in subcutaneous, visceral, and epididymal WAT depots. In this study, we wanted to investigate whether the metabolic increase of the transplant can be a result of “browning” of the transplanted WAT and whether it was donor-site specific. In this study, we examined the metabolic and histological characteristics and BAT marker Ucp1 expression in different types of WAT grafts placed either subcutaneously or intramuscularly. The purpose of the study was to investigate whether fat grafting can induce browning of WAT, especially when fat is transferred to a metabolically more active area such as muscle tissue, and determine the potential benefits of fat grafting in the surgical treatment of metabolic disorders.

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MATERIALS AND METHODS

Mouse Model

Permissions for the animal studies were obtained from the National Animal Experiment Board of Finland. We used 3 different types of WAT as free fat grafts transferred into subcutaneous and muscle tissue, as described in Figure 1. According to the WAT type, 3 groups of graft mice were formed and maintained during the experiment: epididymal (n = 6), visceral (n = 5), and subcutaneous group (n = 5). A control group (n = 5) was used as a reference to determine the basic muscle, BAT, and WAT metabolism. C57BL/6 mice (C57BL/6NCrl, Harlan, The Netherlands) were killed and used as donor mice for harvesting WAT. Athymic nude mice (Hsd:Athymic Nude-Foxn1nu, Harlan, The Netherlands) with inhibited immune system were used as recipients to avoid graft rejection response. All mice were anesthetized with xylazine hydrochloride 5 mg/kg (Rompun 20 mg/mL, Bayer Animal Health, Leverkusen, Germany) and ketamine 70 mg/kg (Ketalar, Hameln Pharmaceuticals, Hameln, Germany). For analgesia, buprenorphine hydrochloride 0.075 mg/kg (Temgesic, RB Pharmaceuticals Limited, Slough, Berkshire, Great Britain) was administered to recipient mice during 2 days postoperatively.

Fig. 1

Fig. 1

After harvesting, the excised grafts were weighted and subsequently placed under the skin of forehead to subcutaneous space and among muscle tissue in hind leg of the recipient mice (n = 16). Into forehead, the fat was placed as a whole piece, and into leg with a 14 G cannula after mechanical disruption combined with a small amount of saline. The average volume of grafted fat to forehead was 0.25 ± 0.09 mL and 0.13 ± 0.05 mL to leg, respectively. Wounds were closed using 5-0 Polysorb sutures (Covidien, Dublin, Ireland).

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In Vivo FDG-PET/CT Imaging and Data Analysis

Metabolic activity of fat grafts was examined in mice at 4- and 12-week time points by PET/CT (Siemens Medical Solutions USA, Knoxville, Tenn.) using 18F-FDG, a glucose analogue known to accumulate to metabolically active tissues. Metabolism of BAT increases in cold temperature, and to stimulate the activity of BAT and induce thermogenesis, PET/CT scan was performed on 2 consecutive days: first with cold exposure (26–28°C) and the second with warm exposure (36–38°C).21 FDG was given approximately 5 MBq into the tail vein and the 2-step whole-body PET/CT scan was performed at fasting state (4 h) during isoflurane gas anesthesia on. The cold exposure was accomplished by exposing mice to cold air by circulating propylene glycol through an animal holder using a heating circulator (S-12 Julabo, Seelbach, Germany) with simultaneous temperature monitoring. The warm exposure was carried out in normal room temperature by using a heating pad. At 4-week time point, PET/CT was performed only with warm exposure, and at 12-weeks with both cold and warm scans.

FDG images were reconstructed as described by Tervala et al.20 Volumes of interest (VOIs) were drawn on the forehead subcutaneous fat graft and leg region intramuscular fat graft by using either radioactivity uptake or the computed tomography template as an anatomical reference. In the leg where grafts were smaller and less visible than that of the forehead, VOIs were drawn to cover the whole leg. VOIs were drawn also on a part of liver, interscapular BAT, and contralateral hind leg (control muscle) as a reference. Standardized uptake value (SUV) was defined as the ratio of FDG radioactivity (Bq) per milliliter (mL) of tissue to the radioactivity in the injected dose corrected by decay and by animal body weight. The SUV of fat grafts were compared with that of liver, and results expressed as fat-to-liver uptake ratios (SUV of fat/SUV of liver).

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Ex Vivo Radioactivity Analysis of Tissue Samples

Immediately after the last follow-up scan at 12-week time point, the graft mice were killed for ex vivo tissue sample analysis. Samples were measured for 18F-radioactivity in a gamma counter (Wizard2 3”, PerkinElmer, Turku, Finland) and expressed as the percentage of injected dose per gram tissue (% ID/g). Thereafter, samples were fixed in formalin for histologic examination. A separate tissue sample for RNA analysis was snap frozen in liquid nitrogen and stored in −70°C.

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Gene Expression Analysis

Tissue samples were homogenized in QIAzol Lysis Reagent (Qiagen), and total RNA was extracted according to the manufacturer’s recommendations. RNA was cleaned up from the aqueous phase of the extracts using the RNeasy Micro Kit (Qiagen) according to the manufacturer’s recommendations and included an on-column DNase I treatment step. cDNA synthesis was performed using the first Strand cDNA Synthesis Kit for real-time polymerase chain reaction (PCR) (AMV) (Roche). Quantitative real-time PCR was performed on a ViiA7 instrument (Applied Biosystems) using Power SYBR Green PCR Master Mix (Applied Biosystems). The standard curve method with Rplp0 as the normalizing gene was used to determine relative Ucp1 gene expression levels. Primer sequences are supplied in Supplementary Table 1 (see table, Supplementary Digital Content 1, which displays primer sequences, http://links.lww.com/PRSGO/A793).

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Histology and Immunohistochemistry

Tissue samples fixed overnight in formalin were embedded in paraffin. Sections of 4 μm thickness were cut and stained with hematoxylin and eosin for the evaluation and grading (0–5) or percentage (0–100%) of adipose tissue survival, fibrosis, cystic degeneration, presence of multilocular BAT morphology, and degree of inflammation. To confirm the Ucp1 gene expression results at protein level, UCP1 immunohistochemical staining was performed. Samples were stained with rabbit antimouse anti-UCP1 (dilution 1:1,000, Abcam, United Kingdom). An horseradish peroxidase (HRP)-conjugated goat-antirabbit immunoglobulin G (IgG) polyclonal (ImmunoLogic, Netherlands) was used as the secondary antibody.

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Statistical Analysis

All results were analyzed using SPSS (IBM SPSS Statistics IBM SPSS Statistics for Macintosh, version 23.0. Armok, NY: IBM Corp.). Groups were compared using 1-way ANOVA, and pairwise comparisons were made using the Kruskall-Wallis test or Student’s t test. Statistical significance was set at P ≤ 0.05.

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RESULTS

In Visual Analysis of FDG-PET/CT Imaging, Most Grafts Were Visible and Showed FDG Uptake

At 4-week time point, all subcutaneous grafts at the forehead region were visible and showed FDG uptake, and most grafts (63%) showed increase in volume (mean graft volume 0.32 ± 0.19 mL, median 0.30 mL). Visual FDG uptake in the intramuscular grafts at leg region was seen in 11 of 16 mice (68.8%) evenly distributed in all groups. Intramuscular graft volume was not measurable with PET/CT due to small amount of transferred fat.

At 12-week time point, the FDG uptake remained visible in 10 of 16 subcutaneous grafts during follow-up. Poorest survival of grafts was in the visceral group, where only 1 graft was visible. Graft volumes showed great variability (mean 0.53 ± 0.61 mL, median 0.24 mL). Eight intramuscular grafts showed visual FDG uptake with even distribution between groups (Fig. 2).

Fig. 2

Fig. 2

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FDG-PET/CT Quantitative Analysis Showed High Uptake in Both Graft Regions and BAT But Low Uptake in Control WATs

The FDG uptake in VOI was expressed as fat-to-liver ratio shown in Table 1. PET/CT scans at both 4-week and 12-week time points showed increased FDG uptake subcutaneous grafts without significant difference between the groups (P = 0.069). In intramuscular grafts, FDG uptake was greater in all graft groups compared with control leg (P = 0.019). There was no statistical difference between fat-to-liver ratios in different time points at 4 and 12 weeks (P = 0.421). Overall, FDG uptake in all regions was higher in warm temperature scans (P < 0.001; Fig. 3A). Ex vivo tissue samples were also measured for 18F-FDG uptake (Fig. 3B) showing high uptake in both graft regions and BAT but low uptake in control WATs.

Table 1

Table 1

Fig. 3

Fig. 3

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Gene Expression Analysis Showed Elevated Ucp1 Expression in 4 out of 15 Intramuscular Grafts

Fifteen intramuscular and 13 subcutaneous graft samples were analyzed in addition to control BAT and WAT samples (Fig. 4). The highest Ucp1/Rplp0 ratio of all fat tissue samples was used as a reference, and results are expressed as percentage (%) of the reference value. The Ucp1 expression was relatively low in all subcutaneous grafts (mean 0.0015% ± 0.0022%), whereas the Ucp1 level in intramuscular grafts was elevated in all groups (mean 2.51% ± 7.65%), but the comparison did not reach statistical significance (P = 0.25). The mean Ucp1 expression in the control samples was 0.0015% ± 0.00077% in epididymal fat, 0.017% ± 0.025% in visceral fat, and 0.12% ± 0.10% in subcutaneous fat. Average BAT Ucp1 level was 63% ± 12%. In individual analysis, 4 intramuscular fat grafts showed significantly elevated expression of Ucp1 (mean, 9.4% ± 14%) compared with control WAT and presented later in this section.

Fig. 4

Fig. 4

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Histological Analysis Revealed Brown Adipose Tissue-like, UCP1-positive Multilocular Fat in 4 of 15 Intramuscular Grafts

The histological analysis did not make any difference between the types of WAT used in grafting, and therefore comparison was performed mainly between the graft locations. The average percentage of survived fat was 23% ± 28%, and there seemed to be a trend toward a greater adipose tissue percentage in the intramuscular grafts (P = 0.12). No significant statistical difference was observed with respect to the degree of inflammation and fibrosis between graft locations (P = 0.92 and P = 0.28, respectively), but cystic degeneration was significantly lower in intramuscular grafts (P < 0.001). BAT-like multilocular fat was seen only in intramuscular grafts (mean, 11% ± 21%), but also in control WAT in some degree (7% ± 14%; Fig. 5). However, UCP1 staining was negative and Ucp1 gene expression low regarding these control samples. When examining samples individually, multilocular fat was found in 4 intramuscular grafts (2 in the epididymal group, 1 in the visceral group, and 1 in the subcutaneous group), and these samples showed also positive UCP1 staining and elevated Ucp1 gene and protein expression as a difference to control samples. Detailed results of histological analysis by groups are shown in Table 2.

Table 2

Table 2

Fig. 5

Fig. 5

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In Individual Sample Analysis, 4 of 15 Intramuscular Fat Grafts Showed Browning Toward Beige Fat

According to the results, the same 4 intramuscular fat grafts were characterized by multilocular fat droplets and increased Ucp1 gene and protein expression, both typical for BAT, indicating metabolic and morphologic change toward beige adipose tissue. As seen in Figure 5, with hematoxylin and eosin (HE) staining beige fat was characterized by both multilocular BAT-like fat and large lipid droplets similar WAT, but other grafts showed mostly original WAT-like fat with large oil cysts. To confirm the presence of beige fat, we examined the samples also with UCP1 staining, which showed positively stained tissue samples. Also some WAT samples showed multilocular fat but UCP1 staining remained negative. The amount of the multilocular fat varied in the beige samples (60%, 50%, 10%, and 40%). The beige fat was well preserved in the target region (fat cells 76 ± 8 % versus 15 ± 18 % in other fat grafts, P < 0.001), and there was less inflammation (grading 0.25 ± 0.5 versus 2.96 ± 1.30, P < 0.001), fibrosis (0.5 ± 0.6 versus 3.1 ± 1.2, P < 0.001) and cystic degeneration (0 in beige grafts, others 2.0 ± 1.7, P = 0.03). Glucose uptake in beige grafts was low: the mean ex vivo FDG uptake was 3.5 ± 1.5 %ID/g in the beige grafts and 11.1 ± 6.7 %ID/g in others (P = 0.140; Fig. 3B). Mean Ucp1 expression was 9.4% ± 14 % for beige grafts and 0.002% ± 0.004% for other grafts, respectively, which makes the Ucp1 expression in beige grafts 4,700-fold greater compared with the other grafts (P < 0.001) and from 430 to 1,383-fold greater than in the respective control fat (Fig. 4).

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DISCUSSION

In this article, we aimed to investigate the metabolic adaptation of WAT grafts in subcutaneous and muscle tissue, as the metabolic and morphologic changes in fat grafts are still poorly understood despite the fact that lipotransfer is commonly used in plastic surgery. Our results show a novel phenomenon: browning of intramuscularly placed fat grafts. This was demonstrated with HE and UCP1-stained histology samples showing multilocular lipid droplets and an increase in Ucp1 gene and protein expression. These grafts were also of good quality with limited inflammation, fibrosis, and cystic degeneration.

This finding presents an interesting outcome of a common procedure in the field of plastic surgery. Obesity and the large amount of inactive fat are major factors in metabolic disorders. By changing the metabolism of fat into a more active form, fat grafting could have beneficial effects also on glucose tolerance and body weight. To this point, many experimental studies have shown that fat has effects on glucose balance, but different depots of WAT seem to have different metabolic characteristics. Previous reports have shown that the fatty acid metabolism is lower in epididymal than in subcutaneous WAT.22 It has also been reported that transfer of epididymal or inguinal WAT into the visceral cavity improves glucose tolerance,23 decreases the total amount of fat and weight and insulin resistance in mice.24 Especially the transfer of subcutaneous fat into the visceral cavity reduces the amount of several proinflammatory cytokines (TNF alfa, IL-17, IL-12) in plasma.25

A limited degree of inflammation may be 1 factor allowing browning to initiate. A recent study has shown that inflammation of WAT is associated with diminished generation of Ucp1 expressing beige adipocytes26 giving a possible explanation why browning occurred only in limited amount of samples in our study. Unlike previous studies have shown,27 , 28 also interscapular BAT showed increased glucose (FDG) uptake during warm exposure than in cold exposure. However, recent reports demonstrate that FDG uptake can be increased in BAT of UCP1-deficient mice suggesting also UCP1 independent mechanisms for the increased uptake.29

The amount of BAT precursors in fat grafts also varies, and therefore some grafts may be more prone to browning than others. According to previous studies, the metabolic adaptation of white adipose cells to beige cells through direct transformation is regulated by many factors.16 , 30 , 31 Beige adipocytes, at least in the subcutaneous depot, have been shown to arise from a precursor population rather than from preexisting adipocytes.32 The beige adipocyte precursor population is different from the white precursor population,18 and beige adipocytes have been shown to be most abundant in the inguinal WAT, which is a major subcutaneous depot in rodents.33

An autocrine/paracrine mechanism between muscle and adipose cells may also be the cause behind browning. Myocytes secrete irisin, and its concentrations increase in mice and humans by exercise training and it has been shown to stimulate the browning of WAT through specific actions on the beige preadipocyte population.34 An advantage in muscle tissue is also the abundant vascular bed improving the survival of fat graft.

As a conclusion, this study suggests a novel finding: fat grafting can induce browning of the graft. Subcutaneous and intramuscular grafting might have different outcomes as browning of fat was only seen in grafts placed in muscle tissue. It is known that many factors can initiate browning, and external manipulation (liposuction and lipotransfer) may be 1 of these factors. Also transferring WAT to metabolically more active muscle tissue may bring about metabolic adaptation in the fat. Therefore, fat transfer may have beneficial effects on body metabolism by increasing the amount of metabolically active tissue. Clinical research is still needed to investigate the metabolic changes in autologous fat grafting in humans, but the potential browning and metabolic activation of WAT opens up new research areas in exploiting fat grafting in metabolic diseases.

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ACKNOWLEDGMENTS

The authors thank Marko Vehmanen, Elisa Riuttala, Aake Honkaniemi, and Erica Nyman for excellent technical assistance.

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Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Plastic Surgeons. All rights reserved.