A commentary on  Heart Fat Infiltration In Subjects With and Without Coronary Artery Disease by Mazzali G, Fantin F, Zoico E, Sepe A, Bambace C, Faccioli S, et al. J Clin Endocrinol Metab (2015) 100(9):3364\u201371. doi:10.1210/jc.2015-178

Salvatore Chirumbolo

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A commentary on  Heart Fat Infiltration In Subjects With and Without Coronary Artery Disease by Mazzali G, Fantin F, Zoico E, Sepe A, Bambace C, Faccioli S, et al. J Clin Endocrinol Metab (2015) 100(9):3364–71. doi:10.1210/jc.2015-178

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Commentary: Heart fat infiltration in subjects with and without coronary artery disease

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Commentary: Heart Fat Infiltration in Subjects With and Without Coronary Artery Disease

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February 2016 | Volume 3 | Article 21
General Commentary
published: 01 February 2016
doi: 10.3389/fcvm.2016.00002
Frontiers in Cardiovascular Medicine | www.frontiersin.org
Edited by: 
Dennis W.T. Nilsen, 
University of Bergen, Norway
Reviewed by: 
Frederic P.T. Kontny, 
Stavanger University Hospital, 
Norway 
Shinya Goto, 
Tokai University School of Medicine, 
Japan
*Correspondence:
Salvatore Chirumbolo  
salvatore.chirumbolo@univr.it
Specialty section: 
This article was submitted to 
Coronary Vascular System, 
a section of the journal 
Frontiers in Cardiovascular Medicine
Received: 07 October 2015
Accepted: 11 January 2016
Published: 01 February 2016
Citation: 
Chirumbolo S (2016) Commentary: 
Heart Fat Infiltration In Subjects With 
and Without Coronary Artery 
Disease. Front. Cardiovasc. Med. 
3:2. doi: 10.3389/fcvm.2016.00002
Commentary: Heart Fat Infiltration  
In Subjects With and Without 
Coronary artery Disease
Salvatore Chirumbolo*
Department of Medicine, University of Verona, Verona, Italy
Keywords: lipid droplet, atrium, adipose tissue, adipocytes, coronary disease
A commentary on
Heart Fat Infiltration In Subjects With and Without Coronary Artery Disease
by Mazzali G, Fantin F, Zoico E, Sepe A, Bambace C, Faccioli S, et al. J Clin Endocrinol Metab (2015) 
100(9):3364–71. doi:10.1210/jc.2015-1787
Mazzali et al. showed myocardial steatosis in subjects with coronary artery disease (CAD), describ-
ing a significant increase in lipid droplets (LDs) and metabolically active adipocytes interspersed 
among cardiomyocytes, which were positively associated with changes in BMI and circulating leptin 
and negatively with adiponectin (1).
The authors used perilipin (PLIN-1) and adipophilin (PLIN-2) markers to detect, respectively, 
adipocyte or cardiomyocytes LDs and reported that while PLIN-2 was detected in all subjects, about 
39% of both CAD and non-CAD patients expressed PLIN-1, showing apparently no relationship 
in tissue fat distribution between patients and controls. Yet, when intra-cardiomyocyte fat deposits 
were evaluated, subjects with CAD expressed higher levels of both PLIN-1 and PLIN-2 and higher 
LD diameter than controls, besides apoptosis and hypoxia markers (1). The observed higher 
amount of PLIN-1 and PLIN-2, evaluated by immunohistochemistry rather than gene expression, 
correlated with some metabolic serum markers. While PLIN-1 seems to be associated with larger 
triacylglycerol LDs in mature adipocytes, PLIN-2 is mainly associated with LDs in non-steroidal 
adipose tissues (2). LDs are usually collectively grouped in the PAT family, which includes perilipins 
(P), ADRP (also called adipophilin) (A), Tip-47 (tail-interacting protein of 47 kDa) (T), hence the 
acronym PAT. They also include S3–12 and OXPAT (also termed MLDP or LSDP5) and recently, 
respectively, named PLIN1, PLIN2, PLIN3, PLIN4, and PLIN5 (3). The use of PLIN-1 and PLIN-2 
is particularly useful in evaluating fat deposits in tissues, although some question still remains, as 
LD proteins are expressed in a highly complex way during lipidogenesis in the adipose cell (4). In 
this perspective, some further markers to improve adipocyte detection, such as CIDEC, might be 
suggested (5–7), in order to better differentiate adipocytes from LDs and also to reduce bias during 
the immunological detection of perilipin isoforms, as they share a high sequence homology and 
modification in their N- or C-terminus, depending on their function (4). Unlike other perilipins, 
PLIN-1 is widely associated with any LD moving from membranes and endoplasmic reticulum to 
fat droplets during lipid synthesis in any steroidogenic cells and probably may not be a specific 
marker of isolated white adipocytes (8). Furthermore, the expression of PLIN-2, which the authors 
associated with LDs in cells different from adipocytes, has also been reported in brown adipocytes (9) 
and adipocytes from white adipose tissue may express adipophilin (PLIN-2), in particular metabolic 
conditions (4). Expanding this investigation with further insights may improve the meaning of the 
reported evidence. For example, perilipin-5 (PLIN-5), which is an important marker in cardiac con-
trol of lipolysis (10), is particularly abundant in the heart (11), and as its overexpression could lead 
February 2016 | Volume 3 | Article 22
Chirumbolo Adipocyte and Fats within the Myocardial Tissue
Frontiers in Cardiovascular Medicine | www.frontiersin.org
to myocardial steatosis, including this marker in future research 
on myocardial lipidology, particularly in CAD, may improve our 
knowledge and ability to address this issue (12, 13).
Isolated adipocytes within the myocardium are not a true nov-
elty (14), as adipose tissue was described also within myocardial 
ventricular walls (15) and recently confirmed in atrial dysfunc-
tion (16). Further research in this field should address the origin 
of these adipocytes, e.g., one could investigate the presence of 
fibroblast-like preadipocytes in the atrium, which may add fur-
ther insights on the issue (17). The origin of these adipocytes is 
fundamental to comprehend their role in CAD. Epicardial adipose 
tissue (EAT) in specimens may cause possible bias, as adipocytes 
observed within the atrium may derive from epicardium or even a 
tissue-related mesenchymal transdifferentiation mechanism (1). 
Interestingly, pericytes may be sources of preadipocytes, likewise 
endothelial cells in the adipose tissue, and represent a possible 
source of the observed adipocytes (18, 19). Once highlighted the 
origin of interspersed adipocytes, one could question, which is the 
possible role of these cells, namely if they even play a major role 
in some compensatory mechanism triggered by myocardial tissue 
to prevent serious damage due to CAD. The recently reported 
evidence that at least in skeletal muscle, the increase in PLIN-2 
correlated with an improvement in insulin sensitivity in diabetic 
subjects is intriguing (20). Despite the observation of apoptotic 
and stress response, signals associated with hypoxia and mito-
chondrial impairment and dysfunction lead to LDs formation as 
a positive response to cellular stress (21). In this context, observed 
adipocytes, which would deserve further clarification about their 
nature, may shed a light on a possible role in the heart reaction to 
cardiovascular damage.
PLIN-1 is expressed also by brown adipocytes (8, 22). 
Further investigation on the main brown adipocyte marker, the 
uncoupling protein-1 (UCP-1), should differentiate the nature 
of the observed adipocytes (23, 24). This fact may be important 
to clarify the role of these cells in the myocardial tissue of CAD 
patients. Following a suggestion about the possible existence 
of adipocytes from adult stem cells (ASCs), brown adipose 
tissue (BAT) is an interesting precursor of cardiomyocytes, 
as subepicardial fat embryologically derives from BAT and 
because in aged hearts, a protective mechanism of differentia-
tion of subepicardial stem cells into BAT was recently described 
(23). The use of UCP-1, to elucidate the nature of interspersed 
adipocytes, may support the hypothesis that adipocytes serve as 
an important source to compensate myocardial damage in CAD 
patients. Adipocytes within myocardial tissue may even have a 
protective, damage-repairing role, a suggestion supported by 
the recent evidence that adipose tissue-derived stem cells exert 
paracrine actions that may have therapeutic effect on myocardial 
dysfunction (25).
While the authors showed a greater myocardial steatosis in 
subjects with CAD compared with controls, further research 
should deepen the role of interspersed adipocytes, their origin, 
and cytological nature. Suggestions coming from animal models 
and further experimental research will add insights to the nature 
of this study, highlighting the mechanism of the mesenchymal 
source and the role of these cells in the atrium.
aUtHor ContrIBUtIonS
SC: planned, conceived, wrote, and submitted the whole 
manuscript.
aCKnoWleDGmentS
Many thanks to Dr. Joshua H. Williams (University of California), 
Dr. Samuel G. Havenberger (University of Antwerp), and Ms. 
Silvya Shelton (University of Edinburgh) for their very precious 
and fundamental advices and suggestions.
reFerenCeS
1. Mazzali G, Fantin F, Zoico E, Sepe A, Bambace C, Faccioli S, et  al. Heart 
fat infiltration in subjects with and without coronary artery disease. J Clin 
Endocrinol Metab (2015) 100(9):3364–71. doi:10.1210/jc.2015-1787 
2. Dalen KT, Schoonjans K, Ulven SM, Weedon-Fekjaer MS, Bentzen TG, 
Koutnikova H, et al. Adipose tissue expression of the lipid droplet-associating 
proteins S3-12 and perilipin is controlled by peroxisome proliferator- 
activated receptor-gamma. Diabetes (2004) 53(5):1243–52. doi:10.2337/
diabetes.53.5.1243 
3. Kimmel AR, Brasaemle DL, McAndrews-Hill M, Sztalryd C, Londos C. 
Adoption of PERILIPIN as a unifying nomenclature for the mammalian 
PAT-family of intracellular lipid storage droplet proteins. J Lipid Res (2010) 
51(3):468–71. doi:10.1194/jlr.R000034 
4. Heid H, Rickelt S, Zimbelmann R, Winter S, Schumacher H, Dörflinger Y, 
et al. On the formation of lipid droplets in human adipocytes: the organization 
of the perilipin-vimentin cortex. PLoS One (2014) 9(2):e90386. doi:10.1371/
journal.pone.0090386 
5. Sun Z, Gong J, Wu H, Xu W, Wu L, Xu D, et al. Perilipin1 promotes unilocular 
lipid droplet formation through the activation of Fsp27 in adipocytes. Nat 
Commun (2013) 4:1594. doi:10.1038/ncomms2581 
6. Moreno-Navarrete JM, Ortega F, Serrano M, Rodriguez-Hermosa JI, Ricart 
W, Mingrone G, et  al. CIDEC/FSP27 and PLIN1 gene expression run in 
parallel to mitochondrial genes in human adipose tissue, both increasing 
after weight loss. Int J Obes (Lond) (2014) 38(6):865–72. doi:10.1038/
ijo.2013.171 
7. Grahn TH, Zhang Y, Lee MJ, Sommer AG, Mostoslavsky G, Fried SK, et al. 
FSP27 and PLIN1 interaction promotes the formation of large lipid droplets 
in human adipocytes. Biochem Biophys Res Commun (2013) 432(2):296–301. 
doi:10.1016/j.bbrc.2013.01.113 
8. Skinner JR, Harris LA, Shew TM, Abumrad NA, Wolins NE. Perilipin 1 moves 
between the fat droplet and the endoplasmic reticulum. Adipocyte (2013) 
2(2):80–6. doi:10.4161/adip.22864 
9. Yu J, Zhang S, Cui L, Wang W, Na H, Zhu X, et al. Lipid droplet remodeling 
and interaction with mitochondria in mouse brown adipose tissue during 
cold treatment. Biochim Biophys Acta (2015) 1853(5):918–28. doi:10.1016/j.
bbamcr.2015.01.020 
10. Pollak NM, Jaeger D, Kolleritsch S, Zimmermann R, Zechner R, Lass A, et al. 
The interplay of protein kinase A and perilipin 5 regulates cardiac lipolysis. J 
Biol Chem (2015) 290(3):1295–306. doi:10.1074/jbc.M114.604744 
11. Kuramoto K, Okamura T, Yamaguchi T, Nakamura TY, Wakabayashi S, 
Morinaga H, et al. Perilipin 5, a lipid droplet-binding protein, protects heart 
from oxidative burden by sequestering fatty acid from excessive oxidation. J 
Biol Chem (2012) 287(28):23852–63. doi:10.1074/jbc.M111.328708 
12. Wang H, Sreenivasan U, Gong DW, O’Connell KA, Dabkowski ER, Hecker PA, 
et al. Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial 
February 2016 | Volume 3 | Article 23
Chirumbolo Adipocyte and Fats within the Myocardial Tissue
Frontiers in Cardiovascular Medicine | www.frontiersin.org
steatosis and modest cardiac dysfunction. J Lipid Res (2013) 54(4):953–65. 
doi:10.1194/jlr.M032466 
13. Pollak NM, Schweiger M, Jaeger D, Kolb D, Kumari M, Schreiber R, et  al. 
Cardiac-specific overexpression of perilipin 5 provokes severe cardiac steato-
sis via the formation of a lipolytic barrier. J Lipid Res (2013) 54(4):1092–102. 
doi:10.1194/jlr.M034710 
14. Su L, Siegel JE, Fishbein MC. Adipose tissue in myocardial infarction. 
Cardiovasc Pathol (2004) 13(2):98–102. doi:10.1016/S1054-8807(03)00134-0 
15. Ichikawa Y, Kitagawa K, Chino S, Ishida M, Matsuoka K, Tanigawa T, et al. 
Adipose tissue detected by multislice computed tomography in patients 
after myocardial infarction. JACC Cardiovasc Imaging (2009) 2(5):548–55. 
doi:10.1016/j.jcmg.2009.01.010 
16. Chilukoti RK, Giese A, Malenke W, Homuth G, Bukowska A, Goette A, et al. 
Atrial fibrillation and rapid acute pacing regulate adipocyte/adipositas-related 
gene expression in the atria. Int J Cardiol (2015) 187:604–13. doi:10.1016/j.
ijcard.2015.03.072 
17. Cawthorn WP, Scheller EL, MacDougald OA. Adipose tissue stem cells 
meet preadipocyte commitment: going back to the future. J Lipid Res (2012) 
53(2):227–46. doi:10.1194/jlr.R021089 
18. Tran KV, Gealekman O, Frontini A, Zingaretti MC, Morroni M, Giordano 
A, et  al. The vascular endothelium of the adipose tissue gives rise to both 
white and brown fat cells. Cell Metab (2012) 15(2):222–9. doi:10.1016/j.
cmet.2012.01.008 
19. Caplan AI. All MSCs are pericytes? Cell Stem Cell (2008) 3(3):229–30. 
doi:10.1016/j.stem.2008.08.008 
20. Bosma M, Hesselink MK, Sparks LM, Timmers S, Ferraz MJ, Mattijssen 
F, et  al. Perilipin 2 improves insulin sensitivity in skeletal muscle despite 
elevated intramuscular lipid levels. Diabetes (2012) 61:2679–90. doi:10.2337/
db11-1402 
21. Lee SJ, Zhang J, Choi AM, Kim HP. Mitochondrial dysfunction induces 
formation of lipid droplets as a generalized response to stress. Oxid Med Cell 
Longev (2013) 2013:327167. doi:10.1155/2013/327167 
22. Souza SC, Christoffolete MA, Ribeiro MO, Miyoshi H, Strissel KJ, Stancheva 
ZS, et  al. Perilipin regulates the thermogenic actions of norepinephrine 
in brown adipose tissue. J Lipid Res (2007) 48(6):1273–9. doi:10.1194/jlr.
M700047-JLR200 
23. Rusu MC, Vrapciu AD, Hostiuc S, Hariga CS. Brown adipocytes, cardiac 
protection and a common adipo- and myogenic stem precursor in aged 
human hearts. Med Hypotheses (2015) 85(2):212–4. doi:10.1016/j.
mehy.2015.04.027 
24. Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for 
different functions? Endocrinology (2013) 154(9):2992–3000. doi:10.1210/
en.2013-1403 
25. Madonna R, Petrov L, Teberino MA, Manzoli L, Karam JP, Renna FV, et al. 
Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-
releasing microcarriers promotes repair in murine myocardial infarction. 
Cardiovasc Res (2015) 108(1):39–49. doi:10.1093/cvr/cvv197 
Conflict of Interest Statement: The author declares that the research was con-
ducted in the absence of any commercial or financial relationships that could be 
construed as a potential conflict of interest.
Copyright © 2016 Chirumbolo. This is an open-access article distributed under the 
terms of the Creative Commons Attribution License (CC BY). The use, distribution or 
reproduction in other forums is permitted, provided the original author(s) or licensor 
are credited and that the original publication in this journal is cited, in accordance 
with accepted academic practice. No use, distribution or reproduction is permitted 
which does not comply with these terms.


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