Available via license: CC BY-NC 4.0
Content may be subject to copyright.
World Journal of
Stem Cells
World J Stem Cells 2019 March 26; 11(3): 147-211
ISSN 1948-0210 (online)
Published by Baishideng Publishing Group Inc
W J S C World Journal of
Stem Cells
Contents Monthly Volume 11 Number 3 March 26, 2019
REVIEW
147 Adipose-derived stromal/stem cells from different adipose depots in obesity development
Silva KR, Baptista LS
167 Long non-coding RNA: The functional regulator of mesenchymal stem cells
Xie ZY, Wang P, Wu YF, Shen HY
ORIGINAL ARTICLE
Basic Study
180 Circulating factors present in the sera of naturally skinny people may influence cell commitment and
adipocyte differentiation of mesenchymal stromal cells
Alessio N, Squillaro T, Monda V, Peluso G, Monda M, Melone MA, Galderisi U, Di Bernardo G
196 Stromal cell-derived factor-1α promotes recruitment and differentiation of nucleus pulposus-derived stem
cells
Ying JW, Wen TY, Pei SS, Su LH, Ruan DK
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
I
Contents World Journal of Stem Cells
Volume 11 Number 3 March 26, 2019
ABOUT COVER Editorial Board Member of World Journal of Stem Cells, Aijun Wang, PhD,
Associate Professor, Surgical Bioengineering Laboratory, University of
California, Davis School of Medicine, Sacramento, CA 95817, United States
AIMS AND SCOPE World Journal of Stem Cells (World J Stem Cells, WJSC, online ISSN 1948-0210,
DOI: 10.4252), is a peer-reviewed open access academic journal that aims to
guide clinical practice and improve diagnostic and therapeutic skills of
clinicians.
The WJSC covers topics concerning all aspects of stem cells: embryonic,
neural, hematopoietic, mesenchymal, tissue-specific, and cancer stem cells;
the stem cell niche, stem cell genomics and proteomics, etc.
We encourage authors to submit their manuscripts to WJSC. We will give
priority to manuscripts that are supported by major national and
international foundations and those that are of great basic and clinical
significance.
INDEXING/ABSTRACTING The WJSC is now indexed in PubMed, PubMed Central, Science Citation Index
Expanded (also known as SciSearch®), Journal Citation Reports/Science Edition,
Biological Abstracts, and BIOSIS Previews. The 2018 Edition of Journal Citation
Reports cites the 2017 impact factor for WJSC as 4.376 (5-year impact factor: N/A),
ranking WJSC as 7 among 24 journals in Cell and Tissue Engineering (quartile in
category Q2), and 65 among 190 journals in Cell Biology (quartile in category Q2).
RESPONSIBLE EDITORS
FOR THIS ISSUE Responsible Electronic Editor: Han Song Proofing Editorial Office Director: Jin-Lei Wang
NAME OF JOURNAL
World Journal of Stem Cells
ISSN
ISSN 1948-0210 (online)
LAUNCH DATE
December 31, 2009
FREQUENCY
Monthly
EDITORS-IN-CHIEF
Tong Cao, Shengwen Calvin Li, Carlo Ventura
EDITORIAL BOARD MEMBERS
https://www.wjgnet.com/1948-0210/editorialboard.htm
EDITORIAL OFFICE
Jin-Lei Wang, Director
PUBLICATION DATE
March 26, 2019
COPYRIGHT
© 2019 Baishideng Publishing Group Inc
INSTRUCTIONS TO AUTHORS
https://www.wjgnet.com/bpg/gerinfo/204
GUIDELINES FOR ETHICS DOCUMENTS
https://www.wjgnet.com/bpg/GerInfo/287
GUIDELINES FOR NON-NATIVE SPEAKERS OF ENGLISH
https://www.wjgnet.com/bpg/gerinfo/240
PUBLICATION MISCONDUCT
https://www.wjgnet.com/bpg/gerinfo/208
ARTICLE PROCESSING CHARGE
https://www.wjgnet.com/bpg/gerinfo/242
STEPS FOR SUBMITTING MANUSCRIPTS
https://www.wjgnet.com/bpg/GerInfo/239
ONLINE SUBMISSION
https://www.f6publishing.com
© 2019 Baishideng Publishing Group Inc. All rights reserved. 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
E-mail: bpgoffice@wjgnet.com https://www.wjgnet.com
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
II
W J S C World Journal of
Stem Cells
Submit a Manuscript: https://www.f6publishing.com World J Stem Cells 2019 March 26; 11(3): 147-166
DOI: 10.4252/wjsc.v11.i3.147 ISSN 1948-0210 (online)
REVIEW
Adipose-derived stromal/stem cells from different adipose depots in
obesity development
Karina Ribeiro Silva, Leandra Santos Baptista
ORCID number: Karina Ribeiro Silva
(0000-0001-7394-2494); Leandra
Santos Baptista
(0000-0001-9998-8044).
Author contributions: Silva KR
drafted the article, contributed to
the conception and design of the
manuscript, wrote the article and
approved the final version;
Baptista LS drafted the article,
contributed to the conception and
design of the manuscript,
contributed to the writing of the
manuscript, made critical revisions
related to relevant intellectual
content of the manuscript and
approved the final version of the
article.
Conflict-of-interest statement: The
authors declare no conflict of
interest.
Open-Access: This article is an
open-access article which was
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution Non
Commercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See:
http://creativecommons.org/licen
ses/by-nc/4.0/
Manuscript source: Invited
manuscript
Received: September 29, 2018
Peer-review started: September 29,
2018
Karina Ribeiro Silva, Leandra Santos Baptista, Laboratory of Tissue Bioengineering, Directory
of Metrology Applied to Life Sciences, National Institute of Metrology, Quality and
Technology, Duque de Caxias, RJ 25250-020, Brazil
Karina Ribeiro Silva, Leandra Santos Baptista, Post-Graduation Program of Biotechnology,
National Institute of Metrology, Quality and Technology, Duque de Caxias, RJ 25250-020,
Brazil
Leandra Santos Baptista, Multidisciplinary Center for Biological Research (Numpex-Bio),
Federal University of Rio de Janeiro Campus Duque de Caxias, Duque de Caxias, RJ 25245-
390, Brazil
Corresponding author: Leandra Santos Baptista, PhD, Professor, Laboratory of Tissue
Bioengineering, Directory of Metrology Applied to Life Sciences, National Institute of
Metrology, Quality and Technology, Duque de Caxias, RJ 25250-020, Brazil.
leandra.baptista@gmail.com
Telephone: +55-21-21453151
Abstract
The increasing prevalence of obesity is alarming because it is a risk factor for
cardiovascular and metabolic diseases (such as type 2 diabetes). The occurrence
of these comorbidities in obese patients can arise from white adipose tissue
(WAT) dysfunctions, which affect metabolism, insulin sensitivity and promote
local and systemic inflammation. In mammals, WAT depots at different
anatomical locations (subcutaneous, preperitoneal and visceral) are highly
heterogeneous in their morpho-phenotypic profiles and contribute differently to
homeostasis and obesity development, depending on their ability to trigger and
modulate WAT inflammation. This heterogeneity is likely due to the differential
behavior of cells from each depot. Numerous studies suggest that adipose-
derived stem/stromal cells (ASC; referred to as adipose progenitor cells, in vivo)
with depot-specific gene expression profiles and adipogenic and
immunomodulatory potentials are keys for the establishment of the morpho-
functional heterogeneity between WAT depots, as well as for the development of
depot-specific responses to metabolic challenges. In this review, we discuss
depot-specific ASC properties and how they can contribute to the
pathophysiology of obesity and metabolic disorders, to provide guidance for
researchers and clinicians in the development of ASC-based therapeutic
approaches.
Key words: White adipose tissue; Metabolic diseases; Obesity; Adipose-derived
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
147
First decision: October 19, 2018
Revised: January 27, 2019
Accepted: February 28, 2019
Article in press: February 28, 2019
Published online: March 26, 2019
P-Reviewer: Cardile V, Tanabe S
S-Editor: Wang JL
L-Editor: A
E-Editor: Song H
stromal/stem cells; Adipose depot; Inflammation
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: White adipose tissue (WAT) depots at different anatomical locations are highly
heterogeneous in morphology and phenotype, and contribute differently to the
development of obesity and metabolic disorders. Here, we discuss the role of adipose-
derived stem/stromal cells (ASC) in the development of obesity and metabolic disorders,
by reviewing the data suggesting that depot-specific ASC/adipose progenitor cells help
to develop the specific responses of each WAT depot to metabolic challenges. In
particular, we address the importance of ASC-dependent immunomodulation in the
inflammatory response associated with obesity, providing guidance for future research
on the use ASC-based therapeutic approaches.
Citation: Silva KR, Baptista LS. Adipose-derived stromal/stem cells from different adipose
depots in obesity development. World J Stem Cells 2019; 11(3): 147-166
URL: https://www.wjgnet.com/1948-0210/full/v11/i3/147.htm
DOI: https://dx.doi.org/10.4252/wjsc.v11.i3.147
INTRODUCTION
The World Health Organization defines obesity as abnormal or excessive fat
accumulation that represents a risk to health. Obesity can develop due to an
imbalance between energy intake and expenditure by the organism, and it is strongly
related to environmental factors, such as high caloric food consumption and se-
dentary lifestyle. In addition, the intestinal microbiota, stress levels, endocrine and
genetic profiles can also contribute to increase an individual’s susceptibility to
obesity[1,2]. The increasing prevalence of obesity is alarming because it is a risk factor
for several diseases, including hypertension, ischemic cardiovascular disease,
dyslipidemia, insulin-resistance, diabetes, metabolic syndrome[3-7] and also cancer[8-11].
The primary site for energy storage in humans is white adipose tissue (WAT)[12].
The discovery that metabolic diseases such as obesity and type-2 diabetes arise from
WAT dysfunctions has revealed immune and endocrine non-classical functions of
WAT, which strongly impact on metabolism, insulin sensitivity and promote local
and systemic inflammation[13-15]. Mammalian WAT depots found in distinct anatomical
locations are highly heterogeneous in their morpho-phenotypic profiles[16,17]. The
differential accumulation of fat in specific anatomical depots (rather than the total
body fat mass) is the crucial factor that determines the clinical outcomes of obesity
and other metabolic diseases. Depot-specific adipose-derived stem/stromal cells
(ASC) could be pivotal to determine the different pathophysiological roles of each
depot, by modulating the depot’s gene expression profile and its adipogenic and
immunomodulatory potentials. Therefore, a deep understanding of the contribution
of depot-specific ASC to the differential properties and pathogenicity of WAT depots
can be crucial for developing new therapeutic approaches against metabolic
disorders.
In this review, we discuss the current knowledge on depot-dependent ASC
properties and how they can contribute to the pathophysiology of obesity and
metabolic disorders. The discussion here aims to provide guidance for researchers
and clinicians in the future use ASC in therapeutic strategies against obesity and
related pathologies.
WHITE ADIPOSE TISSUE DEPOTS: A MATTER OF
ANATOMICAL LOCATION OR INHERENT PROPERTIES?
In most mammals species, fat storage occurs mainly in WAT, inside specialized cells
called adipocytes[18], which accumulate triglyceride molecules (consisting of glycerol
and fatty acid chains). Adipocytes can dramatically alter their size according to
changes in metabolic demand. After a meal, insulin stimulates WAT to store energy in
the form of neutral lipids, mainly triacylglycerol, in a process known as lipogenesis.
Conversely, adipocytes provide free fat acids to be metabolized by the organism
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
148
through lipolysis, in periods of fasting[19].
In humans, WAT is distributed in two main depots – the subcutaneous and the
visceral WAT - with distinct structure, cell content, gene expression and secretion
profiles, as well as responsiveness to neuro-endocrine stimuli. The subcutaneous
WAT is distributed along the body surface, forming the hypodermis, with distinct
depots in the abdominal, femoral, gluteal, facial and cranial regions. On the other
hand, visceral WAT surrounds the organs of the abdominal cavity, and is also found
in smaller amounts around the heart (epicardial visceral WAT), stomach (epigastric
visceral WAT) and blood vessels (perivascular visceral WAT)[16,17,20].
Evidence links obesity and metabolic dysfunction to the total body fat mass,
particularly in the abdominal region[5]. In the abdominal WAT, subcutaneous WAT is
subdivided by the Scarpa’s fascia into superficial and deep depots[21,22], while visceral
WAT is subdivided into omental (surrounding the surface of the intestines),
mesenteric (deeply within the intestines) and retroperitoneal (near the kidneys, at the
back) fat depots[16,23]. In the 1950s, Vague[24] showed that the anatomical fat distribution
could have important metabolic implications, with certain distributions favoring
diabetes and atherosclerosis. Krotkiewsk et al[25] showed that subjects with a higher
waist-to-hip ratio had increased blood pressure, low carbohydrate tolerance and high
insulin plasma levels. By connecting clinical, epidemiological and physiological
evidence with WAT measurements, different research groups concluded that visceral
fat accumulation (central obesity) is more strongly associated with higher metabolic
and cardiovascular risk, while subcutaneous fat accumulation in the thighs and hips
(peripheral obesity) is associated with a lower risk of these diseases [26-30].
However, it remained unclear whether the differential impact on systemic
metabolism was due to the anatomical location of the WAT depot, to intrinsic
properties of the cells in each depot, or both. WAT depot transplantation in mice shed
light on the influence of depot anatomical location on systemic metabolism. Both lean
and obese mice had increased glucose tolerance, insulin sensitivity and reduced body
weight after receiving a transplant of subcutaneous WAT from lean mice into the
visceral cavity[31-34]. The metabolic improvement exerted by subcutaneous WAT
transplanted into a different anatomical location suggested that subcutaneous and
visceral WAT depots are intrinsically different.
The studies mentioned above triggered the search for intrinsic biological
differences between depots that could explain the link between depot heterogeneity
and metabolic complications, both in lean and obese rodents and humans. Indeed,
gene expression analysis revealed significant differences in hundreds of genes
between distinct adipose tissue depots[35-37]. Moreover, visceral WAT has a higher
triglyceride turnover compared to subcutaneous WAT, probably due to a higher
sensitivity to the lipolytic function of catecholamines and a lower sensitivity to the
antilipolytic effects of insulin[38-40].
Thus far, the vast majority of studies on the heterogeneity of abdominal WAT
depots focused on the comparison between subcutaneous and visceral WAT.
However, abdominal WAT comprises not only these two types of depots but also the
preperitoneal (also known as endoabdominal or extraperitoneal) WAT, located
between the transverse fascia and the parietal peritoneum[41]. Interestingly, the
preperitoneal WAT has the highest size variation during weight loss by dieting,
compared with subcutaneous and visceral WAT[42]. Like subcutaneous and visceral
WAT, preperitoneal WAT can also be identified in non-obese and obese subjects by
computer-tomography and ultrasonography[43-46].
Suzuki et al[43] suggested that the abdominal wall fat index (AFI) determined by
ultrasonography could be a novel indicator of visceral fat deposition. This study
showed that the AFI - which represents the ratio between the preperitoneal WAT
maximum thickness (Pmax) and the subcutaneous WAT minimum thickness (Smin) -
positively correlates with the visceral to subcutaneous WAT ratio (V/S). These data
indicate that the thickness of the preperitoneal WAT depot is positively associated
with the visceral depot mass. Moreover, the AFI correlated positively with the plasma
levels of triglycerides and with the basal insulin levels in obese individuals, but was
inversely correlated with high density lipoprotein levels[43]. Whether preperitoneal
and visceral WAT depots have similar properties or even similar impact on metabolic
dysfunctions remains controversial. While some studies showed that the
preperitoneal WAT maximum thickness or the AFI are associated with cardiovascular
risk factors[47,48], others indicated that visceral WAT thickness showed a better
association with cardiovascular risk factors compared with subcutaneous and
preperitoneal WAT thickness[49,50]. Similarly to visceral WAT, the preperitoneal WAT
is covered by the peritoneum; however, visceral (but not preperitoneal) WAT contains
portal vein circulation[51,52]. A functional comparison of the preperitoneal WAT depot
with subcutaneous and visceral WAT, both in lean and in metabolically disrupted
patients, is necessary to clarify the impact of each WAT depot on metabolic and
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
149
cardiovascular disease risks.
Therefore, the relationship between different WAT depots and systemic homeo-
stasis and the development of metabolic diseases is mainly dependent on the intrinsic
properties rather than the anatomical location of each depot. The metabolic and
genetic differences observed between abdominal whole WAT depots could be related
to the behavior of the cells that dwell in each depot.
STROMAL-VASCULAR FRACTION AND THE INHERENT
PROPERTIES OF WAT DEPOTS
WAT is composed of two main cell fractions: mature unilocular adipocytes and
stromal-vascular cells, known as the stromal-vascular fraction (SVF). After enzymatic
digestion of the adipose tissue and centrifugation, the adipocytes float to the surface,
while SVF cells sediment to the pellet[53].
Adipocytes have the fundamental role of accumulating triacylglycerols during
periods of caloric excess, and then breaking this reservoir into free fatty acids when
energy consumption is required. Mature adipocytes are equipped with enzymes and
regulatory proteins to perform lipolysis and lipogenesis, which are orchestrated by
hormones, cytokines and other factors involved in energy metabolism[16].
The adipose SVF is highly heterogeneous, and can be sub-divided into hemato-
poietic and stromal compartments[53]. The hematopoietic compartment comprises cells
that express CD45, including lymphocytes (Natural Killer, helper and regulatory T
cells, and B cells)[54], eosinophils[55], neutrophils[56], hematopoietic progenitors[57], mast
cells[58] and macrophages. Notably, the presence of macrophages has been repeatedly
reported in human and murine adipose tissue[59-61]. The percentage of macrophages
varies according to the presence of pathophysiological conditions, such as obesity,
which is characterized by monocytic/macrophagic infiltration into adipose tissue[62,63].
The stromal compartment of the adipose SVF is composed of mesenchymal and
endothelial cells associated with blood vessels. Zimmerlin et al[64] distinguished the
following four cell subpopulations in the stromal SVF compartment, using a
combination of in situ immunolabeling and cell sorting: (1) Pericytes/mesenchymal
stem cells (MSC; CD146+/CD34-/CD31-); (2) Adipocyte progenitors/Pre-adipocytes
(CD146-/CD34+/CD31-); (3) Endothelial progenitor cells (CD31+/CD34+); and (4)
Mature endothelial cells (CD31+/CD34-). All cells in the stromal compartment are
negative for the pan-hematopoietic marker CD45. In the adipose tissue, MSC give rise
to endothelial progenitors and pre-adipocytes, which differentiate into endothelial
cells and adipocytes, respectively. Therefore, adipose MSC can maintain or increase
adipocyte numbers, thereby modulating the adipose tissue lipid store capacity, as
well as its ability for homeostasis or regeneration through adipogenesis[65].
SVF culture generates a population of adherent cells characterized by the
expression of mesenchymal markers including CD44, CD73, CD90 and CD105, but
negative for CD45 and CD31[66,67]. These cells can differentiate in vitro into mature cells
of mesodermal lineages, such as adipocytes, osteoblasts and chondrocytes[66-69]. These
combined phenotypic features and differentiation properties are diagnostic of ASC[70].
These cells can also lead to angiogenesis, by differentiating directly into endothelial
cells[71], by interacting with endothelial cells to induce vascular formation[72], or by
secreting angiogenic factors such as VEGF, HGF, FGF and PDGF[73-75]. The angiogenic
potential of ASC has important therapeutic implications. ASC secrete different types
of chemical mediators, including cytokines and growth factors, which have paracrine
activities that stimulate local cell survival and proliferation, angiogenesis, differenti-
ation of local stem cells, and reduce apoptosis[75-77]. Moreover, ASC can suppress
mixed lymphocyte reaction[78] and their low immunogenicity could enable their safe
use in allogeneic transplants, as part of cell-based regenerative therapies[79]. Therefore,
the differentiation capacity of ASC and their trophic effects directly contribute to
adipose tissue homeostasis, cell renewal, tissue repair and tissue immunogenic
balance[80].
Lafontan et al[81] postulated that metabolic and genetic differences observed
between abdominal whole WAT depots could be related to the unique properties of
the cells that dwell in each of these depots. Besides, these unique cell properties could
also account for the different responses of each depot to metabolic challenges[81,82].
Proteomic analysis of adipocytes and SVF cells isolated from subcutaneous and
visceral WAT from lean subjects showed that the SVF could have a higher contri-
bution to the functional differences observed between these depots[83].
The in vivo counterparts of the cultured ASC still remain to be defined and studies
sometimes refer to these cells as mesenchymal stem/stromal cells. Throughout this
review the term “ASC” only will be used for the adherent cells derived from the SVF
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
150
with the diagnostic features mentioned previously, which we use as criteria for ASC
identification[70]. In contrast, when describing resident adipose cells with progenitor
potential in vivo, the term “adipose progenitors” will be used instead. Given the
ability of ASC/adipose progenitors to govern adipose tissue development and
homeostasis, some studies have suggested that depot-specific ASC with unique cell-
autonomous properties could be responsible for the morpho-functional heterogeneity
of WAT depots[84-86].
RELATIONSHIP BETWEEN OBESITY-INDUCED
INFLAMMATION AND ADIPOGENESIS
WAT inflammation in obesity
The ability of adipocytes to increase in size (adipocyte hypertrophy) during
lipogenesis was believed to be the only mechanism by which adult WAT expands
upon insulin stimulation. However, it is now widely accepted that an increase in
adipocytes number - or adipose tissue hyperplasia - also contributes to WAT mass
gain through the recruitment and differentiation of adipose progenitors, in a process
known as adipogenesis[2]. Therefore, the ability of WAT to expand during life in
response to metabolic needs depends not only on adipocytes, but also on the
adipogenic potential of adipose progenitors. Other factors such as vasculature and
extracellular matrix remodeling also contribute to the plasticity of adipose tissue and
influence adipocyte hypertrophy and adipogenesis from stem cells[87].
During the development of obesity, WAT expands to an extent that leads to chronic
tissue inflammation[62], which is associated with an increased risk of type-2 diabetes
and cardiovascular disease[88]. The first functional connection between obesity and
inflammation was the observation that obese WAT secretes large amounts of the
proinflammatory cytokine tumor necrosis factor (TNF)-α, and that this cytokine had a
direct role in obesity-induced insulin resistance[89,90]. As well as increased levels of
proinflammatory cytokines, obese WAT also exhibits low level of anti-inflammatory
mediators[89,91]. The discovery that obesity is characterized by macrophage accumu-
lation in adipose tissue added a new dimension to our understanding of how obesity
propagates inflammation, as macrophage recruitment is an important factor in
promoting insulin resistance[62,63]. A clue to the origin of these recruited macrophages
came from the observation that, in CD45.2 mice transplanted with bone marrow cells
from CD45.1 mice, 85% of the adipose tissue macrophage (F4/80+) cell population had
the CD45.1 marker. Therefore, during obesity development, the expanding WAT
secretes chemoattractants (such as the mouse chemoattractant protein-1, MCP-1, and
the macrophage inflammatory protein-1α, MIP-1α) that recruit monocytes from the
bone marrow to adipose tissue[62,63].
In obesity, the infiltrating macrophages adopt a proinflammatory (“M1”)
phenotype, becoming a source of proinflammatory cytokines such as IL-1β and TNF-
α[63], which trigger local and systemic insulin resistance[62]. These infiltrating
macrophages differ from adipose tissue resident (“M2”) macrophages, which exhibit
anti-inflammatory characteristics[92,93]. In mice, high-fat diets turn the secretion pattern
of M2 macrophages into M1, by the reduction of IL-10 and arginase levels, and the
increase in TNF-α and iNOS levels[94]. Diet-induced obesity increases the expression of
the M1 marker CD11c in WAT, while decreasing CD206 expression, which is typical
of M2 macrophages[95].
The poorly-defined mechanisms that initiate inflammation and connect the
inflammatory scenario of obese WAT to other diseases are the subject of intense
investigation, in a research area known as “metabolic inflammation”[96]. Metabolically
altered adipose tissue cells may interact with immune cells to initiate the infla-
mmatory process. Interactions between immune and metabolic cells occurs in other
metabolic tissues and organs (liver, muscle and pancreas) in obese individuals,
suggesting that metabolic inflammation could be a systemic feature of obesity[97].
Immune-metabolic interactions occur in obesity between adipocytes or SVF cells
and macrophages. Indeed, adipocyte hypertrophy is a potential trigger for macro-
phage accumulation in WAT[98]. In association with the large increase in protein
synthesis, hypertrophied adipocytes display mitochondrial and endoplasmic
reticulum stress, which could lead to the activation of inflammatory signaling
pathways[99-101]. In line with this hypothesis, hypertrophied adipocytes in obese
individuals change their intrinsic secretion profile towards a proinflammatory
phenotype (characterized by high TNF-α and low adiponectin levels)[19,102,103]. TNF-α
could stimulate pre-adipocytes and endothelial cells to secrete MCP-1, attracting
monocytes from the bone marrow[62,63]. In addition, pro-inflammatory cytokines and
fatty acids secreted by hypertrophic adipocytes can lead recruited macrophages
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
151
towards an M1 proinflammatory phenotype[104]. Moreover, groups of hypoxic and
hypertrophic adipocytes undergo necrosis, and are cleared by macrophage
phagocytosis. Indeed, macrophages form crown-like structures around necrotic
adipocytes in obese WAT, in a typical chronic inflammatory response[95,105].
While the M1 profile is pro-inflammatory, the potentiation of M2 pathways in
macrophages appears to reduce metabolic inflammation (or “metainflammation”),
improving insulin sensitivity[103]. The M2 phenotype of resident adipose-tissue
macrophages is maintained by the paracrine action of lymphocytes and eosinophils;
however, in obesity, the recruitment of these cells to WAT is suppressed[106,107].
Tolerogenic CD4+ T-regulatory cells (Tregs) are also downregulated in WAT during
obesity, which could lead to metainflammation[108,109]. Aside from Tregs, other
leukocytes, including NK, NKT and mast cells, have a yet poorly-defined role in
metainflammation[110-112]. Further studies on the temporal and spatial immune-
metabolic interactions between leukocytes and WAT cells should shed light on the
mechanisms underlying inflammation in obesity, to identify potential targets for
clinical intervention.
Complex molecular signaling pathways may link metabolic challenges (e.g.,
excessive fat storage) with inflammation in obesity[113], including pathways involving
the NLRP3 inflammasome, a cytoplasmic protein complex that promotes the
conversion of pro-cytokines into active cytokines, which are then secreted[114]. NLRP3
inflammasome activity can be modulated by several metabolites, including fatty
acids, and the activation of this complex can interfere with insulin signaling[115,116].
Inflammasome activity can be triggered by endogenous or exogenous stress signals
(e.g., cytokines, free fatty acids, glucose, reactive oxygen species, ATP), which function
as “pathogen-associated molecular patterns” that interact with pattern recognition
receptors, especially toll-like receptors (TLRs), in WAT cells. The interaction of stress
signals with TLR4, for example, activates the nuclear factor-κB pathway, which
increases NLRP3 expression[116-118].
Adipose progenitors could be key regulators of macrophage recruitment and
activation in WAT[84]. Indeed, human ASC express active TLRs, including TLR4,
whose activation results in the secretion of the pro-inflammatory cytokines IL-6 and
IL-8[119]. Moreover, adipose progenitors express molecules that favor immune
differentiation, such as osteopontin, which was identified as one of the factors
involved in macrophage accumulation during diet-induced obesity[120]. In line with
this notion, we showed that human ASC secrete MCP-1 in vitro[121], and that mouse
ASC populations enriched in pre-adipocytes (CD34+ ASC) could be responsible for
most of the MCP-1 secretion in mice[122]. In addition, we observed that ASC can
support in vitro hematopoiesis, with a tendency to generate macrophages from
hematopoietic progenitors[67]. Moreover, while adipocytes are the main source of
hormones that regulate energy metabolism (such as adiponectin and leptin),
inflammatory cytokines are mostly secreted by cells from the SVF[123]. Therefore,
adipose progenitors can be key players in the regulation of the metabolic infla-
mmation established during obesity, acting as a key source of secreted immune-
mediators in adipose tissue, both in normal and in pathological conditions[124].
Although macrophage infiltration in obese adipose tissue potentiates inflammation
and favors the development of comorbidities, the pro-inflammatory cytokines
secreted by infiltrating macrophages with an M1-phenotype could also decrease WAT
mass by stimulating adipocyte lipolysis and inhibiting adipogenesis[98]. In fact,
classically activated M1 macrophages impair insulin signaling and adipogenesis in
adipocytes, by both direct and paracrine signals[94]. The immune and metabolic
interactions that occur within WAT may have evolved as a mechanism to regain
homeostasis, in order to prevent the obesity-associated mobility impairment that
makes animals more vulnerable to predators[125].
The mechanisms regulating adipogenesis and inflammatory responses from
stromal cells have been the subject of several studies, using various in vivo and in vitro
model systems[126-129]. These studies have shown that the TNF-receptor superfamily
molecule CD40 is expressed during adipogenic differentiation and interacts with
surrounding immune cells, modulating adipocyte inflammatory responses and
insulin resistance[127,128]. Additionally, a study by Tous et al[129] identified sphingosine
kinase-1 as a potential therapeutic target to attenuate chronic inflammation in obesity
and related metabolic diseases, as this molecule regulates the pro-inflammatory
response in adipose progenitors.
Impact of inflammation induction on ASC functionality
ASC functionality is directly affected by obesity-induced inflammation[121,130]. Some
studies have reported an inverse correlation between the body-mass index (BMI, a
commonly used obesity indicator) and ASC differentiation capacity[130-132]. In
agreement with these data, our studies and those of others demonstrated that ASC
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
152
from obese subjects have decreased ability to differentiate into adipocytes in vitro,
when compared with those from lean subjects, as assessed by intracellular lipid
accumulation and/or the expression of adipogenic genes[121,130-133]. Isakson et al[134]
suggested that the inflammatory state in adipose tissue may be responsible for the
impaired adipocyte differentiation observed in obesity. Indeed, inflammatory
cytokines are anti-adipogenic[135], and it is possible that ASC from obese patients carry
a “memory” of differentiation inhibition from the inflammatory environment in vivo,
and which manifests itself as impaired adipogenesis in vitro. Pro-inflammatory
macrophages secrete factors that impair human adipogenesis from ASC in vitro[136,137],
and there is a negative correlation between the adipogenic capacity of obese ASC and
the up-regulation of inflammatory genes[130,138]. In contrast, some studies reported that
ASC from obese donors showed higher expression of adipogenic genes, suggesting
that obese ASC are more potent in adipogenesis[138,139]. A recent study showed that
ASC from obese pigs (given a high-fat diet) exhibited increased adipogenic potential
relative to those from lean pigs, at the onset of obesity[140]. The discrepancies between
studies on the impact of inflammation on the adipogenic potential of ASC could be
due to differences in the methods used to evaluate adipogenesis, or to the use of
donors with different adiposity grades, or at different stages of obesity development.
The pro-angiogenic potential of ASC is also altered in obesity. ASC from morbidly
obese individuals have higher mRNA and protein expression of the anti-angiogenic
factor TSP-1 than ASC from lean individuals[130]. In addition, “lean” ASC (i.e., those
differentiated from adipose tissue of lean individuals) had increased capacity to form
tube-like networks while “obese” ASC (derived from obese individuals) were not
responsive to angiogenic stimuli[141], showing a reduced capacity to form capillary-like
structures[142]. Moreover, extracellular vesicles from obese ASC exhibited lower levels
of angiogenic-related factors and, consequently, reduced angiogenic potential
compared with those derived from lean ASC[143].
The ASC differentiation capacity is also disrupted in patients with type-2 diabetes
mellitus. Global gene expression profiling revealed that ASC from type-2 diabetes
donors have low levels of adipogenic genes compared with those from non-diabetic
donors[144], indicating a decreased potential for adipogenic differentiation in diabetes.
Additionally, ASC from diabetic rats were less effective at forming microvessels in
vivo than those from non-diabetic animals[145].
Obesity also alters the immunomodulatory properties of ASC, and their ability to
secrete chemical mediators. ASC isolated from patients with different adiposity
grades exhibit different secretion patterns[146,147]. In particular, we demonstrated that
ASC from morbidly obese patients secrete more proinflammatory cytokines, such as
IL-6 and IL-8[121], which is in agreement with data from other groups showing that
obese ASC display up-regulation of inflammatory genes (including IL-6, IL-8, IL-10
and MCP-1) compared with lean ASC[138,148]. In addition to the increased expression of
inflammatory markers, obese ASC had increased migration and phagocytosis capacity
compared with lean ASC. Besides, ASC from obese individuals show reduced
capacity to activate the M2 macrophage phenotype and to suppress lymphocyte
proliferation[149]. Therefore, the immunomodulatory properties of ASC are altered in
obesity, which may be related to the role of adipose progenitors as key regulators of
the immune response during obesity development. As well as in obesity, alterations
in immunomodulatory properties are observed in patients with type-2 diabetes
mellitus[149], and global gene expression profiling revealed that genes involved in
inflammation are upregulated in ASC from type-2 diabetes patients[144]. Recently, Liu
and colleagues[150] showed that ASC derived from mice with type-2 diabetes are less
effective at restricting CD4+T lymphocyte proliferation and pro-inflammatory
“polarization” (during pro-inflammatory immune phenotype acquisition) than ASC
from lean mice.
Collectively, these data show that obesity and other immune metabolic pathologies
disrupt ASC/adipose progenitor functionality, favoring a pro-inflammatory response.
This response, in turn, impairs ASC adipogenic capacity, which may reduce the
ability of adipose progenitors to generate new adipocytes in WAT depots, ultimately
leading to ectopic fat storage. Overall, evidence from a large number of studies
indicate that ASC/adipose progenitors are key regulators of the immune response in
obesity and other metabolic disorders, highlighting the potential of ASC use in cell-
based regenerative therapies.
REGIONAL DIFFERENCES IN ASC FUNCTIONALITY IN
OBESITY AND THEIR EFFECT ON FAT EXPANSION AND
DISTRIBUTION PATTERNS
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
153
ASC behavior in WAT depots in obesity
Numerous studies evaluated the behavior of ASC derived from different WAT depots
(in both rodents and humans; Table 1), to test the hypothesis that the properties of
depot-specific ASC could account for some of the differences in morphology, function
and response to metabolic challenges observed between WAT depots.
Baglioni et al[85] reported that, for both lean and overweight subjects, ASC derived
from subcutaneous WAT depots have higher growth rate and adipogenic potential
than those derived from visceral WAT depots. In addition, adipocytes derived from
subcutaneous ASC have greater capacity to secrete adiponectin and are less
susceptible to lipolysis than adipocytes derived from visceral ASC. Therefore,
functional differences between subcutaneous and visceral WAT depots could
originate from differences in depot-specific stem cells. Moreover, microarray analysis
revealed that the genes differentially expressed between subcutaneous and visceral
ASC are implicated in energy and lipid metabolism; importantly, genes involved in
cholesterol biosynthesis and triacylglycerol metabolism were upregulated in visceral
ASC[151]. Genome-wide expression profiles of ASC derived from subcutaneous and
visceral depots are highly distinct, in particular for the expression of genes
responsible for early development, which gave rise to the idea that adipose depots
exist as individual mini-organs[152,153].
Numerous studies have compared depot-specific ASC from lean and obese
subjects, to investigate if the differences between depot-specific ASC may account for
the differential responses of adipose depots during the development of metabolic
dysfunctions. We have recently demonstrated that ASC from the visceral depot
secreted the highest levels of IL-6 and IL-8 compared with ASC derived from
subcutaneous and preperitoneal WAT depots[86]. Other studies also reported increased
secretion of pro-inflammatory, pro-angiogenic and pro-migratory molecules (IL-
6[154,155], IL-8[154], CCL-5[154], MCP-1[86,154,155], G-CSF[86], GM-CSF[155], eotaxin[155], IL-1ra[155]
and VEGF[155]) by ASC from the visceral depot, when compared with those derived
from the subcutaneous depot. Therefore, visceral ASC appear to secrete more pro-
inflammatory cytokines than subcutaneous ASC, both in obese and in non-obese
states, which is in line with the stronger pro-inflammatory pattern adopted by visceral
WAT in response to metabolic challenges.
Fernández et al[156] were the first to report the isolation of ASC from the
preperitoneal WAT depot. These authors observed that preperitoneal ASC have a
higher adipogenic potential than those derived from the subcutaneous WAT depot.
Comparing ASC from abdominal subcutaneous, preperitoneal and visceral WAT
depots of morbidly obese women, we demonstrated that preperitoneal ASC have the
highest ability to differentiate to the adipogenic lineage in vitro. In addition, we
observed that ASC derived from the visceral depot had the lowest adipogenic
potential[86], which could be explained by the strongly pro-inflammatory milieu
established in this depot during obesity. For example, IL-6 production in visceral
WAT is 3 fold higher than in the subcutaneous depot[146,157]. Moreover, the macrophage
accumulation observed in WAT depots during obesity development[62,63] is particularly
high in the visceral compared with the subcutaneous WAT depot[158]. We have
recently demonstrated that, compared with subcutaneous SVF cells, visceral SVF
populations have higher numbers of CD14+CD206- cells, a phenotype associated with
M1 macrophages[86].
Although some studies showed that visceral ASC have higher adipogenic potential
than those from subcutaneous depots, others studies reported the opposite, both in
humans[85,86,151,153,159-166] and in mice[152,167-169], with no differences reported in two studies
in humans[131,170]. Thus, there is currently no clear consensus regarding the differences
in adipogenic potential between depot-specific ASC populations. Differences in donor
adiposity grades and sex, in ASC isolation and adipogenic induction protocols, as
well as in methods of adipogenic evaluation could account for this discrepancy, and
highlight the importance of technical standardization in this area[173]. Nevertheless, as
most studies suggest that there are differences in the adipogenic capacity of ASC
derived from distinct WAT depots, together with differences regarding their pro-
inflammatory potential (Figure 1), it is likely that ASC/adipogenic precursors
contribute to establish distinct fat distribution and expansion patterns between
depots, and the balance between hypertrophy and hyperplasia during obesity
development.
Fat distribution and expansion capacity of different WAT depots
As mentioned earlier, WAT can expand through increases in the size of adipocytes
(hypertrophy), as well as by increases in the number of adipocytes (hyperplasia,
through adipogenesis). Obese individuals where the visceral WAT is expanded
preferentially have a greater risk of developing other metabolic and cardiovascular
diseases than those who have more subcutaneous WAT expansion[174-176], which has a
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
154
Table 1 Functional aspects of human adipose-derived stem/stromal cells derived from different adipose depots
ASC depot origin Species Metabolic status
of subjects Gender Sample number
(n)
Functional
aspects of ASC Publications
SC and VC Human Non-obese Male and female 18 Proliferation: SC >
VC
Baglioni et al[85], 2012
Adipogenic
potential: SC > VC
Adiponectin
secretion by ASC-
derived adipocytes:
SC > VC
Lipolysis
susceptibility of
ASC-derived
adipocytes: VC > SC
SC, PP, VC Human Morbidly obese Female 12 Adipogenic
potential: PP > SC >
VC
Silva et al[86], 2017
IL-6, IL-8, MCP-1, G-
CSF secretion: VC >
SC = PP
PAI-1 secretion:
SC=PP > VC
Adiponectin
secretion by ASC-
derived adipocytes:
PP > SC = VC
SC e VC Human Obese Male and female 29 Proliferation: SC >
VC
van Harmelen et
al[131], 2004
Adipogenic
potential: SC = VC
SC and VC Human Non-obese Female 5 Surface markers
(CD31-, CD34-,
CD45-, CD73+,
CD90+, CD105+): SC
= VC
Kim et al[151], 2016
Proliferation: SC >
VC ;
Adipogenic
potential: SC > VC ;
Genetic pattern: SC
≠ VC
Lipid biosynthesis
and metabolism
genes expression:
VC > SC
DNA-dependent
transcription: SC >
VC
SC and VC Mice and human Non-obese and
obese
Male and female 198 (human) Genome-wide
expression profiles
(including embrionic
development and
pattern specification
genes): SC ≠ VC
Gesta et al[152], 2006
SC, VC Human Lean and obese Male and female 12 Proliferation: SC >
VC
Tchkonia et al[153],
2007
Adipogenic
potential: SC > VC
mesenteric > VC
omentum
Induced-apoptosis
susceptibility VC >
SC
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
155
Genome-wide
expression profiles
(including early
development genes):
SC ≠ VC
SC and VC Human Obese Female 8 MCP-1, IL-6, IL-8,
CCL-5 secretion: VC
> SC
Zhu et al[154], 2015
SC and VC Human Non-obese Male and female 15 MCP-1, eotaxin, IL-
1ra, IL-6, GM-CSF,
VEGF secretion: VC
> SC
Perrini et al[155], 2013
SC and PP Human Non-obese and
obese
Male 8 Proliferation: SC >
PP
Fernández et al[156],
2010
Adipogenic
potential: PP > SC
SC and VC Human Lean and obese Female 14 Adipogenic
potential: SC > VC
Hauner et al[159],
1988
SC and VC Human Not stated Not stated Not stated Adipogenic
potential: SC > VC
Adams et al[160], 1997
SC and VC Human Non-obese and
obese
Male and female 12 Adipogenic
potential: SC > VC
Niesler et al[161], 1998
Susceptibility to
induced apoptosis:
VC > SC
SC and VC Human Non-obese and
obese
Male and female Not stated Adipogenic
potential: SC > VC
Digby et al[162], 2000
SC, VC Human Obese Male and female 16 Adipogenic
potential: SC > VC
mesenteric > VC
omentum
Tchkonia et al[163],
2002
SC, VC Human Obese Male and female 18 Adipogenic
potential: SC > VC
omentum
Tchkonia et al[164],
2005
Resistance to
induced apoptosis:
SC > VC omentum
Proliferation: SC =
VC mesenteric > VC
omentum
SC, VC Human Overweight and
obese
Male and female 31 Adipogenic
potential: SC > VC
Tchkonia et al[165],
2006
Resistance to
induced apoptosis:
SC > VC mesenteric
> VC omentum
SC and VC Human Not stated Not stated 21 Proliferation: SC =
VC
Toyoda et al[166]2009
Adipogenic and
osteogenic potential:
SC > VC
SC and VC Mice Non-obese and
obese
Not stated Not stated Proliferation: SC >
VC
Macotela et al[167],
2012
Adipogenic
potential: SC > VC
SC and VC Mice Not stated Male Not stated Adipogenic
potential: SC > VC
Meissburger et al[168],
2016
SV and VC Mice High-fat diet Male and female Not stated Proliferation in
response to high-fat
diet: SC > VC
Joe et al[169], 2009
Adipogenic
potential: SC > VC
SC and VC Human Non-obese and
obese
Male and female 18 Adipogenic
potential: SC = VC
Shahparaki et al[170],
2002
SC and VC Human Non-obese Male and female 13 ASC-derived
adipocytes C/EBP,
AP-2 and
adiponection
expression: SC > VC
Perrini et al[171], 2008
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
156
Adiponectin
secretion of ASC-
derived adipocytes:
VC > SC
Stimulated glucose
uptake ASC-derived
adipocytes: VC > SC
SC e VC Mice Lean Male Not stated MMP14 expression:
SC = VC
Tokunaga et al[172],
2014
MMP8 and MMP13:
VC > SC
ASC: Adipose-derived stem/stromal cells; G-CSF: Granulocyte colony-stimulating factor; GM-CSF: Granulocyte-Macrophage colony-stimulating factor; IL:
Interleukine; MCP-1: Monocyte chemoattractant protein-1; MMP: Matrix metaloproteinase; PP: Preperitoneal; SC: Subcutaneous; VEGF: Vascular
endothelial growth factor; VC: Visceral.
protective role against the metabolic complications of obesity induced by high-fat
diets[177,178].
Hypertrophic adipocytes are associated with adipose tissue dysfunction and
inflammation[179-181], while adipocyte hyperplasia is associated with improved insulin
sensitivity and other metabolic parameters[182], indicating that the balance between
hypertrophy and hyperplasia during WAT expansion can determine the effect of
adipose tissue expansion on metabolic disease development. A comparison of WAT
depots suggested that hyperplasia contributes to subcutaneous WAT expansion more
than to the expansion of visceral WAT, after a high-fat diet[169]. Given the association
of hypertrophic adipocytes with adipose tissue dysfunction, the preferential
expansion of visceral WAT by hypertrophy rather than hyperplasia could represent
the mechanism underlying the link between visceral WAT expansion and obesity. On
the other hand, the preferential expansion of subcutaneous WAT in humans by
hyperplasia may explain why subcutaneous WAT expansion is considered com-
paratively “healthier” than visceral WAT expansion.
However, lineage-tracing experiments in transgenic male mice have challenged this
view, by detecting an increase in the formation of new adipocytes in the epididymal
visceral WAT, with no measurable adipocyte formation in the subcutaneous WAT, in
mice given a high-fat diet[183,184]. Later studies demonstrated that in vivo hyperplasia in
WAT varies according to the specific depot and the sex, being influenced by sex
hormones[185]. While males have higher potential for expansion by hyperplasia in the
visceral WAT only, females exhibit WAT hyperplasia in both visceral and sub-
cutaneous depots after a high-fat diet[185]. This may also occur in humans, since obesity
development in men is associated predominantly with visceral WAT expansion, while
obesity development in women involves subcutaneous WAT expansion[22,186]. Adding
further complexity to this issue, Tchoukalova et al[187] reported that overfeeding in
humans induces different mechanisms of WAT expansion in upper- and lower-body
subcutaneous WAT depots: while upper-body abdominal subcutaneous WAT
predominantly expands by adipocyte hypertrophy, lower-body subcutaneous WAT
preferentially expands by adipocyte hyperplasia. Moreover, differences in
preadipocyte replication or apoptosis could explain the differential patterns of
expansion between upper- and lower-body subcutaneous WAT depots.
The numerous in vitro and in vivo studies described in this review suggests that the
different physiopathological properties of distinct WAT depots could be attributed to
the intrinsic properties - including gene expression, adipogenic and angiogenic
potentials, and inflammatory behavior - of adipose progenitors cells within each
adipose compartment. However, Jeffery et al[185] recently challenged this hypothesis by
demonstrating, in a series of elegant transplantation experiments in transgenic mice,
that donor adipose progenitor cells behave as resident progenitors after
transplantation. As previously described, levels of hyperplasia were only detected in
visceral WAT of male mice fed with a high-fat diet, but not in subcutaneous WAT,
indicating that subcutaneous adipose progenitors did not enter adipogenesis[184].
Importantly, when subcutaneous adipose progenitors were injected into the visceral
WAT depot, they proliferated in response to the high-fat diet, but neither
subcutaneous nor visceral adipose progenitors proliferated when transplanted into
the subcutaneous WAT depot[185]. These exciting data may suggest that adipose
progenitors from distinct WAT depots, despite having different developmental
origins[188,189], are functionally plastic and capable of responding to high-fat diets
according to cell-extrinsic factors of the depot microenvironment. Therefore, these
new data suggest that, irrespective of their origin, adipose progenitors behave
according to the WAT depot in which they dwell. Although it is clear that ASC from
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
157
Figure 1
Figure 1 Adipogenic and pro-inflammatory potentials of adipose-derived stem/stromal cells derived from different abdominal adipose tissue depots.
Adipose-derived stem/stromal cells (ASC) from different abdominal adipose tissues have different adipogenic and immunomodulatory properties. Pre-peritoneal ASC
have the highest capacity to generate new adipocytes by adipogenesis and low pro-inflammatory profile. ASC from visceral abdominal depot have the highest capacity
to secrete pro-inflammatory cytokines such as interleukine (IL)-1ra, IL-6 and IL-8 together with the lowest adipogenic potential. ASC: Adipose-derived stem/stromal
cells; WAT: White adipose tissue.
distinct fat depots contribute differently to obesity, further studies are now necessary
to clarify the contribution of cell-extrinsic and/or intrinsic factors in obesity
development.
CONCLUSION
Adipose progenitors play an important role in obesogenic WAT growth and the
regulation of adipogenesis by these cells may be used in novel therapeutic strategies
against obesity and related diseases. There is no doubt that ASC from different WAT
depots have distinct properties, which are not totally autonomous, as the distinct
microenvironments of each WAT depot influence the function of adipose progenitor
in WAT expansion. Moreover, distinct in vivo niches of adipose progenitors may
account for the differential susceptibilities of adipose depot to the development of
metabolic dysfunction. Future studies on adipose progenitor niches, considering the
depot-specific microenvironment and the influence of sex influence on adipose
progenitor activation, should elucidate the regulatory signals that govern adipose
progenitor function. Ultimately, these studies may allow adipose progenitors to be
targeted in therapeutic approaches to prevent obesity development or to allow obese
individuals to reach a healthier metabolic status.
ACKNOWLEDGEMENTS
The authors thank the National Council for Scientific and Technological Development
(CNPq), the Carlos Chagas Filho Foundation for Research Support of the State of Rio
de Janeiro (FAPERJ) and the Coordination of High Education Personnel Improvement
(CAPES) for financial support.
REFERENCES
1Conway B, Rene A. Obesity as a disease: no lightweight matter. Obes Rev 2004; 5: 145-151 [PMID:
15245383 DOI: 10.1111/j.1467-789X.2004.00144.x]
2de Ferranti S, Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic
consequences. Clin Chem 2008; 54: 945-955 [PMID: 18436717 DOI: 10.1373/clinchem.2007.100156]
3Björntorp P. Metabolic implications of body fat distribution. Diabetes Care 1991; 14: 1132-1143 [PMID:
1773700 DOI: 10.2337/diacare.14.12.1132]
4Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and
risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747-1757 [PMID:
16731270 DOI: 10.1016/S0140-6736(06)68770-9]
5Després JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, Rodés-Cabau J, Bertrand OF, Poirier
P. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk.
Arterioscler Thromb Vasc Biol 2008; 28: 1039-1049 [PMID: 18356555 DOI:
10.1161/ATVBAHA.107.159228]
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
158
6Pi-Sunyer X. The medical risks of obesity. Postgrad Med 2009; 121: 21-33 [PMID: 19940414 DOI:
10.3810/pgm.2009.11.2074]
7Aune D, Sen A, Norat T, Janszky I, Romundstad P, Tonstad S, Vatten LJ. Body Mass Index, Abdominal
Fatness, and Heart Failure Incidence and Mortality: A Systematic Review and Dose-Response Meta-
Analysis of Prospective Studies. Circulation 2016; 133: 639-649 [PMID: 26746176 DOI: 10.1161/CIR-
CULATIONAHA.115.016801]
8Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a
systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569-578
[PMID: 18280327 DOI: 10.1016/S0140-6736(08)60269-X]
9Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: new mechanistic insights from
epidemiology. Nat Rev Cancer 2015; 15: 484-498 [PMID: 26205341 DOI: 10.1038/nrc3967]
10 Font-Burgada J, Sun B, Karin M. Obesity and Cancer: The Oil that Feeds the Flame. Cell Metab 2016;
23: 48-62 [PMID: 26771116 DOI: 10.1016/j.cmet.2015.12.015]
11 Donohoe CL, Lysaght J, O'Sullivan J, Reynolds JV. Emerging Concepts Linking Obesity with the
Hallmarks of Cancer. Trends Endocrinol Metab 2017; 28: 46-62 [PMID: 27633129 DOI:
10.1016/j.tem.2016.08.004]
12 Frayn KN, Karpe F, Fielding BA, Macdonald IA, Coppack SW. Integrative physiology of human adipose
tissue. Int J Obes Relat Metab Disord 2003; 27: 875-888 [PMID: 12861227 DOI: 10.1038/sj.ijo.0802326]
13 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat
Rev Immunol 2006; 6: 772-783 [PMID: 16998510 DOI: 10.1038/nri1937]
14 Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev
Immunol 2011; 11: 85-97 [PMID: 21252989 DOI: 10.1038/nri2921]
15 Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 2012;
8: 709-716 [PMID: 22847239 DOI: 10.1038/nrendo.2012.114]
16 Wronska A, Kmiec Z. Structural and biochemical characteristics of various white adipose tissue depots.
Acta Physiol (Oxf) 2012; 205: 194-208 [PMID: 22226221 DOI: 10.1111/j.1748-1716.2012.02409.x]
17 Schoettl T, Fischer IP, Ussar S. Heterogeneity of adipose tissue in development and metabolic function. J
Exp Biol 2018; 221: jeb162958 [PMID: 29514879 DOI: 10.1242/jeb.162958]
18 Cinti S. The adipose organ. Prostaglandins Leukot Essent Fatty Acids 2005; 73: 9-15 [PMID: 15936182
DOI: 10.1016/j.plefa.2005.04.010]
19 Blüher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR. Adipose tissue selective
insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 2002;
3: 25-38 [PMID: 12110165]
20 Iozzo P. Myocardial, perivascular, and epicardial fat. Diabetes Care 2011; 34 Suppl 2: S371-S379 [PMID:
21525485 DOI: 10.2337/dc11-s250]
21 Smith SR, Lovejoy JC, Greenway F, Ryan D, deJonge L, de la Bretonne J, Volafova J, Bray GA.
Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose
tissue to the metabolic complications of obesity. Metabolism 2001; 50: 425-435 [PMID: 11288037 DOI:
10.1053/meta.2001.21693]
22 Lancerotto L, Stecco C, Macchi V, Porzionato A, Stecco A, De Caro R. Layers of the abdominal wall:
anatomical investigation of subcutaneous tissue and superficial fascia. Surg Radiol Anat 2011; 33: 835-842
[PMID: 21212951 DOI: 10.1007/s00276-010-0772-8]
23 Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 2007; 131:
242-256 [PMID: 17956727 DOI: 10.1016/j.cell.2007.10.004]
24 Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to
diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956; 4: 20-34 [PMID:
13282851 DOI: 10.1093/ajcn/4.1.20]
25 Krotkiewski M, Björntorp P, Sjöström L, Smith U. Impact of obesity on metabolism in men and women.
Importance of regional adipose tissue distribution. J Clin Invest 1983; 72: 1150-1162 [PMID: 6350364
DOI: 10.1172/JCI111040]
26 Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue
distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the
study of men born in 1913. Br Med J (Clin Res Ed) 1984; 288: 1401-1404 [PMID: 6426576 DOI:
10.1136/bmj.288.6428.1401]
27 Fujioka S, Matsuzawa Y, Tokunaga K, Tarui S. Contribution of intra-abdominal fat accumulation to the
impairment of glucose and lipid metabolism in human obesity. Metabolism 1987; 36: 54-59 [PMID:
3796297 DOI: 10.1016/0026-0495(87)90063-1]
28 von Eyben FE, Mouritsen E, Holm J, Montvilas P, Dimcevski G, Suciu G, Helleberg I, Kristensen L, von
Eyben R. Intra-abdominal obesity and metabolic risk factors: a study of young adults. Int J Obes Relat
Metab Disord 2003; 27: 941-949 [PMID: 12861235 DOI: 10.1038/sj.ijo.0802309]
29 Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY, Vasan RS, Murabito JM,
Meigs JB, Cupples LA, D'Agostino RB Sr, O'Donnell CJ. Abdominal visceral and subcutaneous adipose
tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation
2007; 116: 39-48 [PMID: 17576866 DOI: 10.1161/CIRCULATIONAHA.106.675355]
30 Primeau V, Coderre L, Karelis AD, Brochu M, Lavoie ME, Messier V, Sladek R, Rabasa-Lhoret R.
Characterizing the profile of obese patients who are metabolically healthy. Int J Obes (Lond) 2011; 35:
971-981 [PMID: 20975726 DOI: 10.1038/ijo.2010.216]
31 Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on
metabolism. Cell Metab 2008; 7: 410-420 [PMID: 18460332 DOI: 10.1016/j.cmet.2008.04.004]
32 Hocking SL, Chisholm DJ, James DE. Studies of regional adipose transplantation reveal a unique and
beneficial interaction between subcutaneous adipose tissue and the intra-abdominal compartment.
Diabetologia 2008; 51: 900-902 [PMID: 18340430 DOI: 10.1007/s00125-008-0969-0]
33 Foster MT, Softic S, Caldwell J, Kohli R, de Kloet AD, Seeley RJ. Subcutaneous Adipose Tissue
Transplantation in Diet-Induced Obese Mice Attenuates Metabolic Dysregulation While Removal
Exacerbates It. Physiol Rep 2013; 1: e00015 [PMID: 23914298 DOI: 10.1002/phy2.15]
34 Hocking SL, Stewart RL, Brandon AE, Suryana E, Stuart E, Baldwin EM, Kolumam GA, Modrusan Z,
Junutula JR, Gunton JE, Medynskyj M, Blaber SP, Karsten E, Herbert BR, James DE, Cooney GJ,
Swarbrick MM. Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and
inflammation in mice. Diabetologia 2015; 58: 1587-1600 [PMID: 25899451 DOI:
10.1007/s00125-015-3583-y]
35 Vidal H. Gene expression in visceral and subcutaneous adipose tissues. Ann Med 2001; 33: 547-555
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
159
[PMID: 11730162 DOI: 10.3109/07853890108995965]
36 Vohl MC, Sladek R, Robitaille J, Gurd S, Marceau P, Richard D, Hudson TJ, Tchernof A. A survey of
genes differentially expressed in subcutaneous and visceral adipose tissue in men. Obes Res 2004; 12:
1217-1222 [PMID: 15340102 DOI: 10.1038/oby.2004.153]
37 Linder K, Arner P, Flores-Morales A, Tollet-Egnell P, Norstedt G. Differentially expressed genes in
visceral or subcutaneous adipose tissue of obese men and women. J Lipid Res 2004; 45: 148-154 [PMID:
14563828 DOI: 10.1194/jlr.M300256-JLR200]
38 Bolinder J, Kager L, Ostman J, Arner P. Differences at the receptor and postreceptor levels between
human omental and subcutaneous adipose tissue in the action of insulin on lipolysis. Diabetes 1983; 32:
117-123 [PMID: 6337893 DOI: 10.2337/diab.32.2.117]
39 Rebuffé-Scrive M, Andersson B, Olbe L, Björntorp P. Metabolism of adipose tissue in intraabdominal
depots of nonobese men and women. Metabolism 1989; 38: 453-458 [PMID: 2725284 DOI:
10.1016/0026-0495(89)90198-4]
40 Rebuffé-Scrive M, Anderson B, Olbe L, Björntorp P. Metabolism of adipose tissue in intraabdominal
depots in severely obese men and women. Metabolism 1990; 39: 1021-1025 [PMID: 2215250 DOI:
10.1016/0026-0495(90)90160-E]
41 Moore KL, Dalley AF. Anatomia orientada para a clínica. Rio de Janeiro: Guanabara Koogan 2001; 1023
42 Sabir N, Pakdemirli E, Sermez Y, Zencir M, Kazil S. Sonographic assessment of changes in thickness of
different abdominal fat layers in response to diet in obese women. J Clin Ultrasound 2003; 31: 26-30
[PMID: 12478649 DOI: 10.1002/jcu.10129]
43 Suzuki R, Watanabe S, Hirai Y, Akiyama K, Nishide T, Matsushima Y, Murayama H, Ohshima H,
Shinomiya M, Shirai K. Abdominal wall fat index, estimated by ultrasonography, for assessment of the
ratio of visceral fat to subcutaneous fat in the abdomen. Am J Med 1993; 95: 309-314 [PMID: 8368228
DOI: 10.1016/0002-9343(93)90284-V]
44 Tayama K, Inukai T, Shimomura Y. Preperitoneal fat deposition estimated by ultrasonography in patients
with non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1999; 43: 49-58 [PMID: 10199588
DOI: 10.1016/S0168-8227(98)00118-1]
45 Kawamoto R, Ohtsuka N, Nakamura S, Ninomiya D, Inoue A. Preperitoneal fat thickness by
ultrasonography and obesity-related disorders. J Med Ultrason (2001) 2007; 34: 93-99 [PMID: 27278292
DOI: 10.1007/s10396-007-0137-z]
46 Guldiken S, Tuncbilek N, Okten OO, Arikan E, Tugrul A. Visceral fat thickness determined using
ultrasonography is associated with anthropometric and clinical parameters of metabolic syndrome. Int J
Clin Pract 2006; 60: 1576-1581 [PMID: 16669827 DOI: 10.1111/j.1742-1241.2005.00803.x]
47 Nishina M, Kikuchi T, Yamazaki H, Kameda K, Hiura M, Uchiyama M. Relationship among systolic
blood pressure, serum insulin and leptin, and visceral fat accumulation in obese children. Hypertens Res
2003; 26: 281-288 [PMID: 12733695 DOI: 10.1291/hypres.26.281]
48 Kawamoto R, Kajiwara T, Oka Y, Takagi Y. Association between abdominal wall fat index and carotid
atherosclerosis in women. J Atheroscler Thromb 2002; 9: 213-218 [PMID: 12409630 DOI:
10.5551/jat.9.213]
49 Liu KH, Chan YL, Chan WB, Kong WL, Kong MO, Chan JC. Sonographic measurement of mesenteric
fat thickness is a good correlate with cardiovascular risk factors: comparison with subcutaneous and
preperitoneal fat thickness, magnetic resonance imaging and anthropometric indexes. Int J Obes Relat
Metab Disord 2003; 27: 1267-1273 [PMID: 14513076 DOI: 10.1038/sj.ijo.0802398]
50 Kim SK, Kim HJ, Hur KY, Choi SH, Ahn CW, Lim SK, Kim KR, Lee HC, Huh KB, Cha BS. Visceral fat
thickness measured by ultrasonography can estimate not only visceral obesity but also risks of
cardiovascular and metabolic diseases. Am J Clin Nutr 2004; 79: 593-599 [PMID: 15051602 DOI:
10.1093/ajcn/79.4.593]
51 Vague J, Vague P, Meignen JM. Android and gynoid obesities, past and present. In: Vague J, BjoÌrntorp
P, Guy-Grand B, editors. Metabolic complications of human obesities. Amsterdam: Ex-cerpta Medica
1985; 3
52 Busetto L, Baggio MB, Zurlo F, Carraro R, Digito M, Enzi G. Assessment of abdominal fat distribution in
obese patients: anthropometry versus computerized tomography. Int J Obes Relat Metab Disord 1992; 16:
731-736 [PMID: 1330952]
53 Cousin B, Caspar-Bauguil S, Planat-Bénard V, Laharrague P, Pénicaud L, Casteilla L. [Adipose tissue: a
subtle and complex cell system]. J Soc Biol 2006; 200: 51-57 [PMID: 17144162 DOI:
10.1051/jbio:2006007]
54 Caspar-Bauguil S, Cousin B, Galinier A, Segafredo C, Nibbelink M, André M, Casteilla L, Pénicaud L.
Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett 2005; 579: 3487-
3492 [PMID: 15953605 DOI: 10.1016/j.febslet.2005.05.031]
55 Schipper HS, Prakken B, Kalkhoven E, Boes M. Adipose tissue-resident immune cells: key players in
immunometabolism. Trends Endocrinol Metab 2012; 23: 407-415 [PMID: 22795937 DOI:
10.1016/j.tem.2012.05.011]
56 Elgazar-Carmon V, Rudich A, Hadad N, Levy R. Neutrophils transiently infiltrate intra-abdominal fat
early in the course of high-fat feeding. J Lipid Res 2008; 49: 1894-1903 [PMID: 18503031 DOI:
10.1194/jlr.M800132-JLR200]
57 Cousin B, André M, Arnaud E, Pénicaud L, Casteilla L. Reconstitution of lethally irradiated mice by cells
isolated from adipose tissue. Biochem Biophys Res Commun 2003; 301: 1016-1022 [PMID: 12589814
DOI: 10.1016/S0006-291X(03)00061-5]
58 Anderson EK, Gutierrez DA, Hasty AH. Adipose tissue recruitment of leukocytes. Curr Opin Lipidol
2010; 21: 172-177 [PMID: 20410821 DOI: 10.1097/MOL.0b013e3283393867]
59 Cousin B, André M, Casteilla L, Pénicaud L. Altered macrophage-like functions of preadipocytes in
inflammation and genetic obesity. J Cell Physiol 2001; 186: 380-386 [PMID: 11169977 DOI:
10.1002/1097-4652(2001)9999:9999<000::AID-JCP1038>3.0.CO;2-T]
60 Villena JA, Cousin B, Pénicaud L, Casteilla L. Adipose tissues display differential phagocytic and
microbicidal activities depending on their localization. Int J Obes Relat Metab Disord 2001; 25: 1275-
1280 [PMID: 11571587 DOI: 10.1038/sj.ijo.0801680]
61 Curat CA, Miranville A, Sengenès C, Diehl M, Tonus C, Busse R, Bouloumié A. From blood monocytes
to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes
2004; 53: 1285-1292 [PMID: 15111498 DOI: 10.2337/diabetes.53.5.1285]
62 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H.
Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
160
Clin Invest 2003; 112: 1821-1830 [PMID: 14679177 DOI: 10.1172/JCI19451]
63 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with
macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808 [PMID: 14679176 DOI:
10.1172/JCI19246]
64 Zimmerlin L, Donnenberg VS, Pfeifer ME, Meyer EM, Péault B, Rubin JP, Donnenberg AD. Stromal
vascular progenitors in adult human adipose tissue. Cytometry A 2010; 77: 22-30 [PMID: 19852056 DOI:
10.1002/cyto.a.20813]
65 Gray SL, Vidal-Puig AJ. Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr
Rev 2007; 65: S7-12 [PMID: 17605308 DOI: 10.1301/nr.2007.jun.S7-S12]
66 Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P,
Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13: 4279-
4295 [PMID: 12475952 DOI: 10.1091/mbc.e02-02-0105]
67 Baptista LS, Pedrosa CGS, Silva KR, Otazú IB, Takyia CM, Dutra HS, Cláudio-da-silva C, Borojevic R,
Rossi MID. Bone Marrow and Adipose Tissue-Derived Mesenchymal Stem Cells: How Close Are They? J
Stem Cells 2007; 2: 2
68 Hattori H, Sato M, Masuoka K, Ishihara M, Kikuchi T, Matsui T, Takase B, Ishizuka T, Kikuchi M,
Fujikawa K, Ishihara M. Osteogenic potential of human adipose tissue-derived stromal cells as an
alternative stem cell source. Cells Tissues Organs 2004; 178: 2-12 [PMID: 15550755 DOI:
10.1159/000081088]
69 Guilak F, Awad HA, Fermor B, Leddy HA, Gimble JM. Adipose-derived adult stem cells for cartilage
tissue engineering. Biorheology 2004; 41: 389-399 [PMID: 15299271]
70 Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, Redl H, Rubin JP, Yoshimura K,
Gimble JM. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded
adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose
Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy
2013; 15: 641-648 [PMID: 23570660 DOI: 10.1016/j.jcyt.2013.02.006]
71 Planat-Benard V, Silvestre JS, Cousin B, André M, Nibbelink M, Tamarat R, Clergue M, Manneville C,
Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Pénicaud L, Casteilla L. Plasticity of human adipose
lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 2004; 109:
656-663 [PMID: 14734516 DOI: 10.1161/01.CIR.0000114522.38265.61]
72 Merfeld-Clauss S, Gollahalli N, March KL, Traktuev DO. Adipose tissue progenitor cells directly interact
with endothelial cells to induce vascular network formation. Tissue Eng Part A 2010; 16: 2953-2966
[PMID: 20486792 DOI: 10.1089/ten.tea.2009.0635]
73 Vilahur G, Oñate B, Cubedo J, Béjar MT, Arderiu G, Peña E, Casaní L, Gutiérrez M, Capdevila A, Pons-
Lladó G, Carreras F, Hidalgo A, Badimon L. Allogenic adipose-derived stem cell therapy overcomes
ischemia-induced microvessel rarefaction in the myocardium: systems biology study. Stem Cell Res Ther
2017; 8: 52 [PMID: 28279225 DOI: 10.1186/s13287-017-0509-2]
74 Hsiao ST, Asgari A, Lokmic Z, Sinclair R, Dusting GJ, Lim SY, Dilley RJ. Comparative analysis of
paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose,
and dermal tissue. Stem Cells Dev 2012; 21: 2189-2203 [PMID: 22188562 DOI: 10.1089/scd.2011.0674]
75 Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH,
Considine RV, March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal
cells. Circulation 2004; 109: 1292-1298 [PMID: 14993122 DOI: 10.1161/01.CIR.0000121425.42966.F1]
76 Nakagami H, Maeda K, Morishita R, Iguchi S, Nishikawa T, Takami Y, Kikuchi Y, Saito Y, Tamai K,
Ogihara T, Kaneda Y. Novel autologous cell therapy in ischemic limb disease through growth factor
secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol 2005; 25: 2542-
2547 [PMID: 16224047 DOI: 10.1161/01.ATV.0000190701.92007.6d]
77 Wang M, Crisostomo PR, Herring C, Meldrum KK, Meldrum DR. Human progenitor cells from bone
marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent
mechanism. Am J Physiol Regul Integr Comp Physiol 2006; 291: R880-R884 [PMID: 16728464 DOI:
10.1152/ajpregu.00280.2006]
78 Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M,
Laharrague P, Penicaud L, Casteilla L, Blancher A. Immunomodulatory effect of human adipose tissue-
derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 2005;
129: 118-129 [PMID: 15801964 DOI: 10.1111/j.1365-2141.2005.05409.x]
79 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses.
Blood 2005; 105: 1815-1822 [PMID: 15494428 DOI: 10.1182/blood-2004-04-1559]
80 Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006; 98: 1076-
1084 [PMID: 16619257 DOI: 10.1002/jcb.20886]
81 Lafontan M, Berlan M. Do regional differences in adipocyte biology provide new pathophysiological
insights? Trends Pharmacol Sci 2003; 24: 276-283 [PMID: 12823953 DOI:
10.1016/S0165-6147(03)00132-9]
82 Lebovitz HE. The relationship of obesity to the metabolic syndrome. Int J Clin Pract Suppl 2003; 18-27
[PMID: 12793594]
83 Peinado JR, Jimenez-Gomez Y, Pulido MR, Ortega-Bellido M, Diaz-Lopez C, Padillo FJ, Lopez-Miranda
J, Vazquez-Martínez R, Malagón MM. The stromal-vascular fraction of adipose tissue contributes to major
differences between subcutaneous and visceral fat depots. Proteomics 2010; 10: 3356-3366 [PMID:
20706982 DOI: 10.1002/pmic.201000350]
84 Cignarelli A, Perrini S, Ficarella R, Peschechera A, Nigro P, Giorgino F. Human adipose tissue stem cells:
relevance in the pathophysiology of obesity and metabolic diseases and therapeutic applications. Expert
Rev Mol Med 2012; 14: e19 [PMID: 23302474 DOI: 10.1017/erm.2012.13]
85 Baglioni S, Cantini G, Poli G, Francalanci M, Squecco R, Di Franco A, Borgogni E, Frontera S, Nesi G,
Liotta F, Lucchese M, Perigli G, Francini F, Forti G, Serio M, Luconi M. Functional differences in visceral
and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS One 2012; 7: e36569
[PMID: 22574183 DOI: 10.1371/journal.pone.0036569]
86 Silva KR, Côrtes I, Liechocki S, Carneiro JR, Souza AA, Borojevic R, Maya-Monteiro CM, Baptista LS.
Characterization of stromal vascular fraction and adipose stem cells from subcutaneous, preperitoneal and
visceral morbidly obese human adipose tissue depots. PLoS One 2017; 12: e0174115 [PMID: 28323901
DOI: 10.1371/journal.pone.0174115]
87 Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to
pathophysiological cues. Diabetologia 2016; 59: 1075-1088 [PMID: 27039901 DOI:
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
161
10.1007/s00125-016-3933-4]
88 Freitas Lima LC, Braga VA, do Socorro de França Silva M, Cruz JC, Sousa Santos SH, de Oliveira
Monteiro MM, Balarini CM. Adipokines, diabetes and atherosclerosis: an inflammatory association. Front
Physiol 2015; 6: 304 [PMID: 26578976 DOI: 10.3389/fphys.2015.00304]
89 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct
role in obesity-linked insulin resistance. Science 1993; 259: 87-91 [PMID: 7678183 DOI:
10.1126/science.7678183]
90 Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes
link. Diabetes 1994; 43: 1271-1278 [PMID: 7926300 DOI: 10.2337/diab.43.11.1271]
91 Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations
with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from
adipose tissue? Arterioscler Thromb Vasc Biol 1999; 19: 972-978 [PMID: 10195925 DOI:
10.1161/01.ATV.19.4.972]
92 Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Györi G, Zlabinger GJ, Stulnig TM. Human
adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-
inflammatory mediator production. Int J Obes (Lond) 2007; 31: 1420-1428 [PMID: 17593905 DOI:
10.1038/sj.ijo.0803632]
93 Bourlier V, Zakaroff-Girard A, Miranville A, De Barros S, Maumus M, Sengenes C, Galitzky J, Lafontan
M, Karpe F, Frayn KN, Bouloumié A. Remodeling phenotype of human subcutaneous adipose tissue
macrophages. Circulation 2008; 117: 806-815 [PMID: 18227385 DOI:
10.1161/CIRCULATIONAHA.107.724096]
94 Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage
polarization. J Clin Invest 2007; 117: 175-184 [PMID: 17200717 DOI: 10.1172/JCI29881]
95 Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue
macrophages recruited during diet-induced obesity. Diabetes 2007; 56: 16-23 [PMID: 17192460 DOI:
10.2337/db06-1076]
96 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867 [PMID: 17167474
DOI: 10.1038/nature05485]
97 Cao H. Adipocytokines in obesity and metabolic disease. J Endocrinol 2014; 220: T47-T59 [PMID:
24403378 DOI: 10.1530/JOE-13-0339]
98 Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an
allostatic perspective. Biochim Biophys Acta 2010; 1801: 338-349 [PMID: 20056169 DOI:
10.1016/j.bbalip.2009.12.006]
99 Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH,
Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science
2004; 306: 457-461 [PMID: 15486293 DOI: 10.1126/science.1103160]
100 Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka TA, Ozawa K, Ogawa S, Hori
M, Yamasaki Y, Matsuhisa M. Involvement of endoplasmic reticulum stress in insulin resistance and
diabetes. J Biol Chem 2005; 280: 847-851 [PMID: 15509553 DOI: 10.1074/jbc.M411860200]
101 Ozawa K, Miyazaki M, Matsuhisa M, Takano K, Nakatani Y, Hatazaki M, Tamatani T, Yamagata K,
Miyagawa J, Kitao Y, Hori O, Yamasaki Y, Ogawa S. The endoplasmic reticulum chaperone improves
insulin resistance in type 2 diabetes. Diabetes 2005; 54: 657-663 [PMID: 15734840 DOI: 10.2337/dia-
betes.54.3.657]
102 Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine
expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023-1033 [PMID: 17164304 DOI:
10.1210/jc.2006-1055]
103 Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res 2005; 96: 939-
949 [PMID: 15890981 DOI: 10.1161/01.RES.0000163635.62927.34]
104 Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72:
219-246 [PMID: 20148674 DOI: 10.1146/annurev-physiol-021909-135846]
105 Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin
MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and
humans. J Lipid Res 2005; 46: 2347-2355 [PMID: 16150820 DOI: 10.1194/jlr.M500294-JLR200]
106 Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM.
Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis.
Science 2011; 332: 243-247 [PMID: 21436399 DOI: 10.1126/science.1201475]
107 Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H,
Koyasu S. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid
cells. Nature 2010; 463: 540-544 [PMID: 20023630 DOI: 10.1038/nature08636]
108 Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson
S, Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect
metabolic parameters. Nat Med 2009; 15: 930-939 [PMID: 19633656 DOI: 10.1038/nm.2002]
109 Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi
F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM. Normalization of obesity-associated
insulin resistance through immunotherapy. Nat Med 2009; 15: 921-929 [PMID: 19633657 DOI:
10.1038/nm.2001]
110 O'Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II, Jobe BA, Roberts CT, Slifka
MK, Marks DL. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-
gamma in inflammation in human adipose tissue. Int J Obes (Lond) 2009; 33: 978-990 [PMID: 19564875
DOI: 10.1038/ijo.2009.133]
111 Liu J, Divoux A, Sun J, Zhang J, Clément K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ,
Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP. Genetic deficiency and
pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med
2009; 15: 940-945 [PMID: 19633655 DOI: 10.1038/nm.1994]
112 Ohmura K, Ishimori N, Ohmura Y, Tokuhara S, Nozawa A, Horii S, Andoh Y, Fujii S, Iwabuchi K, Onoé
K, Tsutsui H. Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in
diet-induced obese mice. Arterioscler Thromb Vasc Biol 2010; 30: 193-199 [PMID: 19910631 DOI:
10.1161/ATVBAHA.109.198614]
113 Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011;
121: 2111-2117 [PMID: 21633179 DOI: 10.1172/JCI57132]
114 McArdle MA, Finucane OM, Connaughton RM, McMorrow AM, Roche HM. Mechanisms of obesity-
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
162
induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. Front
Endocrinol (Lausanne) 2013; 4: 52 [PMID: 23675368 DOI: 10.3389/fendo.2013.00052]
115 Finucane OM, Lyons CL, Murphy AM, Reynolds CM, Klinger R, Healy NP, Cooke AA, Coll RC,
McAllan L, Nilaweera KN, O'Reilly ME, Tierney AC, Morine MJ, Alcala-Diaz JF, Lopez-Miranda J,
O'Connor DP, O'Neill LA, McGillicuddy FC, Roche HM. Monounsaturated fatty acid-enriched high-fat
diets impede adipose NLRP3 inflammasome-mediated IL-1β secretion and insulin resistance despite
obesity. Diabetes 2015; 64: 2116-2128 [PMID: 25626736 DOI: 10.2337/db14-1098]
116 Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC
inflammasome activation interferes with insulin signaling. Nat Immunol 2011; 12: 408-415 [PMID:
21478880 DOI: 10.1038/ni.2022]
117 Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J,
Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-kappaB activating pattern recognition
and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J
Immunol 2009; 183: 787-791 [PMID: 19570822 DOI: 10.4049/jimmunol.0901363]
118 Tsutsui H, Imamura M, Fujimoto J, Nakanishi K. The TLR4/TRIF-Mediated Activation of NLRP3
Inflammasome Underlies Endotoxin-Induced Liver Injury in Mice. Gastroenterol Res Pract 2010; 2010:
641865 [PMID: 20634907 DOI: 10.1155/2010/641865]
119 Lombardo E, DelaRosa O, Mancheño-Corvo P, Menta R, Ramírez C, Büscher D. Toll-like receptor-
mediated signaling in human adipose-derived stem cells: implications for immunogenicity and
immunosuppressive potential. Tissue Eng Part A 2009; 15: 1579-1589 [PMID: 19061425 DOI:
10.1089/ten.tea.2008.0340]
120 Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, Jones KL, Kawamori R, Cassis
LA, Tschöp MH, Bruemmer D. Osteopontin mediates obesity-induced adipose tissue macrophage
infiltration and insulin resistance in mice. J Clin Invest 2007; 117: 2877-2888 [PMID: 17823662 DOI:
10.1172/JCI31986]
121 Silva KR, Liechocki S, Carneiro JR, Claudio-da-Silva C, Maya-Monteiro CM, Borojevic R, Baptista LS.
Stromal-vascular fraction content and adipose stem cell behavior are altered in morbid obese and post
bariatric surgery ex-obese women. Stem Cell Res Ther 2015; 6: 72 [PMID: 25884374 DOI:
10.1186/s13287-015-0029-x]
122 Zhou HR, Kim EK, Kim H, Claycombe KJ. Obesity-associated mouse adipose stem cell secretion of
monocyte chemotactic protein-1. Am J Physiol Endocrinol Metab 2007; 293: E1153-E1158 [PMID:
17726148 DOI: 10.1152/ajpendo.00186.2007]
123 Siklova-Vitkova M, Klimcakova E, Polak J, Kovacova Z, Tencerova M, Rossmeislova L, Bajzova M,
Langin D, Stich V. Adipose tissue secretion and expression of adipocyte-produced and stromavascular
fraction-produced adipokines vary during multiple phases of weight-reducing dietary intervention in obese
women. J Clin Endocrinol Metab 2012; 97: E1176-E1181 [PMID: 22535973 DOI: 10.1210/jc.2011-2380]
124 Itoh M, Suganami T, Hachiya R, Ogawa Y. Adipose tissue remodeling as homeostatic inflammation. Int J
Inflam 2011; 2011: 720926 [PMID: 21755030 DOI: 10.4061/2011/720926]
125 Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human
studies. Am J Physiol Endocrinol Metab 2013; 304: E466-E477 [PMID: 23269411 DOI:
10.1152/ajpendo.00266.2012]
126 Ruiz-Ojeda FJ, Rupérez AI, Gomez-Llorente C, Gil A, Aguilera CM. Cell Models and Their Application
for Studying Adipogenic Differentiation in Relation to Obesity: A Review. Int J Mol Sci 2016; 17: E1040
[PMID: 27376273 DOI: 10.3390/ijms17071040]
127 Zhou D, Samovski D, Okunade AL, Stahl PD, Abumrad NA, Su X. CD36 level and trafficking are
determinants of lipolysis in adipocytes. FASEB J 2012; 26: 4733-4742 [PMID: 22815385 DOI:
10.1096/fj.12-206862]
128 Poggi M, Jager J, Paulmyer-Lacroix O, Peiretti F, Gremeaux T, Verdier M, Grino M, Stepanian A, Msika
S, Burcelin R, de Prost D, Tanti JF, Alessi MC. The inflammatory receptor CD40 is expressed on human
adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 2009; 52: 1152-
1163 [PMID: 19183933 DOI: 10.1007/s00125-009-1267-1]
129 Tous M, Ferrer-Lorente R, Badimon L. Selective inhibition of sphingosine kinase-1 protects adipose tissue
against LPS-induced inflammatory response in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab
2014; 307: E437-E446 [PMID: 25053402 DOI: 10.1152/ajpendo.00059.2014]
130 Oñate B, Vilahur G, Ferrer-Lorente R, Ybarra J, Díez-Caballero A, Ballesta-López C, Moscatiello F,
Herrero J, Badimon L. The subcutaneous adipose tissue reservoir of functionally active stem cells is
reduced in obese patients. FASEB J 2012; 26: 4327-4336 [PMID: 22772162 DOI: 10.1096/fj.12-207217]
131 Van Harmelen V, Röhrig K, Hauner H. Comparison of proliferation and differentiation capacity of human
adipocyte precursor cells from the omental and subcutaneous adipose tissue depot of obese subjects.
Metabolism 2004; 53: 632-637 [PMID: 15131769 DOI: 10.1016/j.metabol.2003.11.012]
132 Tchoukalova Y, Koutsari C, Jensen M. Committed subcutaneous preadipocytes are reduced in human
obesity. Diabetologia 2007; 50: 151-157 [PMID: 17096115 DOI: 10.1007/s00125-006-0496-9]
133 Wu CL, Diekman BO, Jain D, Guilak F. Diet-induced obesity alters the differentiation potential of stem
cells isolated from bone marrow, adipose tissue and infrapatellar fat pad: the effects of free fatty acids. Int
J Obes (Lond) 2013; 37: 1079-1087 [PMID: 23164698 DOI: 10.1038/ijo.2012.171]
134 Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human
abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes 2009; 58: 1550-
1557 [PMID: 19351711 DOI: 10.2337/db08-1770]
135 Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM, Moller DE. Negative
regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the
antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol 1996; 10: 1457-1466 [PMID:
8923470 DOI: 10.1210/mend.10.11.8923470]
136 Bilkovski R, Schulte DM, Oberhauser F, Mauer J, Hampel B, Gutschow C, Krone W, Laudes M. Adipose
tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans. Int J Obes
(Lond) 2011; 35: 1450-1454 [PMID: 21285942 DOI: 10.1038/ijo.2011.6]
137 Lacasa D, Taleb S, Keophiphath M, Miranville A, Clement K. Macrophage-secreted factors impair human
adipogenesis: involvement of proinflammatory state in preadipocytes. Endocrinology 2007; 148: 868-877
[PMID: 17082259 DOI: 10.1210/en.2006-0687]
138 Oñate B, Vilahur G, Camino-López S, Díez-Caballero A, Ballesta-López C, Ybarra J, Moscatiello F,
Herrero J, Badimon L. Stem cells isolated from adipose tissue of obese patients show changes in their
transcriptomic profile that indicate loss in stemcellness and increased commitment to an adipocyte-like
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
163
phenotype. BMC Genomics 2013; 14: 625 [PMID: 24040759 DOI: 10.1186/1471-2164-14-625]
139 Nuermaimaiti N, Liu J, Liang X, Jiao Y, Zhang D, Liu L, Meng X, Guan Y. Effect of lncRNA HOXA11-
AS1 on adipocyte differentiation in human adipose-derived stem cells. Biochem Biophys Res Commun
2018; 495: 1878-1884 [PMID: 29217197 DOI: 10.1016/j.bbrc.2017.12.006]
140 Zhu XY, Ma S, Eirin A, Woollard JR, Hickson LJ, Sun D, Lerman A, Lerman LO. Functional Plasticity of
Adipose-Derived Stromal Cells During Development of Obesity. Stem Cells Transl Med 2016; 5: 893-900
[PMID: 27177576 DOI: 10.5966/sctm.2015-0240]
141 Pérez LM, Bernal A, San Martín N, Gálvez BG. Obese-derived ASCs show impaired migration and
angiogenesis properties. Arch Physiol Biochem 2013; 119: 195-201 [PMID: 23672297 DOI:
10.3109/13813455.2013.784339]
142 Pérez LM, Suárez J, Bernal A, de Lucas B, San Martin N, Gálvez BG. Obesity-driven alterations in
adipose-derived stem cells are partially restored by weight loss. Obesity (Silver Spring) 2016; 24: 661-669
[PMID: 26833860 DOI: 10.1002/oby.21405]
143 Togliatto G, Dentelli P, Gili M, Gallo S, Deregibus C, Biglieri E, Iavello A, Santini E, Rossi C, Solini A,
Camussi G, Brizzi MF. Obesity reduces the pro-angiogenic potential of adipose tissue stem cell-derived
extracellular vesicles (EVs) by impairing miR-126 content: impact on clinical applications. Int J Obes
(Lond) 2016; 40: 102-111 [PMID: 26122028 DOI: 10.1038/ijo.2015.123]
144 van Tienen FH, van der Kallen CJ, Lindsey PJ, Wanders RJ, van Greevenbroek MM, Smeets HJ.
Preadipocytes of type 2 diabetes subjects display an intrinsic gene expression profile of decreased
differentiation capacity. Int J Obes (Lond) 2011; 35: 1154-1164 [PMID: 21326205 DOI:
10.1038/ijo.2010.275]
145 Ferrer-Lorente R, Bejar MT, Tous M, Vilahur G, Badimon L. Systems biology approach to identify
alterations in the stem cell reservoir of subcutaneous adipose tissue in a rat model of diabetes: effects on
differentiation potential and function. Diabetologia 2014; 57: 246-256 [PMID: 24132782 DOI:
10.1007/s00125-013-3081-z]
146 Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by
adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose
tissues of obese humans. Endocrinology 2004; 145: 2273-2282 [PMID: 14726444 DOI:
10.1210/en.2003-1336]
147 Zvonic S, Lefevre M, Kilroy G, Floyd ZE, DeLany JP, Kheterpal I, Gravois A, Dow R, White A, Wu X,
Gimble JM. Secretome of primary cultures of human adipose-derived stem cells: modulation of serpins by
adipogenesis. Mol Cell Proteomics 2007; 6: 18-28 [PMID: 17018519 DOI:
10.1074/mcp.M600217-MCP200]
148 Pérez LM, de Lucas B, Lunyak VV, Gálvez BG. Adipose stem cells from obese patients show specific
differences in the metabolic regulators vitamin D and Gas5. Mol Genet Metab Rep 2017; 12: 51-56
[PMID: 28580301 DOI: 10.1016/j.ymgmr.2017.05.008]
149 Serena C, Keiran N, Ceperuelo-Mallafre V, Ejarque M, Fradera R, Roche K, Nuñez-Roa C, Vendrell J,
Fernández-Veledo S. Obesity and Type 2 Diabetes Alters the Immune Properties of Human Adipose
Derived Stem Cells. Stem Cells 2016; 34: 2559-2573 [PMID: 27352919 DOI: 10.1002/stem.2429]
150 Liu MH, Li Y, Han L, Zhang YY, Wang D, Wang ZH, Zhou HM, Song M, Li YH, Tang MX, Zhang W,
Zhong M. Adipose-derived stem cells were impaired in restricting CD4+T cell proliferation and
polarization in type 2 diabetic ApoE-/- mouse. Mol Immunol 2017; 87: 152-160 [PMID: 28445787 DOI:
10.1016/j.molimm.2017.03.020]
151 Kim B, Lee B, Kim MK, Gong SP, Park NH, Chung HH, Kim HS, No JH, Park WY, Park AK, Lim JM,
Song YS. Gene expression profiles of human subcutaneous and visceral adipose-derived stem cells. Cell
Biochem Funct 2016; 34: 563-571 [PMID: 27859461 DOI: 10.1002/cbf.3228]
152 Gesta S, Blüher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, Boucher J, Lewis C, Kahn CR.
Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl
Acad Sci U S A 2006; 103: 6676-6681 [PMID: 16617105 DOI: 10.1073/pnas.0601752103]
153 Tchkonia T, Lenburg M, Thomou T, Giorgadze N, Frampton G, Pirtskhalava T, Cartwright A, Cartwright
M, Flanagan J, Karagiannides I, Gerry N, Forse RA, Tchoukalova Y, Jensen MD, Pothoulakis C, Kirkland
JL. Identification of depot-specific human fat cell progenitors through distinct expression profiles and
developmental gene patterns. Am J Physiol Endocrinol Metab 2007; 292: E298-E307 [PMID: 16985259
DOI: 10.1152/ajpendo.00202.2006]
154 Zhu Y, Tchkonia T, Stout MB, Giorgadze N, Wang L, Li PW, Heppelmann CJ, Bouloumié A, Jensen MD,
Bergen HR, Kirkland JL. Inflammation and the depot-specific secretome of human preadipocytes. Obesity
(Silver Spring) 2015; 23: 989-999 [PMID: 25864718 DOI: 10.1002/oby.21053]
155 Perrini S, Ficarella R, Picardi E, Cignarelli A, Barbaro M, Nigro P, Peschechera A, Palumbo O, Carella
M, De Fazio M, Natalicchio A, Laviola L, Pesole G, Giorgino F. Differences in gene expression and
cytokine release profiles highlight the heterogeneity of distinct subsets of adipose tissue-derived stem cells
in the subcutaneous and visceral adipose tissue in humans. PLoS One 2013; 8: e57892 [PMID: 23526958
DOI: 10.1371/journal.pone.0057892]
156 Fernández M, Acuña MJ, Reyes M, Olivares D, Hirsch S, Bunout D, de la Maza MP. Proliferation and
differentiation of human adipocyte precursor cells: differences between the preperitoneal and subcutaneous
compartments. J Cell Biochem 2010; 111: 659-664 [PMID: 20589764 DOI: 10.1002/jcb.22753]
157 Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release
interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998; 83: 847-
850 [PMID: 9506738 DOI: 10.1210/jcem.83.3.4660]
158 Harman-Boehm I, Blüher M, Redel H, Sion-Vardy N, Ovadia S, Avinoach E, Shai I, Klöting N, Stumvoll
M, Bashan N, Rudich A. Macrophage infiltration into omental versus subcutaneous fat across different
populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 2007;
92: 2240-2247 [PMID: 17374712 DOI: 10.1210/jc.2006-1811]
159 Hauner H, Wabitsch M, Pfeiffer EF. Differentiation of adipocyte precursor cells from obese and nonobese
adult women and from different adipose tissue sites. Horm Metab Res Suppl 1988; 19: 35-39 [PMID:
3235057]
160 Adams M, Montague CT, Prins JB, Holder JC, Smith SA, Sanders L, Digby JE, Sewter CP, Lazar MA,
Chatterjee VK, O'Rahilly S. Activators of peroxisome proliferator-activated receptor gamma have depot-
specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149-3153 [PMID:
9399962 DOI: 10.1172/JCI119870]
161 Niesler CU, Siddle K, Prins JB. Human preadipocytes display a depot-specific susceptibility to apoptosis.
Diabetes 1998; 47: 1365-1368 [PMID: 9703343 DOI: 10.2337/diab.47.8.1365]
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
164
162 Digby JE, Crowley VE, Sewter CP, Whitehead JP, Prins JB, O'Rahilly S. Depot-related and
thiazolidinedione-responsive expression of uncoupling protein 2 (UCP2) in human adipocytes. Int J Obes
Relat Metab Disord 2000; 24: 585-592 [PMID: 10849580 DOI: 10.1038/sj.ijo.0801201]
163 Tchkonia T, Giorgadze N, Pirtskhalava T, Tchoukalova Y, Karagiannides I, Forse RA, DePonte M,
Stevenson M, Guo W, Han J, Waloga G, Lash TL, Jensen MD, Kirkland JL. Fat depot origin affects
adipogenesis in primary cultured and cloned human preadipocytes. Am J Physiol Regul Integr Comp
Physiol 2002; 282: R1286-R1296 [PMID: 11959668 DOI: 10.1152/ajpregu.00653.2001]
164 Tchkonia T, Tchoukalova YD, Giorgadze N, Pirtskhalava T, Karagiannides I, Forse RA, Koo A,
Stevenson M, Chinnappan D, Cartwright A, Jensen MD, Kirkland JL. Abundance of two human
preadipocyte subtypes with distinct capacities for replication, adipogenesis, and apoptosis varies among fat
depots. Am J Physiol Endocrinol Metab 2005; 288: E267-E277 [PMID: 15383371 DOI:
10.1152/ajpendo.00265.2004]
165 Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, DePonte M, Koo A, Forse RA, Chinnappan D,
Martin-Ruiz C, von Zglinicki T, Kirkland JL. Fat depot-specific characteristics are retained in strains
derived from single human preadipocytes. Diabetes 2006; 55: 2571-2578 [PMID: 16936206 DOI:
10.2337/db06-0540]
166 Toyoda M, Matsubara Y, Lin K, Sugimachi K, Furue M. Characterization and comparison of adipose
tissue-derived cells from human subcutaneous and omental adipose tissues. Cell Biochem Funct 2009; 27:
440-447 [PMID: 19691084 DOI: 10.1002/cbf.1591]
167 Macotela Y, Emanuelli B, Mori MA, Gesta S, Schulz TJ, Tseng YH, Kahn CR. Intrinsic differences in
adipocyte precursor cells from different white fat depots. Diabetes 2012; 61: 1691-1699 [PMID: 22596050
DOI: 10.2337/db11-1753]
168 Meissburger B, Perdikari A, Moest H, Müller S, Geiger M, Wolfrum C. Regulation of adipogenesis by
paracrine factors from adipose stromal-vascular fraction - a link to fat depot-specific differences. Biochim
Biophys Acta 2016; 1861: 1121-1131 [PMID: 27317982 DOI: 10.1016/j.bbalip.2016.06.010]
169 Joe AW, Yi L, Even Y, Vogl AW, Rossi FM. Depot-specific differences in adipogenic progenitor
abundance and proliferative response to high-fat diet. Stem Cells 2009; 27: 2563-2570 [PMID: 19658193
DOI: 10.1002/stem.190]
170 Shahparaki A, Grunder L, Sorisky A. Comparison of human abdominal subcutaneous versus omental
preadipocyte differentiation in primary culture. Metabolism 2002; 51: 1211-1215 [PMID: 12200769 DOI:
10.1053/meta.2002.34037]
171 Perrini S, Laviola L, Cignarelli A, Melchiorre M, De Stefano F, Caccioppoli C, Natalicchio A, Orlando
MR, Garruti G, De Fazio M, Catalano G, Memeo V, Giorgino R, Giorgino F. Fat depot-related differences
in gene expression, adiponectin secretion, and insulin action and signalling in human adipocytes
differentiated in vitro from precursor stromal cells. Diabetologia 2008; 51: 155-164 [PMID: 17960360
DOI: 10.1007/s00125-007-0841-7]
172 Tokunaga M, Inoue M, Jiang Y, Barnes RH 2nd, Buchner DA, Chun TH. Fat depot-specific gene
signature and ECM remodeling of Sca1(high) adipose-derived stem cells. Matrix Biol 2014; 36: 28-38
[PMID: 24726953 DOI: 10.1016/j.matbio.2014.03.005]
173 Cleal L, Aldea T, Chau YY. Fifty shades of white: Understanding heterogeneity in white adipose stem
cells. Adipocyte 2017; 6: 205-216 [PMID: 28949833 DOI: 10.1080/21623945.2017.1372871]
174 Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of generalized and regional
adiposity to insulin sensitivity in men. J Clin Invest 1995; 96: 88-98 [PMID: 7615840 DOI:
10.1172/JCI118083]
175 Miyazaki Y, DeFronzo RA. Visceral fat dominant distribution in male type 2 diabetic patients is closely
related to hepatic insulin resistance, irrespective of body type. Cardiovasc Diabetol 2009; 8: 44 [PMID:
19656356 DOI: 10.1186/1475-2840-8-44]
176 McLaughlin T, Lamendola C, Liu A, Abbasi F. Preferential fat deposition in subcutaneous versus visceral
depots is associated with insulin sensitivity. J Clin Endocrinol Metab 2011; 96: E1756-E1760 [PMID:
21865361 DOI: 10.1210/jc.2011-0615]
177 Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H,
Li G, Jelicks LA, Mehler MF, Hui DY, Deshaies Y, Shulman GI, Schwartz GJ, Scherer PE. Obesity-
associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007; 117:
2621-2637 [PMID: 17717599 DOI: 10.1172/JCI31021]
178 Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, Askew GR, Simcox JA, McClain DA,
Li C, Scherer PE. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial
adaptive process that preserves insulin sensitivity in obesity. Nat Med 2012; 18: 1539-1549 [PMID:
22961109 DOI: 10.1038/nm.2899]
179 Livingston JN, Cuatrecasa P, Lockwood DH. Insulin insensitivity of large fat cells. Science 1972; 177:
626-628 [PMID: 5049308 DOI: 10.1126/science.177.4049.626]
180 Rajala MW, Scherer PE. Minireview: The adipocyte--at the crossroads of energy homeostasis,
inflammation, and atherosclerosis. Endocrinology 2003; 144: 3765-3773 [PMID: 12933646 DOI:
10.1210/en.2003-0580]
181 Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer
PE. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 2009; 29: 1575-
1591 [PMID: 19114551 DOI: 10.1128/MCB.01300-08]
182 Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47:
507-514 [PMID: 9568680 DOI: 10.2337/diabetes.47.4.507]
183 Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue
development, expansion and regeneration. Nat Med 2013; 19: 1338-1344 [PMID: 23995282 DOI:
10.1038/nm.3324]
184 Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS. Rapid depot-specific activation of adipocyte
precursor cells at the onset of obesity. Nat Cell Biol 2015; 17: 376-385 [PMID: 25730471 DOI:
10.1038/ncb3122]
185 Jeffery E, Wing A, Holtrup B, Sebo Z, Kaplan JL, Saavedra-Peña R, Church CD, Colman L, Berry R,
Rodeheffer MS. The Adipose Tissue Microenvironment Regulates Depot-Specific Adipogenesis in
Obesity. Cell Metab 2016; 24: 142-150 [PMID: 27320063 DOI: 10.1016/j.cmet.2016.05.012]
186 Karastergiou K, Smith SR, Greenberg AS, Fried SK. Sex differences in human adipose tissues - the
biology of pear shape. Biol Sex Differ 2012; 3: 13 [PMID: 22651247 DOI: 10.1186/2042-6410-3-13]
187 Tchoukalova YD, Koutsari C, Votruba SB, Tchkonia T, Giorgadze N, Thomou T, Kirkland JL, Jensen
MD. Sex- and depot-dependent differences in adipogenesis in normal-weight humans. Obesity (Silver
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
165
Spring) 2010; 18: 1875-1880 [PMID: 20300084 DOI: 10.1038/oby.2010.56]
188 Chau YY, Bandiera R, Serrels A, Martínez-Estrada OM, Qing W, Lee M, Slight J, Thornburn A, Berry R,
McHaffie S, Stimson RH, Walker BR, Chapuli RM, Schedl A, Hastie N. Visceral and subcutaneous fat
have different origins and evidence supports a mesothelial source. Nat Cell Biol 2014; 16: 367-375 [PMID:
24609269 DOI: 10.1038/ncb2922]
189 Krueger KC, Costa MJ, Du H, Feldman BJ. Characterization of Cre recombinase activity for in vivo
targeting of adipocyte precursor cells. Stem Cell Reports 2014; 3: 1147-1158 [PMID: 25458893 DOI:
10.1016/j.stemcr.2014.10.009]
WJSC https://www.wjgnet.com
March 26, 2019 Volume 11 Issue 3
Silva KR et al. ASC is known by its adipose depot
166
Published By Baishideng Publishing Group Inc
7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Telephone: +1-925-2238242
Fax: +1-925-2238243
E-mail: bpgoffice@wjgnet.com
Help Desk: https://www.f6publishing.com/helpdesk
https://www.wjgnet.com
© 2019 Baishideng Publishing Group Inc. All rights reserved.
