International audienceCentral obesity and long-term glucocorticoid exposure are both characterized by visceral fat enlargement and increased risk for metabolic diseases. In this issue of Cell Metabolism, Lindroos et al. identify LIM domain only 3 as a molecular partner for glucocorticoids required for adipocyte differentiation specifically in human visceral fat

Bouloumié, Anne

Galitzky, Jean

Cell Metabolism

Central obesity and long-term glucocorticoid exposure are both characterized by visceral fat enlargement and increased risk for metabolic diseases. In this issue of Cell Metabolism, Lindroos et al. identify LIM domain only 3 as a molecular partner for glucocorticoids required for adipocyte differentiation specifically in human visceral fat

Elsevier - Publisher Connector 

Cell Metabolism
PreviewsHuman Visceral-Fat-Specific Glucocorticoid Tuning
of AdipogenesisJean Galitzky1,2 and Anne Bouloumie´1,2,*
1INSERM, UMR1048, Team 1, Institute of Metabolic and Cardiovascular Diseases, BP84225, F-31432, Toulouse Cedex 4, France
2Paul Sabatier University, 118, Route de Narbonne, 31062 Toulouse Cedex 9, France
*Correspondence: anne.bouloumie@inserm.fr
http://dx.doi.org/10.1016/j.cmet.2013.06.008
Central obesity and long-term glucocorticoid exposure are both characterized by visceral fat enlargement
and increased risk formetabolic diseases. In this issue ofCell Metabolism, Lindroos et al. identify LIM domain
only 3 as a molecular partner for glucocorticoids required for adipocyte differentiation specifically in human
visceral fat.In humans, the availability of energy-rich
foods and reduced physical activity are
key factors involved in the increased prev-
alence of obesity. The accumulation of
abdominal fat in central obesity, deter-
mined by large waist circumference or a
high waist-hip ratio, has emerged as a
common trait linking obesity, type 2 dia-
betes, and cardiovascular pathologies.
Given that the distribution of fat, rather
than total fat mass, is a key determinant
for developing obesity-associated dis-
eases, extensive research efforts have
been put forward to identify the processes
responsible for the enlargement of spe-
cific adipose depots. In this issue of Cell
Metabolism, Lindroos et al. (2013) investi-
gate the control of adipogenesis by gluco-
corticoids (GCs) and show that LIM
domain only 3 (LMO3) acts as a new
partner in GC-dependent signaling to
modulate the key adipogenic master
switch PPARg in human, but not mouse,
visceral adipose progenitors.
Stress hormones, such as GCs and
catecholamines, are major regulators of
fat metabolism and have both catabolic
(lipolytic) and anabolic (antilipolytic and
adipogenic) effects. In human adipocytes,
the balance between adipocyte a2-
adrenergic receptor (AR) (antilipolytic)
and b1/2-AR (lipolytic) expression deter-
mines the net catecholamine response;
i.e., antilipolytic in gluteo-femoral and
lipolytic in abdominal fat. The mecha-
nisms underlying GC effects on specific
fat depots have yet to be fully character-
ized. In humans, long-term GC exposure
due to either anti-inflammatory and immu-
nosuppressive therapies or endocrine
disturbances, as observed in individuals
with Cushing syndrome, is associatedwith the accumulation of abdominal fat
and the loss of limb fat, whereas, in ro-
dents, sustained GCs treatment reduces
body weight. The intra-adipose GC pool,
derived from both systemic circulation
and local regeneration of cortisol by
type 1 11b-hydroxysteroid dehydroge-
nase (11b-HSD1), drives GC receptor
(GR)-dependent activation of gene tran-
scription via GC response elements
(GREs) (Figure 1). GC-mediated genomic
effects are involved in the control of adi-
pogenesis. In murine preadipocyte cell
lines, GCs inhibit cell proliferation and
promote differentiation via increased
expression of proadipogenic transcription
factors (Abdou et al., 2013) and the
modulation of the Akt/PKB signaling
pathway (Laplante et al., 2012).
In order to further characterize the GC
pathway in human preadipocytes, Lind-
roos et al. (2013) analyzed the transcrip-
tome of GC-treated human adipose
stromal cells (hASCs) and identified
LMO3 as robustly induced by natural
and synthetic GR ligands, such as dexa-
methasone, hydrocortisone, and cortico-
sterone. LMO3 expression was enhanced
during early adipogenesis in hASCs, but
not in mouse adipose stromal cells.
Gain- or loss-of-function experiments
showed that LMO3 was required for
human adipocyte differentiation. The
authors showed that the LMO3 promoter
region contains two GRE half sites,
whereas the lack of conservation of the
GRE1 site in mice renders the mouse
Lmo3 gene irresponsive to GCs (Figure 1).
In agreement, no Lmo3 expression was
detected in mouse perigonadal adipose
stromal cells, murine preadipocyte cell
line, or subcutaneous and visceral fatCell Metabodepots of mice fed a standard or high-
fat diet. Next, Lindroos et al. (2013)
investigated the mechanism by which
LMO3 regulates adipocyte differentiation
in response to GCs and found that modu-
lation of LMO3 messenger RNA levels in
hASCs impacted the DNA-binding activity
of PPARg, a master transcriptional regu-
lator of adipogenesis. LMO3 was shown
to directly inhibit ERK-dependent phos-
phorylation of PPARg at serine 112, a
site known to block the activation of
PPARg-dependent adipogenic program.
These results suggest that GCs pro-
mote adipogenesis via LMO3-mediated
removal of MAPK/ERK-induced PPARg
inhibition (Figure 1). Furthermore, the
authors showed that higher LMO3
expression levels in visceral in com-
parison to subcutaneous hASCs are
associated with increased 11bHSD1
expression, suggesting that greater
amounts of active visceral intra-adipose
GCs may constitute a specific local
microenvironment favoring LMO3-medi-
ated adipogenesis, which might explain
the specific enlargement of the visceral
fat depot associated with GC exposure.
Thus, Lindroos et al. (2013) have identi-
fied LMO3 as a novel GC partner involved
in the anabolic impact of GCs in humans.
However, several important questions
remain to be fully answered, for example,
concerning the fat-depot-specific impact
of GCs on adipogenesis. A recent report
demonstrates the predominant role of
adipogenesis, rather than adipocyte
hypertrophy, in human visceral fat ex-
pansion (Arner et al., 2013). However,
in vitro studies have shown that hASCs
from visceral fat exhibit lower adipogenic
potential than subcutaneous hASCs,lism 18, July 2, 2013 ª2013 Elsevier Inc. 3
Figure 1. Central Control of the Stress Hormone Cortisol and Peripheral Effects on Adipose
Tissue
Cortisol production is under the control of hypothalamus-pituitary gland axes (HPA) and exhibits a circa-
dian regulation. In the paraventricular nucleus of the hypothalamus, neuroendocrine neurons synthesize
and secrete corticotropin-releasing hormone (CRH), which stimulates the secretion of adrenocorticotropic
hormone (ACTH) by the anterior lobe of the pituitary gland. In turn, ACTH acts on the adrenal cortex, which
produces GC hormones, mainly cortisol in humans and corticosterone in rodents. In turn, GCs suppress
CRH and ACTH production from the hypothalamus and pituitary in a negative feedback regulatory loop.
Under stress situations, cortisol is released and reaches the adipose tissue. Acute effects (first hours) of
cortisol include (1) reduction of glucose utilization and (2) the promotion of fatty acid release. Long-term
effects involve GC receptor (GR) activation by intra-adipose GC pool. This local pool originates from
both circulating cortisol and the local activation of inactive cortisone by type 1 11b-hydroxysteroid dehy-
drogenase (11b-HSD). After translocation to the nucleus, GC and GR binding to specific GC response
elements (GREs) induces LMO3 expression. The LMO3 promoter region contains two GRE half sites
(GRE1 andGRE2), whereas themouse Lmo3 promoter contains amutated GRE1 site (GRE1*) that renders
4 Cell Metabolism 18, July 2, 2013 ª2013 Elsevier Inc.
Cell Metabolism
Previewseven in the presence of GCs (Tchkonia
et al., 2013), and one might have ex-
pected the contrary because the higher
basal LMO3 expression in visceral hASCs
reported by Lindroos et al. (2013). There-
fore, additional investigations are needed
in order to clarify the regional differences
in the control of adipogenesis in human
adipose tissues. The first priority will be
to define the nature of the adipocyte pro-
genitor cells within the crude stroma cell
fraction in human fat depots. Interestingly,
the upregulation of LMO3 in visceral fat
was localized primarily in the adipocyte
fraction. The presence of LMO3 in mature
adipocytes might open new investiga-
tions on the impact of GCs and the
potential involvement of LMO3-depen-
dent pathways in the modulation of
visceral adipocyte functions. Thus, key
metabolic enzymes and adipokines,
including lipolytic enzymes and leptin
known to be modulated by GCs, may
represent potential LMO3 targets. Given
the role of GC-dependent pathways in
the modulation of inflammation, it will
also be of interest to define the role
of adipocyte LMO3 in inflammatory-
related processes, especially those asso-
ciated with obesity. Finally, steroids play
an important intracrine role in adipose
tissue physiology. Although systemic
circulating GCs are not elevated in
obesity, intra-adipose conversion of GCs
certainly plays a key role in determining
the levels of active GCs. The presence
in human fat of type 2 11b-HSD, which
rapidly inactivates GCs by converting
them to cortisone, raises questions
regarding its role in GC regulation (Lee
et al., 2008). Besides a direct proadipo-
genic action, GCs may also regulate
the bioavailability of dihydrotestosterone
(DHT) in visceral adipose tissue, reducing
DHT-mediated antiadipogenic effect and
consequently creating a propitious micro-
environment for adipogenesis (Veilleux
et al., 2012).
In conclusion, the study of Lindroos
et al. (2013) identifies LMO3 as new
partner in GC- and GR-dependent sig-
naling specifically in human visceral fat.
It also highlights the need for preciselythe mouse Lmo3 gene irresponsive to GCs. Induc-
tion of LMO3 increases PPARg tone, potentially
via reducing MAPK-mediated phosphorylation of
PPARg, inducing preadipocyte differentiation and
leading to enhanced adipogenesis.
Cell Metabolism
Previewsexploring the biology of human adipocyte
progenitor cells in their microenvironment
and for testing whether findings obtained
with a rodent model are relevant to
human physiological or patho-physiolog-
ical conditions.
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First Step toward Regenerative Therapy?Heiko Lickert1,2,*
1Institute of Diabetes and Regeneration Research
2Institute of Stem Cell Research
Helmholtz Center Munich, Am Parkring 11, 85748 Garching, Germany
*Correspondence: heiko.lickert@helmholtz-muenchen.de
http://dx.doi.org/10.1016/j.cmet.2013.06.006
Millions of diabetic patients are waiting for better treatment options, ideally by replenishing the lost or
dysfunctional insulin-producing b cell mass. Yi et al. (2013) now identify Betatrophin, a hormone that
specifically increases b cell proliferation with promising therapeutic potential.Pancreatic b cells are perfect sensors of
blood glucose levels and secrete just the
right amount of insulin into the blood-
stream to systemically regulate glucose
and energy homeostasis. Type 1 diabetes
results from autoimmune destruction of b
cells, whereas in type 2 diabetes, a failure
of b cells to compensate for peripheral
insulin resistance leads to exhaustion,
dedifferentiation, and loss of functional b
cell mass. Unfortunately, neither pharma-
cological treatment nor insulin injections
can fully substitute for endogenous b cell
function to prevent uncontrolled hypergly-
cemia and the devastating micro- and
macrovascular complications associated
with both forms of diabetes. Thus, the
only way for a better treatment and a
potential cure for the disease is to replace
or regenerate the lost or dysfunctional b
cell mass (Bonner-Weir and Weir, 2005).
Work by the Melton laboratory now
reports on Betatrophin, a hormone that
specifically increases b cell mass in mice
and therefore raises hope for regenerative
b cell therapy in humans (Yi et al., 2013).It has long been known that insulin
resistance causes compensatory b cell
mass expansion in the pancreas, likely
due to circulating growth factor(s)
(Michael et al., 2000). Identification of
these factors could possibly allow
regenerative b cell therapy. Gut-derived
incretins, macrophage-derived cyto-
kines, muscle-derived myokines, and
adipocyte-derived adipokines have all
been shown to increase b cell mass
but remain unchanged in the peripheral
bloodstream of insulin-resistant mice (El
Ouaamari et al., 2013). In a recent
study published in Cell (Yi et al., 2013),
a novel pharmacological mouse model
of severe insulin resistance was used
to identify these unknown factor(s) that
trigger compensatory b cell prolifera-
tion. For this purpose, a 43 amino
acid inhibitory peptide with high affinity
and selectivity for the insulin receptor
was infused into mice. Inhibition of
insulin signaling caused dose-dependent
hyperglycemia and glucose intolerance
in the short period of 1 week. Moreover,plasma insulin levels were increased,
likely due to compensatory b cell pro-
liferation and b cell mass expansion
triggered by expression changes of cell-
cycle regulators. As the inhibitory
peptide did not directly act on b cells
per se, further genome-wide expression
profiling of metabolically active tissues
(liver, fat, muscle, and b cells) was used
to identify potential mediators of this
response. This pointed to Betatrophin, a
secreted protein of 198 amino acids
that is highly conserved in all mammalian
species. Betatrophin shows increased
expression in liver and fat in mouse
models that expand b cell mass upon
insulin resistance, pregnancy, or leptin
deficiency. Intriguingly, transgenic over-
expression of Betatrophin in the liver
induces a rapid, robust, and specific
increase of b cell proliferation and
improves glucose tolerance in young
adult mice. Together, these results sug-
gest that Betatrophin may be one of the
factors that we have searched for for
over a decade, a hormone that triggerslism 18, July 2, 2013 ª2013 Elsevier Inc. 5


Human visceral-fat-specific glucocorticoid tuning of adipogenesis.

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