MINIREVIEW
Adipocyte hyperplasia and RMI1 in the treatment
of obesity
Akira Suwa, Takeshi Kurama and Teruhiko Shimokawa
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan
Introduction
Obesity is a complex disorder and a major risk factor
for metabolic diseases such as type 2 diabetes mellitus,
hypertension and cardiovascular disease. Obesity devel-
ops as the result of an imbalance between energy
intake and expenditure. To state simply, chronic reduc-
tion of energy expenditure versus intake causes an
increased storage of the excess energy in the form of
intracellular triacylglycerol droplets in adipose cells,
leading to an increased fat mass and ultimately result-
ing in obesity.
Adipocyte hyperplasia (increase in cell number) and
hypertrophy (increase in cell size) are thought to be
directly responsible for the observed increase in adi-
pose tissue mass [1,2]. Adipocyte hypertrophy in par-
ticular is considered the main cause of adult obesity,
and hyperplasia of adipocytes in obese adults some-
times occurs secondary to adipocyte hypertrophy, pos-
sibly due to an increased number of adipocytes
capable of secreting paracrine growth factors that
induce adipocyte hyperplasia [3].
Whereas the basic number of adipocytes is estab-
lished during childhood and adolescence in both
humans and rodents, adipose tissue retains the ability
to generate new adipocytes throughout life. Increased
adipocyte number during aging has been implicated in

review recent progress in the regulation of adipocyte hyperplasia as a novel
emerging nontraditional approach. In this minireview, we focus on recQ-
mediated genome instability 1 (RMI1), a recently identified novel molecular
target for obesity treatment. RMI1-deficient mice have been found to be
resistant to high-fat diet- and genetics-related obesity. Expression of this
protein is regulated by E2F transcription factors, and recent studies have
suggested that RMI1 plays an important role in the control of energy
homeostasis during the development of obesity, with a mode of action
based on the regulation of adipocyte hyperplasia.
Abbreviations
A
y
, lethal yellow agouti; BLM, Bloom’s syndrome gene; E2F, E2F transcription factor; RB, retinoblastoma protein; RMI1, recQ-mediated
genome instability 1; Skp2, S-phase kinase-associated protein 2.
FEBS Journal 278 (2011) 565–569 ª 2010 The Authors Journal compilation ª 2010 FEBS 565
pogenesis, resulting in increased adipose tissue mass
and thereby obesity [5].
This growing body of evidence suggests that adipo-
cyte hyperplasia may be a key event in the develop-
ment and subsequent clinical course of some types of
obesity. In this minireview, we focus on adipocyte
hyperplasia as a novel therapeutic target for the treat-
ment of obesity and discuss the merits of targeting
recQ-mediated genome instability 1 (RMI1), a recently
identified energy homeostasis-related molecule, for
obesity treatment.
Adipocyte hyperplasia
Preclinical studies have demonstrated that adipocyte
hyperplasia occurs in two steps: an increase in num-
bers of preadipocytes, followed by the differentiation

RB is phosphorylated by cyclin ⁄ cyclin-dependent
kinase holoenzymes, releasing the E2F complex and
thereby resulting in activation of the E2F target genes
[9]. Fajas et al. [10] demonstrated that the E2F protein
family plays a central role in preadipocyte proliferation
and that E2F1-deficient mice are resistant to obesity
induced by a high-fat diet (due to suppression of fat
mass accumulation).
Cyclin-dependent kinase inhibitors include two fami-
lies of proteins, the Cip (Kip) family and Ink4 family,
and are central players in the exit of cells from the cell
cycle [11]. Loss of p27
Kip1
or p21
Cip1
in mice leads to
adipocyte hyperplasia as a result of increased prolifera-
tion or recruitment of preadipocytes [12], suggesting
that these cyclin-dependent kinase inhibitors are
important in the regulation of adipocyte number.
The S-phase kinase-associated protein (Skp)1–Cullin-
F-box protein (SCF) ubiquitin ligase (E3) complex
targets cyclin-dependent kinase inhibitors for degrada-
tion by the 26S proteasome and thereby regulates cell
cycle progression [13]. Sakai et al. [14] showed that a
deficiency in Skp2, the substrate-binding subunit of the
SCF
Skp2
complex, contributes to the degradation of
p27

RMI1 as a novel regulator of energy homeostasis [19],
which was reported to be an essential component
of Bloom’s syndrome protein complexes [20], although
no evidence had linked it to energy homeostasis until
our findings. RMI1, an enzyme-binding protein, has
previously been reported to mediate DNA recombina-
tion, chromosome organization and biogenesis, as well
Adipocyte hyperplasia and RMI1 A. Suwa et al.
566 FEBS Journal 278 (2011) 565–569 ª 2010 The Authors Journal compilation ª 2010 FEBS
as to regulate cell-cycle checkpoint machinery [21].
RMI1 is also a member of Bloom’s syndrome gene
(BLM)–topoisomerase complex; targeted mutations of
BLM are developmentally delayed and die off by
embryonic day 13.5 [22,23] and RMI1 homozygous
knockout embryos die due to an unknown cause [19].
Bloom’s syndrome is a rare recessive genetic disorder
characterized by dwarfism, telangiectatic erythema,
immune deficiency and a predisposition towards devel-
oping cancer [24,25].
RMI1 heterozygous knockout mice (RMI1+ ⁄ ))
have a phenotype almost identical to that of the wild-
type, although body weight and fasting-plasma glucose
are significantly lower in wild-type mice. However,
RMI1+ ⁄ ) mice possess a number of striking features
that render them resistant to metabolic diseases. When
fed a high-fat diet, the mutant mice were not only
resistant to obesity, they showed improved glucose
intolerance and reduced abdominal fat tissue mass.
In addition, the mutants were also resistant to obesity
induced by the A

puter analysis has shown evidence of E2F response ele-
ment consensus sites in the RMI1 promoter (Suwa A,
Kurama T, Shimokawa T and Aramori I, unpublished
observations), suggesting that E2F may transactivate
the promoter. Taken together, these results indicate
that RMI1 expression can be regulated by E2F family
molecules in adipose tissue under high-glucose condi-
tions, influencing preadipocyte proliferation.
RMI1 as a novel target for obesity
treatment
Recent studies in vivo and in vitro have demonstrated
that RMI1 plays an important role in the regulation of
energy homeostasis via an interaction with E2F path-
ways, at least in part, suggesting the involvement in
the regulation of adipocyte hyperplasia. RMI1 expres-
sion is induced by glucose in vitro, and its in vivo
expression is also induced by metabolic abnormalities
such as hyperglycemia and obesity in metabolic tissues
such as liver and adipose tissues.
However, targeting RMI1 may not affect whole-body
proliferation, because changes in RMI1 expression in
metabolic disorders are restricted to metabolic tissues;
indeed, RMI1-deficient mice have not shown any
abnormalities in nonmetabolic tissues. More impor-
tantly, the in vivo evidence of anti-obesity effects was
obtained from RMI1 heterozygous mice, suggesting
that a 50% reduction in RMI1 level would be sufficient
to treat energy homeostasis disorders. Recent advanced
findings about RMI1 suggest that RMI1-targeting is a
helpful therapeutic approach to treating energy homeo-

knockout mice would be required.
Conclusions
Obesity develops as a result of the disruption of the
homeostasis between food intake and energy expendi-
ture, and therefore factors affecting these processes are
the focus of extensive research targeting the develop-
ment of effective anti-obesity drugs. To date, however,
only limited success has been achieved in this endeavor
[28], highlighting the need for additional therapeutic
options. Recently, interesting novel approaches and tar-
gets for obesity treatment have been reported, many of
which have been cited in the other minireviews in this
series. One such approach is the concept of central regu-
lation, focusing on the malonyl-CoA pathway [29],
while another approach uses the adipocyte-derived
inflammatory mediator [30]. However, here we focus on
a recently identified novel approach involving adipocyte
hyperplasia, differing clearly from both the central and
inflammatory approaches. Given that a number of
molecular causes have been implicated in the develop-
ment of obesity, combining these different approaches
likely represents the most effective treatment method.
Excessive calorie intake associated with hyperphagia
and ingesting a high-fat diet in mice results in storage
of the extra energy, initially through an increase in adi-
pocyte size. However, as adipocytes have a limited
capacity for enlargement, long-term intake of excess
calories eventually results in an increase in adipocyte
number to accommodate storage of the surplus energy.
In this minireview, we have summarized evidence

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RMI1
RMI1
The intake of excess calories
(Hyperphagia, high-fat feeding)
E2F
E2F
Obesity
Obesity
(Energy homeostasis disorder)
(Energy homeostasis disorder)
Adipocyte hyperplasia
Cell cycle regulation
Expression
Expression
regulation
regulation
Fig. 1. A hypothetical model for adipocyte hyperplasia regulation by
RMI1. Excess calorie intake due to hyperphagia and high-fat feed-
ing induces expression of RMI1 and E2Fs in adipocytes, and
causes a positive interaction between the molecules. Increased
expression of RMI1 and E2Fs regulates the cell cycle, leading to
adipocyte hyperplasia and subsequent development of obesity.
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