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Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
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Role of nuclear receptor corepressor RIP140 in metabolic
syndrome☆
Meritxell Rosell1, Marius C. Jones1, and Malcolm G. Parker⁎
Institute of Reproductive and Developmental Biology, Imperial College London, Faculty of
Medicine, Hammersmith Campus 158 Du Cane Road, W12 0NN, UK
Abstract
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Obesity and its associated complications, which can lead to the development of metabolic
syndrome, are a worldwide major public health concern especially in developed countries where
they have a very high prevalence. RIP140 is a nuclear coregulator with a pivotal role in controlling
lipid and glucose metabolism. Genetically manipulated mice devoid of RIP140 are lean with
increased oxygen consumption and are resistant to high-fat diet-induced obesity and hepatic
steatosis with improved insulin sensitivity. Moreover, white adipocytes with targeted disruption of
RIP140 express genes characteristic of brown fat including CIDEA and UCP1 while skeletal
muscles show a shift in fibre type composition enriched in more oxidative fibres. Thus, RIP140 is
a potential therapeutic target in metabolic disorders. In this article we will review the role of
RIP140 in tissues relevant to the appearance and progression of the metabolic syndrome and
discuss how the manipulation of RIP140 levels or activity might represent a therapeutic approach
to combat obesity and associated metabolic disorders. This article is part of a Special Issue
entitled: Translating nuclear receptors from health to disease.
Research Highlights
► RIP140 regulates energy expenditure and storage in adipose tissue. ► RIP140 modulates
muscle fiber type. ► RIP140 affects inflammatory responses. ► RIP140 is a promising target for
treatment of metabolic disorders.
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Abbreviations
AR, androgen receptor; ATF, activating transcription factors; CBP, CRE-binding protein; CIDEA,
cell death-inducing DNA fragmentation factor alpha-like effector A; CPT, 1β carnitine
palmitoyltransferase 1β; CREB, CRE-binding protein; CtBP, C-terminal binding protein; Dnmt,
DNA methyltransferase; EDL, extensor digitorum longus; ERR, estrogen related receptor; FA,
fatty acid; FAS, fatty acid synthase; FOXC2, forkhead-box C2; GLUT4, glucose transporter 4;
GR, glucocorticoid receptor; HDAC, histone deacetylase; HFD, high-fat diet; IL, interleukin;
JNK, Janus N-terminal kinase; MEF, myocyte-specific enhancer binding factor; NCoR, nuclear
receptor corepressor; NF-κB, nuclear factor κB; NR, nuclear receptor; NRF, nuclear respiratory
☆This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
© 2011 Elsevier B.V.
⁎
Corresponding author. Fax: +44 0 20 7594 2184. [email protected].
1M.R and M.J. contributed equally to this publication.
This document was posted here by permission of the publisher. At the time of deposit, it included all changes made during peer
review, copyediting, and publishing. The U.S. National Library of Medicine is responsible for all links within the document and for
incorporating any publisher-supplied amendments or retractions issued subsequently. The published journal article, guaranteed to be
such by Elsevier, is available for free, on ScienceDirect.
Rosell et al.
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factor; PCOS, polycystic ovary syndrome; PEPCK, phosphoenolpyruvate carboxykinase; PGC,
PPARγ coactivator; PPAR, peroxixome proliferator-activated receptor; PRDM16, positive
regulatory domain-containing 16; RAR, retinoic acid receptor; RBP4, retinol binding protein 4;
ROS, reactive oxygen species; RXR, retinoid X receptor; SMRT, silencing mediator of retinoic
acid and thyroid hormone receptor; SRC, steroid receptor coactivator; SREBP1c, sterol regulatory
element binding protein 1c; TAG, triacylglyceride; TLR, Toll-like receptor; TNFα, tumour
necrosis factor α; TR, thyroid hormone receptor; UCP1, uncoupling protein 1; VLDL, very low
density lipoprotein
Keywords
Metabolic syndrome; RIP140; White adipose tissue; Inflammation
1
Introduction
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Obesity has reached worldwide epidemic proportions, especially in Western countries, often
associated with metabolic dysfunctions such as insulin resistance, dyslipidaemia,
cardiovascular disease and even some cancers [1–3]. The clustering of these metabolic
dysfunctions is recognized as the metabolic syndrome and the component disorders are
essentially caused by a positive energy imbalance, where nutrient uptake is greater than
energy expenditure. Strong epidemiological links between obesity, type II diabetes and
cardiovascular diseases have suggested a common molecular pathogenesis. A limit on
adipose tissue expandability has been proposed to provide a unifying causal link to the
development of metabolic syndrome [4–6]. Challenging the body with nutrient excess for a
prolonged period of time results in lipid deposition in adipose tissue. Adipose tissue expands
in order to accommodate the excess of energy with adipocytes undergoing hypertrophy
(increase in size) and hyperplasia (increase in number) to fulfil the increased demand for
lipid storage. Hypertrophic adipocytes have an altered profile of adipokine secretion: a
decrease in hormones/cytokines that promote insulin sensitivity, including adiponectin, and
an increase in those that promote insulin resistance, such as resisitin and retinol binding
protein (RBP) 4, and inflammation, such as interleukin (IL) 6 and tumour necrosis factor
(TNF) α [7–9]. These inflammatory molecules recruit and activate macrophages present in
the tissue to trigger low-grade inflammation in adipose tissue. Furthermore, activated
macrophages block preadipocyte recruitment and limit hyperplasic expansion of the adipose
tissue. Once the storage capacity of the adipose tissue is exceeded, lipids start to accumulate
in non-adipose tissues, leading to lipotoxicity [10,11]. Steatosis of the liver, muscle,
pancreas, heart, and kidney can lead to organ failure or exacerbate whole-body insulin
resistance. In addition, increased levels of circulating free fatty acids (FAs) and development
of type II diabetes are major risk factors for development of atherosclerosis and
cardiovascular complications [12].
Several nuclear receptors (NRs), including peroxisome proliferator-activated receptors
(PPARs), thyroid hormone receptors (TRs) and estrogen-related receptors (ERRs), have
emerged as important metabolic regulators [13]. These receptors control the transcription of
genes involved in metabolic pathways underpinning the pathophysiology of the metabolic
syndrome. The ability of NRs to regulate gene transcription depends on the recruitment of
coactivators and corepressors that remodel chromatin in the vicinity of the promoters. Both
the expression and activity of cofactors are subject to regulation by a number of signalling
pathways in a tissue-specific manner. The activity of many receptors is suppressed in the
absence of ligand passively, in complexes with heat shock proteins in the cytoplasm, as in
the case of androgen receptor (AR) and glucocorticoid receptor (GR) [14,15]. Some NRs,
including TR, retinoid X receptor (RXR) and PPARs, can be actively repressed by
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recruitment of corepressors, such as nuclear receptor corepressor (NCoR) and silencing
mediator of retinoic acid and thyroid hormone receptor (SMRT) [16,17]. Ligand binding
results in conformational changes which lead to the dissociation of repressive complexes
and the recruitment of coactivators, such as p300/CBP, p160/steroid receptor coactivator
(SRC) and PPARγ coactivator (PGC) families, to activate transcription [18,19]. Ligand
binding may not only result in the activation of subsets of genes but also the repression of
certain genes. Receptor interacting protein (RIP) 140 was found to function as a corepressor
for a number of ligand bound nuclear receptors with a role in metabolism (TR2, PPARs,
LXRα, GR, retinoic acid receptor (RAR)/RXR) [20–25]. RIP140 is itself highly expressed
in metabolic tissue like adipose tissue, skeletal muscle and liver [26]. Genome-wide
expression arrays studies have highlighted its role as a global regulator of energy balance,
repressing multiple metabolic pathways to reduce energy expenditure. On the other hand,
recent studies have shown that RIP140 also functions as a coactivator for NR [22,27] or
other types of transcription factors [28,29]. The molecular basis for these opposing functions
is poorly understood and this review will focus on the biological roles of RIP140 in
metabolism and inflammation and considers how targeting its function may provide an
approach to treatment of metabolic syndrome.
2
Role of RIP140 in adipose tissue
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Both white (WAT) and brown (BAT) adipose tissue share many common features such as
their ability to take up glucose, synthesize and store triacylglycerides (TAG), and mobilize
those TAG in situations of energy demand. However, they play largely opposing roles in
mammalian physiology. WAT serves as the prime reservoir for storing excess caloric energy
in the form of TAG. It is also an important source of endocrine hormones involved in
metabolic regulation such as leptin, adiponectin, and resistin [7,30]. In contrast, BAT is the
major site of adaptive thermogenesis capable of generating heat from fatty acid oxidation to
maintain body temperature, particularly in response to cold exposure [31]. Thus, it is a net
consumer of caloric energy. BAT is also a site of diet-induced thermogenesis [31]. The
function of brown adipocytes is critically dependent on the expression and activity of
uncoupling protein (UCP) 1, a mitochondrial protein almost exclusively found in BAT and
therefore considered as a key molecular marker [31]. That WAT and BAT play an important
role in the maintenance of energy homeostasis is reflected in the observation that small
alterations in their function can have a large impact on whole-body metabolism [31].
Moreover, the ability of white and brown adipocytes in each depot to reversibly switch into
one another has been reported [30,32,33], but the extent to which this occurs and the precise
mechanisms involved are not fully understood (reviewed in [34]). The search for regulators
that could mediate conversion of white adipocytes (energy storing) into brown adipocytes
(energy consuming) has led to the identification of PGC1α, forkhead-box (FOX) C2 and
positive regulatory domain-containing (PRDM) 16 as transcriptional regulators that have
been found to promote a brown fat genetic program, while retinoblastoma protein and
RIP140 have been described to favour a white adipose phenotype (reviewed in refs.
[35,36]).
RIP140 is most highly expressed in WAT where it regulates the expression of many genes
involved in catabolic pathways (energy consuming), especially those involved in lipid and
glucose metabolism. Mice devoid of the coregulator express higher levels of genes that
regulate fatty acid oxidation and proteins involved in energy dissipation, highlighting its role
as a corepressor and its role controlling the balance between energy consumption and energy
expenditure [26]. On the contrary, genes involved in FA synthesis and gluconeogenesis
seem to be downregulated in the absence of RIP140. As a consequence, RIP140 null mice
are lean, with a 70% reduction of body fat and a 20% reduction in body weight compared to
wild-type mice and they are resistant to high-fat diet (HFD) induced obesity and hepatic
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steatosis so that the mice maintain their insulin sensitivity [26,37]. It is particularly
noteworthy that in the RIP140 KO animals WAT expresses genes characteristic of BAT
including UCP1, fatty acid transporter carnitine palmitoyltransferase (CPT-1β) and the lipid
droplet protein cell death-inducing DNA fragmentation factor alpha-like effector A
(CIDEA). Targeted disruption in mice of several genes directly involved in energy
metabolism and fat accumulation (LXRα, ERRα and retinoblastoma protein) also leads to a
lean phenotype with a marked increase in UCP1 expression in adipocytes, particularly in
white fat depots (see ref. [38] for a review). RIP140 expression is very low in preadipocytes
and induced upon differentiation [37,39,40]. Studies in different adipocyte cell models (3T3L1, MEFs (mouse embryonic fibroblasts), immortalised white adipocytes) have shown that
RIP140 is not required for adipocyte differentiation. Analysis of gene expression profiles
from the RIP140 null cell lines show that, RIP140 modulates the expression of similar genes
involved in fatty acid and carbohydrate metabolism found in WAT, indicating that it
functions as a cell autonomous corepressor. Most of the upregulated genes in the RIP140null adipocytes are genes involved in catabolic pathways including fatty acid oxidation,
oxidative phosphorylation, glycolysis and the tricarboxilic acid cycle (Fig. 1). Again, some
genes normally restricted to expression in BAT, including UCP1, CIDEA and CPT1-β, are
elevated in RIP140-null adipocytes [37,39]. Many of the genes regulated by RIP140 are also
targets for the coactivator PGC1α that was originally identified in BAT as factor that is
elevated in response to cold. PGC1α is a key regulator of mitochondrial biogenesis and
oxidative metabolism in tissues with high oxidative capacity such as skeletal muscle, liver
and brown fat by acting as a coactivator for a number of different transcription factors
involved in metabolic control [41]. Since RIP140 also can bind to and repress many of these
transcription factors, including PPARα, PPARγ and ERRα [21,39] it appears that the PGC1α
and RIP140 coregulators may play mutually opposing roles in controlling sets of metabolic
genes. We have found that both coregulators can be recruited simultaneously to the CIDEA
promoter and it's noteworthy that they are able to physically interact. These observations
suggest that RIP140 may be acting as a transcriptional brake that could be overcomed under
conditions when the expression or activity of the coactivator is increased [42].
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Recent studies by Li Na Wei and her colleagues indicate that RIP140 may not only be a
transcriptional coregulator but may also function in the cell cytoplasm. They have found that
cytoplasmic RIP140 inhibits glucose metabolism by reducing insulin-stimulated glucose
transporter 4 (GLUT4) trafficking and glucose uptake [43] (Fig. 1). Importantly, the same
study shows that high-fat feeding results in cytoplasmic localization of RIP140 in
epididymal white adipocytes, highlighting the biological relevance of a function for RIP140
in the cytoplasm. The cytoplasmic role of RIP140 is in addition to the direct regulation of
GLUT4 mRNA expression by RIP140 in mouse and human adipocytes [37,40]). These
findings provide the basis for a novel mechanism by which RIP140 might impair glucose
utilization and promote insulin resistance. The observations also suggest that irrespective of
RIP140 expression levels it may also be important to establish whether there are changes in
compartmentalization of the protein.
Very few studies have been carried out in humans. A decrease in RIP140 mRNA in biopsies
of visceral WAT depots from obese patients has been reported with a strong correlation
between body mass index and RIP140 mRNA levels [44]. It is conceivable that decreased
levels of RIP140 serve as a compensatory mechanism to favour energy expenditure to
reduce fat accumulation. In another study no difference was found in RIP140 expression
between obese and lean women with polycystic ovary syndrome (PCOS), or between obese
PCOS and lean controls [45]. Finally, a recent study shows that RIP140 is decreased in
subcutaneous adipose tissue of obese women and increased by weight loss. In the same
study, in primary culture of human adipocytes, RIP140 expression increased during
adipocyte differentiation and its knockdown increased basal glucose transport and mRNA
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levels of GLUT4 and UCP1, a similar behaviour to that of the mouse ortholog [46]. Overall,
high levels of human RIP140 in WAT of lean subjects may minimise energy utilization from
depleted fat stores. At first sight, the overexpression of RIP140 in tissues from obese
individuals would be predicted from the mouse studies, where its absence promotes reduced
TAG accumulation; but on the other hand, the subcellular localisation of RIP140 was not
examined in these studies and we have yet to elucidate signalling pathways that may control
of the activity of RIP140 by post-translational modifications.
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RIP140 is highly expressed in BAT albeit to a lesser extent than in WAT. Interest in the
study of BAT physiology has been renewed by recent demonstration of considerable
amounts of active tissue in many adult humans [47–50]. In adult knock-out mice, the size
and appearance of BAT is similar to the wild-type animals [26]. At the molecular level,
UCP1 expression, together with the expression of nuclear receptors PPARα, PPARγ, and
fatty acid transporter aP2 is similar in both knock-out and wild-type animals. These findings
suggested that BAT might not be a major site for RIP140 function or at least its lack of
expression would not seem to have a big impact under basal conditions. Nevertheless, some
recent experiments seem to point out a role for RIP140 in BAT. It has been shown that adult
RIP140-null mice exhibit a reduced body core temperature and reduced mRNA expression
of coregulator PGC1α in BAT, although response to an adrenergic activator does not seem
impaired in these animals [51]. This is consistent with in vitro observations [21]. However,
newborn and young RIP140-null mice exhibit a significant reduction in BAT mass and
PGC1α mRNA expression, which might be associated with poor thermogenesis and that this
in turn might account for the poor rate of postnatal survival [51]. More recently, in a cell line
model of brown adipocytes, RIP140 was found to be recruited to and repress the CIDEA
promoter through binding to both ERRα and nuclear respiratory factor (NRF) 1 [42].
Moreover, RIP140 has also been described to target and repress UCP1 enhancer in brown
adipocytes trough LXR binding [23]. These findings suggest a role for RIP140 in BAT
physiology, which might not be as evident as in WAT, but which could have important
implication regarding energy expenditure. Further studies need to be carried out in both
adults and newborn mice in order to establish the exact role of RIP140 in this tissue.
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The amount of BAT and the expression of UCP1 correlate with increased basal metabolic
rate and protection from obesity in both mice and humans. Genetic ablation of BAT induces
obesity in mice [52]. Likewise, genetic deletion of UCP1 in mice causes weight gain when
mice are kept at thermoneutrality [53]. On the other hand, ectopic expression of UCP1 in
WAT results in resistance to obesity [54]. Mice with an increase in the amount of active
BAT gain less weight and are more insulin-sensitive. Indeed, BAT mass and activity is
greatly decreased in obese patients, particularly those with morbid obesity [50,55].
Therefore, the increased expression of genes in WAT from RIP140 null mice that are
usually restricted to BAT seems to compromise the function of this tissue as the site of
energy storage. Total energy consumption is increased significantly in RIP140-null mice,
presumably as a consequence of energy dissipation in WAT resulting from the expression of
UCP1 and increased mitochondrial activity [26]. BAT, on the other hand, utilises energy not
only lipid oxidation but also glucose metabolism. Given the high metabolic capacity of
BAT, any reduction in the amount or activity of BAT could perturb the ability of the body to
dispose of glucose. Accordingly, the maintenance of a high glucose-utilizing activity by
BAT could prevent the development of glucose intolerance and insulin resistance. As
RIP140 has been found to control glucose metabolism in white adipocytes it will be of high
interest to study its role in glucose metabolism in BAT. Glucose metabolism in BAT is
under insulin and β-adrenergic control. β-Adrenergic responses were found to be unaltered,
at least in primary cultures of brown adipocytes from RIP140 null mice [21]. It will be
interesting to determine whether insulin signalling is affected when RIP140 levels are
modified and whether high levels of RIP140 inhibit oxidative metabolism and expression of
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genes involved in thermogenesis, which could have a vast impact on the total energy
expenditure in an individual.
3
Role of RIP140 in inflammation
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Lipotoxicity and inflammation are intimately involved in the evolution of a number of
metabolic diseases. Lipid overload of macrophages in vascular endothelium leads to
phenotypic transformation into foam cells, secretion of pro-inflammatory cytokines, and
apoptosis, contributing to atherosclerosis [56]. In steatotic liver, activation of kupffer cells,
the resident macrophages, can drive hepatic inflammation and transition to steatohepatitis
[57]. Accumulation of lipoproteins and lipid derivatives in the kidney induces macrophage
infiltration and activation to initiate renal inflammation in chronic kidney disease [58].
Obesity in mice and humans is associated with a low-grade subclinical inflammation of
adipose tissue [59–62]. Non-obese adipose tissue contains a quiescent population of local
macrophages with little pro-inflammatory activity to support adipocyte function and
maintain insulin sensitivity [63]. When hypertrophic, adipocytes secrete higher amounts of
chemo-attractants to promote macrophage infiltration [9]. Additional macrophages may also
be recruited simply to promote disposal of necrotic cells, which are more abundant in obese
adipose tissue [30,64]. Free FA spill-over from enlarged adipocytes is able to activate Tolllike receptor (TLR) signalling and downstream Janus N-terminal kinase (JNK) and nuclear
factor κB (NF-κB) pathways in the resident macrophages to elicit a switch towards a
classically activated, pro-inflammatory phenotype [65,66]. The subsequent production of
pro-inflammatory cytokines, including IL6 and TNFα, will interfere with insulin signalling
leading to type 2 diabetes and further propagate the state of chronic inflammation [67,68].
The importance of inflammation in metabolic diseases has been reinforced by studies
showing that limiting macrophage activation [67,69–71] and production of proinflammatory signals [72] is of value in reducing insulin resistance.
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In contrast to the corepressor activities in adipose tissue and muscle, RIP140 can function as
a coactivator in macrophages (Fig. 2). Comparison of gene expression profiles of
macrophages derived from wild-type and RIP140 null mice has revealed that RIP140
deficiency impairs full execution of the pro-inflammatory program in response to TLRmediated activation [29]. Downstream of TLRs, NF-kB is a major transcriptional regulator
of pro-inflammatory gene expression, including TNFα, IL1β and IL6. RIP140 is recruited to
these NF-κB-dependent promoters and stimulates transcription by acting as a bridging
factor, stabilizing the formation of a trimeric complex with the RelA subunit and the CBP
coactivator [29]. It is noteworthy that the absence of RIP140 causes only a partial
attenuation of pro-inflammatory gene transcription and in cells where RelA expression is not
limiting the coregulatory contribution of RIP140 might be modest [29]. Thus, the levels of
transcription factors and other interacting cofactors can dictate the efficiency of a particular
coregulator. This is an important concept when considering the inflammatory phenotype.
RIP140 absence does not appear to immunocompromise mice [73,74] since pathogens
provoke a strong immune reaction and in this context the function of RIP140 may have only
a minor impact. However, in a more subtle state of inflammation, as found in obese adipose
tissue, the absence of even a relatively weak activator might have a more pronounced
outcome. Although insulin sensitivity in RIP140 null mice fed a high-fat diet is better than
that in wild-type mice [37], the relative contribution of a blunted inflammatory response in
macrophages relative to the altered lipid metabolism in adipose tissue, liver and muscle is
unclear [22,26,75]. More insights would be provided by generation of mice with myeloid
specific RIP140 deletion.
It is perhaps surprising that the expression of metabolic genes is essentially unaltered in
macrophages in the absence of RIP140 in contrast to the situation in skeletal muscle and
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adipocytes [29]. These genes are regulated by PPARδ [75], PPARα and PPARγ [21] and
LXRα [22], which play important roles in the control of lipid homeostasis and inflammation
in response to endogenous fatty acid or sterol ligands. These NRs have been documented to
mediate repressive effects on inflammatory genes in an NCoR- and SMRT-dependent
manner [76–78]. It remains to be investigated if in macrophages, PPARs and LXRs can also
form repression complexes with RIP140 on some genes, which would provide an interesting
setting, where the coregulator has negative as well as positive functions.
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Communications between adipocytes and macrophages are important in triggering
inflammation in adipose tissue and it is increasingly recognized that both cell types
contribute to the development of obesity-induced insulin resistance. Although the infiltrated
macrophages are the main source of TNFα, adipocytes are responsible for a sizable fraction
of the IL6 concentration in the circulation of obese patients [79,80]. The importance of an
inflammatory response within adipocytes themselves is clear from a study with mice with
adipocyte-specific JNK1 deficiency, which have improved insulin sensitivity in response to
high-fat diet and normal levels of serum IL6 [67]. Interestingly, microarray interrogation of
gene expression profiles shows that depletion of RIP140 in adipocytes causes genes
encoding proteins involved in catabolic pathways for carbohydrates and fatty acids to be
upregulated, but a subset of pro-inflammatory genes, including IL6, are downregulated (D.
Morgenstein, unpublished observations;[39]). Therefore the activity of RIP140 as a
coactivator of pro-inflammatory gene expression is unlikely to be restricted to macrophages
and may also be found in adipocytes and possibly other cell types. This merits further
investigation, for example, in vascular endothelial cells, where inflammation is the basis for
atherosclerosis, or in the muscle, where macrophage infiltration and activation can give rise
to muscle insulin resistance [81,82], and where copious amounts of IL6 are produced during
exercise [83].
4
4.1
Role of RIP140 in muscle
Skeletal muscle
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In both mouse and human, skeletal muscle contains distinct types of fibres, characterized by
differential expression of specific myosin heavy chains. This difference in fibre composition
accounts for different types of contractile function. Type I fibres (slow twitch fibres) are rich
in mitochondria and show high levels of oxidative phosphorylation relaying mainly on fatty
acid oxidation. These are the fibers resistant to fatigue and predominant in red muscles, such
as the soleous. Type II (fast twitch fibers) contain a low number of mitochondria and relay
more on anaerobic respiration via glycolysis or glycogenolysis that enable them to undergo
rapid and short contractile bursts. In comparison to type I fibers, type II are more prone to
fatigue. These types of fibers are predominant in muscles like the gastrocnemius and
extensor digitorum longus (EDL) [84]. There is also an intermediate type of fibers, type IIX,
that have fast twitch characteristics, but depend on oxidative metabolism that is similar to
type I fibres [85]. Muscle fiber type composition can be modulated in response to several
factors such as exercise, aging, hormonal changes or disease [86,87]. An increase in exercise
has been shown to induce a fibre composition switch in the amount of type I fibres in
muscles with predominantly Type II fibers such as the gastrocnemius. The switch in fiber
type is reflected by changes in the expression of the myosin isoforms and other fiber type
markers, as well as an increased expression of genes involved in mitochondrial myogenesis,
fatty acid oxidation and oxidative phosphorylation. At a molecular level, a number of
transcriptional regulators that are able to remodel skeletal muscle have been identified but it
is still uncertain how the pathways are regulated. Nuclear receptors including PPARs, ERRα
and other transcription factors such as CRE-binding protein (CREB), myocyte-specific
enhancer binding factors (MEFs), activating transcription factors (ATFs) and NRFs have
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been found to activate expression of metabolic genes in skeletal muscle while the PGC1α
plays a pivotal role as a coactivator for the aforementioned transcription factors [88,89].
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Skeletal muscles play an important role in whole-body metabolism as they account for the
70% of the total insulin-stimulated glucose uptake. Alterations in its function or fibre
composition can have a big impact on the whole-body metabolism. For example, in insulinresistant states, such as obesity and type II diabetes, insulin-stimulated glucose uptake is
markedly impaired [90], while increasing the number of type I fibres enhances insulinmediated glucose uptake and protects against diabetes and other metabolic diseases [91].
Moreover, in obese patients, skeletal muscles have reduced metabolic oxidative capacities
with morphologic changes that reveal decreased type I slow twitch fibers [92].
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In skeletal muscle, RIP140 is expressed in a fiber type specific manner. RIP140 mRNA
levels seem to be higher in glycolytic muscles, like gastrocnemius and EDL, rather than in
oxidative muscles, like soleus and diaphragm [75]. In the absence of RIP140, EDL and
gastrocnemius muscles exhibit a marked increase in mitochondrial activity accompanied by
a corresponding shift in myofibers favouring the more oxidative type. Muscles appear redder
in colour and express increased levels of type I fibres markers. These changes are
accompanied by an increase in mitochondrial number and oxidative metabolism (most
notably fatty acid oxidation) and are coordinated following upregulation of genes involved
in these processes [75]. PPARδ and ERRα are direct targets for RIP140 action at least for
some of the genes. Conversely, in transgenic animals, elevated RIP140 expression resulted
in a decrease in both mitochondrial activity and the number of oxidative myofibers [75]. In
contrast, muscles that consist of predominantly type I fibres (usually expressing low RIP140
levels) show an unaltered phenotype in the RIP140 null mice. This is consistent with the
function of RIP140 as a corepressor and suggests a role for RIP140 as an inhibitor of
oxidative metabolism in skeletal muscle [75] (Fig. 2). Considering the mass of skeletal
muscle it can have an important impact on the whole-body energetic metabolism. It is
conceivable that alterations in RIP140 expression may contribute to certain metabolic
diseases such as obesity, insulin resistance and type II diabetes but this will require further
investigation.
4.2
Cardiac muscle
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Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid
metabolism, and antioxidant defence mechanisms lead to diminished cardiac substrate
flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. These
mitochondrial abnormalities can predispose to a metabolic cardiomyopathy and have been
observed in insulin-resistant animal models and persons that are at higher risk of developing
type 2 diabetes mellitus, hypertension, and cardiovascular disease [93].
RIP140 mRNA expression is high in cardiac muscle [26,94]. Studies in transgenic mice
overexpressing RIP140 show that these mice are characterized by rapid onset of cardiac
hypertrophy and ventricular fibrosis which results in an increase in the mortality rate from 4
weeks of age [26,94]. Interestingly, females are less sensitive to the deleterious effects of
exogenous RIP140 expression compared to males, suggesting that estrogens might play a
protective role against cardiac hypertrophy [95]. In these mice, overexpression of RIP140
leads to reduced expression of genes involved in fatty acid transport/oxidation and
mitochondrial activity. This is accompanied by a decrease in mitochondrial number and
activity, as demonstrated by decreased state III and state IV membrane potential and oxygen
consumption, associated with abnormal morphology [94]. Thus, decreased energy
production associated to increased fibrosis might be responsible for impaired cardiac
function and decreased survival observed in the RIP140 transgenic mice. This study is
consistent with data for skeletal muscle and myotubes obtained from RIP140-null mice
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where absence of RIP140 leads to increased oxidative metabolism [75]. Moreover, it
highlights the importance of RIP140 in postnatal cardiac function and the possible
implication in adult mitochondrial dysfunction leading to myopathies and cardiac
malfunction.
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5
Role of RIP140 in the liver
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The hepatic manifestation of the Metabolic Syndrome is non-alcoholic fatty liver disease
(NAFLD) and it is associated with insulin resistance although the cause and consequence
relationship is debated [96,97]. NAFLD is diagnosed as the histological presence of lipid in
more than 5% of hepatocytes, which is mostly in the form of TAG derived from the
circulating pool of non-esterified fatty acids (59%), diet (15%) or de novo synthesis (26%)
[98]. Hepatic lipogenesis is regulated by LXRα [99,100] and two studies have identified
roles for RIP140 in this process. Our lab has found that in response to high-fat diet or
agonist treatment, RIP140 is able to act as a coactivator for LXR-dependent induction of
sterol regulatory element binding protein (SREBP) 1c and fatty acid synthase (FAS), which
promote TAG synthesis [22]. Interestingly, RIP140 is also required for LXR-dependent
repression of phosphoenolpyruvate carboxykinase (PEPCK) gene to limit gluconeogenesis
in hepatocytes. Therefore, RIP140 and LXR can partner to form distinct activator or
repressor complexes to either promote lipid generation or reduce glucose production,
respectively [22] (Fig. 2). In contrast, a second study has shown that RIP140 contributed to
hepatic steatosis during starvation and cancer cachexia by repressing SREBP1c [73]. In
addition, RIP140 knockdown in the liver of starved mice altered hepatic FA oxidation, very
low density lipoprotein (VLDL) production, FA uptake, serum TAG and peripheral LPL
activity, to have a wider effect on local and systemic lipid homeostasis [73]. The reason for
the contradicting results is not clear but differences in the experimental models used may
have a contribution. We have utilized high-fat diet-induced liver steatosis with whole-animal
RIP140 knockouts, as opposed to starvation or cachexia-triggered steatosis accompanied by
shRNA-mediated liver-specific RIP140 knockdown. Nevertheless, both studies have found
that RIP140 absence is beneficial by lowering hepatic TAG content in the given
experimental context. Further experiments, perhaps making use of hepatocyte-specific
RIP140-null animals, are required to understand the precise functions of the cofactor in this
tissue.
6
Targeting RIP140 for treatment of metabolic syndrome
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Lipotoxic events are the underlying cause of cellular damage in the metabolic syndrome and
therefore tackling the oversupply of lipid to affected organs is important. Reducing caloric
intake and increasing exercise to favour a negative energy balance should lead to clearance
of ectopic lipid deposition and improve an array of metabolic parameters [101,102].
Nevertheless, although lifestyle changes are beneficial, obesity remains difficult to combat.
A pharmacological approach is to increase the lipid storage capacity of subcutaneous
adipose depots with a view to prevent overspill and accumulation in non-adipose organs.
This is exploited by the thiazolidinedione (TDZ) class of drugs, which, by activating
PPARγ, promote preadipocyte differentiation in addition to its insulin sensitizing effects
[103]. Thus, the improved whole-body insulin sensitivity and reduced hepatic and visceral
lipid content is attributed at least in part to the hyperplasic increase in subcutaneous adipose
tissue seen in patients or animal models treated with TDZ [104–106]. In this case however,
an improvement in metabolic well-being comes with increased obesity as a side-effect.
Excess fatty acids reaching non-adipose tissue can be activated to fatty acyl-CoA (FACoA)
that undergo a series of esterification reaction to form lysophosphatidic acid (LPA),
phosphatidic acid (PA), diacylglycerol (DAG) and finally TAG. Alternatively, FACoA can
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be channelled down the sphingosine synthesis pathway, where ceramide is an intermediate,
or it can undergo β-oxidation to feed the mitochondrial electron transport chain [107]. All
three fates have the potential to present the cell with toxic challenges. LPA, PA, DAG and
ceramide can activate pro-inflammatory kinases to contribute to insulin resistance [108–
111]. Indeed, ceramide levels are elevated in skeletal muscle of obese humans [112,113] and
can further antagonize insulin signalling by inhibition of Akt [114]. Increasing the ability to
oxidize FA, especially in the mitochondria of skeletal muscle, would reduce the
accumulation of such intermediates and therefore protect from insulin resistance. It is
important to note that several lines of evidence have questioned the role of mitochondrial
function in insulin sensitivity and the cause and consequence relationship between the two
remains highly debated [115]. Nevertheless, mitochondrial overload with lipid supply would
increase reactive oxygen species (ROS) production, which has been shown to have a causal
role in insulin resistance [116]. An important facet of treatment of metabolic disorders is
limiting the damaging effects of the three possible fates of fatty acids, and RIP140 is
involved in regulation of all three.
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The pathways underlying the metabolic syndrome are interlinked in a complex network and
an effective approach to treatment may need to target multiple points. For example, TDZ
treatment, which activates PPARγ to reduce inflammation and promote adipogenesis and
enhances adiponectin secretion to increase lipid oxidation [117,118], is often prescribed in
conjunction with metformin to reduce gluconeogenesis in the liver, improve glucose uptake
in peripheral tissue and overall insulin sensitivity. The evidence accumulated form studying
RIP140 suggests that targeting the function of this cofactor for treatment of metabolic
disorders would be of particular value since it would also have multiple beneficial
consequences (Fig. 3). As detailed above, RIP140 null mice have a hypermetabolic
phenotype, largely as a result of upregulation of genes involved in FA β-oxidation, oxidative
phosphorylation, TCA cycle and mitochondrial biogenesis in adipose tissue and muscle
[37,75]. This causes WAT to function in a manner akin to BAT to expend stored fat for
thermogenesis, while in skeletal muscle the proportion of type I oxidative fibres, where
TAGs are mainly used as fuel, is increased. Consequently, lipids are removed from the
circulation, and both visceral and subcutaneous fat depots are reduced [26]. The
upregulation of UCP1 in WAT [119] may also limit the amount of ROS produced by the
mitochondria [120] to prevent inhibition of insulin signalling. Absence of RIP140 may have
an additional protective effect on insulin signalling by preventing downregulation and
inhibition of GLUT4 [43]. Impairing RIP140 function would protect against hepatic
steatosis during a lipid challenge by promoting gluconeogenesis and reducing lipogenesis.
Here, downregulation of SREBP1c and FAS restricts de novo FA synthesis [22], therefore
reducing both TAG and sphingolipid biosynthetic pathways and the production of harmful
intermediates. Furthermore, absence of RIP140 in macrophages would decrease the
inflammation associated with obesity and insulin resistance [29]. The net results are
improved lipid partitioning (decrease in circulating and ectopic load), decrease in adipose
tissue size to allow it to regain normal lipid homeostatic function, and consequently,
improved insulin sensitivity. The phenotype of RIP140 null mice is proof of principle that
targeting RIP140 might constitute a successful approach for the treatment of metabolic
syndrome. Although caution must be exercised since RIP140 function is essential for female
fertility [28,121,122], this might not necessarily be a priority since metabolic disorders
prevail at an age past sexual reproduction. Drugs seldom approach 100% efficiency,
however, even a 50% inhibition of RIP140 activity would be beneficial, since heterozygous
mice challenged with a high-fat diet also display improved metabolic parameters at a level
intermediate between wild-type and null animals [74,75].
What pharmacological approaches could be used to modulate the function of RIP140? Three
possibilities are outlined: (a) regulation of RIP140 expression, (b) regulation of RIP140
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Rosell et al.
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activity and (c) regulation of NR-dependent recruitment. In the first instance, several NR
ligands have been shown to control RIP140 expression. In breast cancer cells estrogens
[123], retinoic acid [124] and androgens [125] upregulate RIP140 mRNA levels thus
providing potential feedback loops to limit nuclear receptor action. Estrogen antagonists
may therefore be of value in preventing an induction in RIP140 expression [125], while
progestins have been found to modestly downregulate RIP140 mRNA [126]. However, the
use of such compounds would not offer efficient action in metabolic tissues that are largely
non-responsive to steroid sex hormones. More interestingly, ERRs, which have been
implicated in control of energy metabolism, can activate RIP140 gene expression by directly
binding to an ERRE and indirectly through SP1 binding sites in the promoter [127]. ERRαnull mice have reduced body weight and peripheral fat deposits [128], reminiscent of the
RIP140-null phenotype, yet the lack of a known ligand leaves modulation of its activity a
difficult proposition. Recently miRNA have become very attractive tools in manipulating
gene expression. The 5′ UTR of the RIP140 mRNA has been found to be targeted by
microRNA (miRNA) mir-346. Rather than silencing RIP140 expression, mir-346 has been
found to function in an atypical manner, increasing the protein levels and therefore the
repressive activity of the cofactor, but a miRNA antagomir can be used to dampen RIP140
activity [129]. Furthermore, RIP140 mRNA contains a large 3′ UTR of ~ 3.5 kb that remains
to be investigated for target sites of additional miRNAs.
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In its role as a transcriptional regulator, RIP140 lacks any intrinsic enzymatic activities but
is thought to function as a scaffold protein, providing a platform for the recruitment of
enzymes such as C-terminal binding protein (CtBP) [130], histone deacetylases (HDACs)
[131], DNA methyltransferese (Dnmt) [119], CBP [29], that change the accessibility of the
promoter to the transcription machinery. Post-translational modifications (PTMs) lie at the
basis of regulating the activity of non-enzymatic proteins. By favouring or disrupting
specific interactions, PTMs can alter not only the recruitment of transcriptional complex
partners but may also have wide-ranging consequences on the behaviour of proteins,
including changes in subcellular localization and half-life. RIP140 is subject to a diverse
array of PTMs. Multiple site of phosphorylation [132], acetylation [133], arginine [134] and
lysine methylation [135] have been identified in RIP140 by mass spectrometry-based
studies. Vitamin B6 [136] and SUMO conjugation [137] have also been described and may
also modulate RIP140 function. Several PTMs may engage in an interplay to modulate
RIP140 activity and affect cellular function. For example, PKCε-stimulated phosphorylation
promotes PRTM1-directed arginine methylation to reduce RIP140 gene repressive activity
by preventing interaction with HDAC3 and facilitating its export to the cytoplasm
[134,138]. Conversely, MAPK-mediated RIP140 phosphorylation may enhance repressive
activity [139,140]. Post-translational modifications are often investigated by ablating or
mimicking them with the use of point mutations of modification sites. A caveat to such
experiments is that a single amino acid can be subject to several modifications. For example,
interpretation of results of a lysine mutant is complicated by the potential of the amino acid
to undergo acetylation, methylation, SUMOylation or ubiquitination. However, if well
validated, mechanistic knowledge of PTMs in RIP140 might be exploited for therapeutic
purposes by targeting upstream signalling pathways that control its activity.
A third method of regulating RIP140 function involves taking advantage of its recruitment
by NR. Partial agonists or antagonists may selectively prevent interaction with RIP140 while
not interfering with other activities of the receptor. Since the metabolic repressor action of
RIP140 is supported by NR-dependent recruitment, the discovery of such compounds would
prove valuable for limiting the dampening effect on catabolism in adipose tissue and skeletal
muscle. Notably, MRL24 has been recently identified as a PPARγ minimal agonist that
inhibits Cdk5-mediated receptor phosphorylation to prevent obesity-associated gene
dysregulation in fat cells [141]. Since chromatin occupancy of PPARγ was not altered, it is
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Rosell et al.
Page 12
likely that differential recruitment of coregulators is responsible for the observed effect.
Such a finding should encourage screening of ligands for PPARγ and other nuclear receptors
for selective interaction with RIP140.
7
Conclusions
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Overall this article summarizes the regulatory effects of RIP140 in tissues with an important
role in the development and progression of the metabolic syndrome including white and
brown adipose tissue, inflammatory cells, skeletal and cardiac muscles and liver. We have
outlined signalling pathways that are subject to regulation by RIP140 and contribute to the
development of the metabolic syndrome and speculated about the possibility of targeting
RIP140 to ameliorate associated metabolic disorders.
In our opinion, therapeutic strategies targeting RIP140 have to be considered with caution,
considering the broad spectrum of actions of RIP140 as well as its recently described role as
a coactivator. Given that RIP140 is likely to be a difficult metabolic target to finely tune it
would be necessary to screen for compounds that modify the recruitment of RIP140 to
specific nuclear receptors at a subset of genes, or alternatively, compounds that can alter its
binding to other components of the transcriptional machinery, such as histone modifying
enzymes.
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References
Sponsored Document
Vernochet C. Peres S.B. Farmer S.R. Mechanisms of obesity and related pathologies: transcriptional
control of adipose tissue development. FEBS J.. 2009; 276:5729–5737. [PubMed: 19754874]
Cornier M.A. Dabelea D. Hernandez T.L. Lindstrom R.C. Steig A.J. Stob N.R. Van Pelt R.E. Wang H.
Eckel R.H. The metabolic syndrome. Endocr. Rev.. 2008; 29:777–822. [PubMed: 18971485]
Bray G.A. Bellanger T. Epidemiology, trends, and morbidities of obesity and the metabolic syndrome.
Endocr.. 2006; 29:109–117.
S. Virtue, A. Vidal-Puig, Adipose tissue expandability, lipotoxicity and the metabolic syndrome—an
allostatic perspective, Biochim Biophys Acta 1801, 338–349.
Virtue S. Vidal-Puig A. It's not how fat you are, it's what you do with it that counts. PLoS Biol.. 2008;
6:e237. [PubMed: 18816166]
Sethi J.K. Vidal-Puig A.J. Targeting fat to prevent diabetes. Cell Metab.. 2007; 5:323–325. [PubMed:
17488634]
Ahima R.S. Flier J.S. Adipose tissue as an endocrine organ. Trends Endocrinol. Metab.. 2000; 11:327–
332. [PubMed: 10996528]
S. Galic, J.S. Oakhill, G.R. Steinberg, Adipose tissue as an endocrine organ, Mol Cell Endocrinol 316,
129–139.
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. [PubMed: 17164304]
Unger R.H. Clark G.O. Scherer P.E. Orci L. Lipid homeostasis, lipotoxicity and the metabolic
syndrome. Biochim. Biophys. Acta. 1801:209–214.
Vidal-Puig A. Unger R.H. Special issue on lipotoxicity. Biochim. Biophys. Acta. 1801:207–208.
Wilding J.P. The importance of free fatty acids in the development of type 2 diabetes. Diabet. Med..
2007; 24:934–945. [PubMed: 17725706]
Desvergne B. Michalik L. Wahli W. Transcriptional regulation of metabolism. Physiol. Rev.. 2006;
86:465–514. [PubMed: 16601267]
Edwards J. Bartlett J.M. The androgen receptor and signal-transduction pathways in hormonerefractory prostate cancer. Part 2: Androgen-receptor cofactors and bypass pathways. BJU Int..
2005; 95:1327–1335. [PubMed: 15892826]
Yang J. DeFranco D.B. Assessment of glucocorticoid receptor-heat shock protein 90 interactions in
vivo during nucleocytoplasmic trafficking. Mol. Endocrinol.. 1996; 10:3–13. [PubMed: 8838140]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 13
Sponsored Document
Sponsored Document
Sponsored Document
Chen J.D. Evans R.M. A transcriptional co-repressor that interacts with nuclear hormone receptors.
Nature. 1995; 377:454–457. [PubMed: 7566127]
Dowell P. Ishmael J.E. Avram D. Peterson V.J. Nevrivy D.J. Leid M. Identification of nuclear receptor
corepressor as a peroxisome proliferator-activated receptor alpha interacting protein. J. Biol.
Chem.. 1999; 274:15901–15907. [PubMed: 10336495]
Bannister A.J. Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature. 1996;
384:641–643. [PubMed: 8967953]
Spencer T.E. Jenster G. Burcin M.M. Allis C.D. Zhou J. Mizzen C.A. McKenna N.J. Onate S.A. Tsai
S.Y. Tsai M.J. O'Malley B.W. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature.
1997; 389:194–198. [PubMed: 9296499]
Lee C.H. Chinpaisal C. Wei L.N. Cloning and characterization of mouse RIP140, a corepressor for
nuclear orphan receptor TR2. Mol. Cell. Biol.. 1998; 18:6745–6755. [PubMed: 9774688]
Debevec D. Christian M. Morganstein D. Seth A. Herzog B. Parker M. White R. Receptor interacting
protein 140 regulates expression of uncoupling protein 1 in adipocytes through specific
peroxisome proliferator activated receptor isoforms and estrogen-related receptor alpha. Mol.
Endocrinol.. 2007; 21:1581–1592. [PubMed: 17456798]
Herzog B. Hallberg M. Seth A. Woods A. White R. Parker M.G. The nuclear receptor cofactor,
receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose
metabolism by liver X receptor. Mol. Endocrinol.. 2007; 21:2687–2697. [PubMed: 17684114]
Wang H. Zhang Y. Yehuda-Shnaidman E. Medvedev A.V. Kumar N. Daniel K.W. Robidoux J. Czech
M.P. Mangelsdorf D.J. Collins S. Liver X receptor alpha is a transcriptional repressor of the
uncoupling protein 1 gene and the brown fat phenotype. Mol. Cell. Biol.. 2008; 28:2187–2200.
[PubMed: 18195045]
Windahl S.H. Treuter E. Ford J. Zilliacus J. Gustafsson J.A. McEwan I.J. The nuclear-receptor
interacting protein (RIP) 140 binds to the human glucocorticoid receptor and modulates hormonedependent transactivation. J. Steroid Biochem. Mol. Biol.. 1999; 71:93–102. [PubMed: 10659697]
Lee C.H. Wei L.N. Characterization of receptor-interacting protein 140 in retinoid receptor activities.
J. Biol. Chem.. 1999; 274:31320–31326. [PubMed: 10531331]
Leonardsson G. Steel J.H. Christian M. Pocock V. Milligan S. Bell J. So P.W. Medina-Gomez G.
Vidal-Puig A. White R. Parker M.G. Nuclear receptor corepressor RIP140 regulates fat
accumulation. Proc. Natl Acad. Sci. USA. 2004; 101:8437–8442. [PubMed: 15155905]
Harnish D.C. Evans M.J. Scicchitano M.S. Bhat R.A. Karathanasis S.K. Estrogen regulation of the
apolipoprotein AI gene promoter through transcription cofactor sharing. J. Biol. Chem.. 1998;
273:9270–9278. [PubMed: 9535920]
J. Nautiyal, J.H. Steel, M.M. Rosell, E. Nikolopoulou, K. Lee, F.J. Demayo, R. White, J.S. Richards,
M.G. Parker, The nuclear receptor cofactor receptor-interacting protein 140 is a positive regulator
of amphiregulin expression and cumulus cell-oocyte complex expansion in the mouse ovary,
Endocrinology 151, 2923–2932.
Zschiedrich I. Hardeland U. Krones-Herzig A. Berriel Diaz M. Vegiopoulos A. Muggenburg J.
Sombroek D. Hofmann T.G. Zawatzky R. Yu X. Gretz N. Christian M. White R. Parker M.G.
Herzig S. Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine gene
expression. Blood. 2008; 112:264–276. [PubMed: 18469200]
Cinti S. The adipose organ. Prostaglandins Leukot. Essent. Fatty Acids. 2005; 73:9–15. [PubMed:
15936182]
Cannon B. Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol. Rev..
2004; 84:277–359. [PubMed: 14715917]
Himms-Hagen J. Melnyk A. Zingaretti M.C. Ceresi E. Barbatelli G. Cinti S. Multilocular fat cells in
WAT of CL-316243-treated rats derive directly from white adipocytes. Am. J. Physiol. Cell
Physiol.. 2000; 279:C670–C681. [PubMed: 10942717]
Granneman J.G. Li P. Zhu Z. Lu Y. Metabolic and cellular plasticity in white adipose tissue I: effects
of beta3-adrenergic receptor activation. Am. J. Physiol. Endocrinol. Metab.. 2005; 289:E608–
E616. [PubMed: 15941787]
Gesta S. Tseng Y.H. Kahn C.R. Developmental origin of fat: tracking obesity to its source. Cell. 2007;
131:242–256. [PubMed: 17956727]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 14
Sponsored Document
Sponsored Document
Sponsored Document
S. Kajimura, P. Seale, B.M. Spiegelman, Transcriptional control of brown fat development, Cell.
Metab. 11, 257–262.
Seale P. Kajimura S. Spiegelman B.M. Transcriptional control of brown adipocyte development and
physiological function–of mice and men. Genes Dev.. 2009; 23:788–797. [PubMed: 19339685]
Powelka A.M. Seth A. Virbasius J.V. Kiskinis E. Nicoloro S.M. Guilherme A. Tang X. Straubhaar J.
Cherniack A.D. Parker M.G. Czech M.P. Suppression of oxidative metabolism and mitochondrial
biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J. Clin. Invest.. 2006;
116:125–136. [PubMed: 16374519]
Hansen J.B. Kristiansen K. Regulatory circuits controlling white versus brown adipocyte
differentiation. Biochem. J.. 2006; 398:153–168. [PubMed: 16898874]
Christian M. Kiskinis E. Debevec D. Leonardsson G. White R. Parker M.G. RIP140-targeted
repression of gene expression in adipocytes. Mol. Cell. Biol.. 2005; 25:9383–9391. [PubMed:
16227589]
Morganstein D.L. Christian M. Turner J.J. Parker M.G. White R. Conditionally immortalized white
preadipocytes: a novel adipocyte model. J. Lipid Res.. 2008; 49:679–685. [PubMed: 18046046]
Puigserver P. Wu Z. Park C.W. Graves R. Wright M. Spiegelman B.M. A cold-inducible coactivator
of nuclear receptors linked to adaptive thermogenesis. Cell. 1998; 92:829–839. [PubMed:
9529258]
Hallberg M. Morganstein D.L. Kiskinis E. Shah K. Kralli A. Dilworth S.M. White R. Parker M.G.
Christian M. A functional interaction between RIP140 and PGC-1alpha regulates the expression of
the lipid droplet protein CIDEA. Mol. Cell. Biol.. 2008; 28:6785–6795. [PubMed: 18794372]
Ho P.C. Lin Y.W. Tsui Y.C. Gupta P. Wei L.N. A negative regulatory pathway of GLUT4 trafficking
in adipocyte: new function of RIP140 in the cytoplasm via AS160. Cell Metab.. 2009; 10:516–
523. [PubMed: 19945409]
Catalan V. Gomez-Ambrosi J. Lizanzu A. Rodriguez A. Silva C. Rotellar F. Gil M.J. Cienfuegos J.A.
Salvador J. Fruhbeck G. RIP140 gene and protein expression levels are downregulated in visceral
adipose tissue in human morbid obesity. Obes. Surg.. 2009; 19:771–776. [PubMed: 19367438]
K.M. Seow, Y.L. Tsai, C.C. Juan, L.W. Huang, J.L. Hwang, L.T. Ho, Omental fat receptor interacting
protein 140 mRNA expression in women with polycystic ovary syndrome, Gynecol. Obstet.
Invest. 69, 51–56.
N. Mejhert, J. Laurencikiene, A.T. Pettersson, M. Kaaman, B.M. Stenson, M. Ryden, I. Dahlman, Role
of Receptor-Interacting Protein 140 in human fat cells, BMC Endocr. Disord. 10, 1.
Cypess A.M. Lehman S. Williams G. Tal I. Rodman D. Goldfine A.B. Kuo F.C. Palmer E.L. Tseng
Y.H. Doria A. Kolodny G.M. Kahn C.R. Identification and importance of brown adipose tissue in
adult humans. N. Engl. J. Med.. 2009; 360:1509–1517. [PubMed: 19357406]
Saito M. Okamatsu-Ogura Y. Matsushita M. Watanabe K. Yoneshiro T. Nio-Kobayashi J. Iwanaga T.
Miyagawa M. Kameya T. Nakada K. Kawai Y. Tsujisaki M. High incidence of metabolically
active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity.
Diabetes. 2009; 58:1526–1531. [PubMed: 19401428]
Virtanen K.A. Lidell M.E. Orava J. Heglind M. Westergren R. Niemi T. Taittonen M. Laine J. Savisto
N.J. Enerback S. Nuutila P. Functional brown adipose tissue in healthy adults. N. Engl. J. Med..
2009; 360:1518–1525. [PubMed: 19357407]
van Marken Lichtenbelt W.D. Vanhommerig J.W. Smulders N.M. Drossaerts J.M. Kemerink G.J.
Bouvy N.D. Schrauwen P. Teule G.J. Cold-activated brown adipose tissue in healthy men. N.
Engl. J. Med.. 2009; 360:1500–1508. [PubMed: 19357405]
Parker M. Leonardsson G. White R. Steel J. Milligan S. Identification of RIP140 as a nuclear receptor
cofactor with a role in female reproduction. FEBS Lett.. 2003; 546:149–153. [PubMed: 12829251]
Lowell B.B. S.S. V, A. Hamann, J.A. Lawitts, J. Himms-Hagen, B.B. Boyer, L.P. Kozak, J.S. Flier,
Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature.
1993; 366:740–742. [PubMed: 8264795]
Feldmann H.M. Golozoubova V. Cannon B. Nedergaard J. UCP1 ablation induces obesity and
abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at
thermoneutrality. Cell Metab.. 2009; 9:203–209. [PubMed: 19187776]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 15
Sponsored Document
Sponsored Document
Sponsored Document
Kopecky J. Clarke G. Enerback S. Spiegelman B. Kozak L.P. Expression of the mitochondrial
uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J. Clin. Invest..
1995; 96:2914–2923. [PubMed: 8675663]
Esterbauer H. Oberkofler H. Liu Y.M. Breban D. Hell E. Krempler F. Patsch W. Uncoupling protein-1
mRNA expression in obese human subjects: the role of sequence variations at the uncoupling
protein-1 gene locus. J. Lipid Res.. 1998; 39:834–844. [PubMed: 9555947]
Wang N. Tabas I. Winchester R. Ravalli S. Rabbani L.E. Tall A. Interleukin 8 is induced by
cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma.
J. Biol. Chem.. 1996; 271:8837–8842. [PubMed: 8621523]
J.M. Olefsky, C.K. Glass, Macrophages, inflammation, and insulin resistance, Annu. Rev. Physiol. 72,
219–246.
Wahba I.M. Mak R.H. Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic
kidney disease. Clin. J. Am. Soc. Nephrol.. 2007; 2:550–562. [PubMed: 17699463]
Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha:
direct role in obesity-linked insulin resistance. Science. 1993; 259:87–91. [PubMed: 7678183]
Kern P.A. Saghizadeh M. Ong J.M. Bosch R.J. Deem R. Simsolo R.B. The expression of tumor
necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to
lipoprotein lipase. J. Clin. Invest.. 1995; 95:2111–2119. [PubMed: 7738178]
Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante A.W. Jr. Obesity is
associated with macrophage accumulation in adipose tissue. J. Clin. Invest.. 2003; 112:1796–1808.
[PubMed: 14679176]
Wellen K.E. Hotamisligil G.S. Inflammation, stress, and diabetes. J. Clin. Invest.. 2005; 115:1111–
1119. [PubMed: 15864338]
Lumeng C.N. Bodzin J.L. Saltiel A.R. Obesity induces a phenotypic switch in adipose tissue
macrophage polarization. J. Clin. Invest.. 2007; 117:175–184. [PubMed: 17200717]
Murano I. Barbatelli G. Parisani V. Latini C. Muzzonigro G. Castellucci M. Cinti S. Dead adipocytes,
detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J.
Lipid Res.. 2008; 49:1562–1568. [PubMed: 18390487]
Shi H. Kokoeva M.V. Inouye K. Tzameli I. Yin H. Flier J.S. TLR4 links innate immunity and fatty
acid-induced insulin resistance. J. Clin. Invest.. 2006; 116:3015–3025. [PubMed: 17053832]
Nguyen M.T. Favelyukis S. Nguyen A.K. Reichart D. Scott P.A. Jenn A. Liu-Bryan R. Glass C.K.
Neels J.G. Olefsky J.M. A subpopulation of macrophages infiltrates hypertrophic adipose tissue
and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J.
Biol. Chem.. 2007; 282:35279–35292. [PubMed: 17916553]
Solinas G. Vilcu C. Neels J.G. Bandyopadhyay G.K. Luo J.L. Naugler W. Grivennikov S. WynshawBoris A. Scadeng M. Olefsky J.M. Karin M. JNK1 in hematopoietically derived cells contributes
to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab.. 2007;
6:386–397. [PubMed: 17983584]
Sabio G. Das M. Mora A. Zhang Z. Jun J.Y. Ko H.J. Barrett T. Kim J.K. Davis R.J. A stress signaling
pathway in adipose tissue regulates hepatic insulin resistance. Science. 2008; 322:1539–1543.
[PubMed: 19056984]
Hevener A.L. Olefsky J.M. Reichart D. Nguyen M.T. Bandyopadyhay G. Leung H.Y. Watt M.J.
Benner C. Febbraio M.A. Nguyen A.K. Folian B. Subramaniam S. Gonzalez F.J. Glass C.K.
Ricote M. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin
sensitivity and full antidiabetic effects of thiazolidinediones. J. Clin. Invest.. 2007; 117:1658–
1669. [PubMed: 17525798]
Odegaard J.I. Ricardo-Gonzalez R.R. Goforth M.H. Morel C.R. Subramanian V. Mukundan L. Red
Eagle A. Vats D. Brombacher F. Ferrante A.W. Chawla A. Macrophage-specific PPARgamma
controls alternative activation and improves insulin resistance. Nature. 2007; 447:1116–1120.
[PubMed: 17515919]
Arkan M.C. Hevener A.L. Greten F.R. Maeda S. Li Z.W. Long J.M. Wynshaw-Boris A. Poli G.
Olefsky J. Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med..
2005; 11:191–198. [PubMed: 15685170]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 16
Sponsored Document
Sponsored Document
Sponsored Document
Uysal K.T. Wiesbrock S.M. Marino M.W. Hotamisligil G.S. Protection from obesity-induced insulin
resistance in mice lacking TNF-alpha function. Nature. 1997; 389:610–614. [PubMed: 9335502]
Berriel Diaz M. Krones-Herzig A. Metzger D. Ziegler A. Vegiopoulos A. Klingenspor M. MullerDecker K. Herzig S. Nuclear receptor cofactor receptor interacting protein 140 controls hepatic
triglyceride metabolism during wasting in mice. Hepatology. 2008; 48:782–791. [PubMed:
18712775]
White R. Leonardsson G. Rosewell I. Ann Jacobs M. Milligan S. Parker M. The nuclear receptor corepressor nrip1 (RIP140) is essential for female fertility. Nat. Med.. 2000; 6:1368–1374. [PubMed:
11100122]
Seth A. Steel J.H. Nichol D. Pocock V. Kumaran M.K. Fritah A. Mobberley M. Ryder T.A. Rowlerson
A. Scott J. Poutanen M. White R. Parker M. The transcriptional corepressor RIP140 regulates
oxidative metabolism in skeletal muscle. Cell Metab.. 2007; 6:236–245. [PubMed: 17767910]
Pascual G. Fong A.L. Ogawa S. Gamliel A. Li A.C. Perissi V. Rose D.W. Willson T.M. Rosenfeld
M.G. Glass C.K. A SUMOylation-dependent pathway mediates transrepression of inflammatory
response genes by PPAR-gamma. Nature. 2005; 437:759–763. [PubMed: 16127449]
Ghisletti S. Huang W. Jepsen K. Benner C. Hardiman G. Rosenfeld M.G. Glass C.K. Cooperative
NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory
and anti-inflammatory signaling pathways. Genes Dev.. 2009; 23:681–693. [PubMed: 19299558]
Ghisletti S. Huang W. Ogawa S. Pascual G. Lin M.E. Willson T.M. Rosenfeld M.G. Glass C.K.
Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by
LXRs and PPARgamma. Mol. Cell. 2007; 25:57–70. [PubMed: 17218271]
Fain J.N. Madan A.K. Hiler M.L. Cheema P. Bahouth S.W. 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. [PubMed: 14726444]
Fried S.K. Bunkin D.A. Greenberg A.S. 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. [PubMed: 9506738]
Muoio D.M. Koves T.R. Lipid-induced metabolic dysfunction in skeletal muscle. Novartis Found.
Symp.. 2007; 286:24–38. discussion 38–46, 162–163, 196–203. [PubMed: 18269172]
Hulver M.W. Dohm G.L. The molecular mechanism linking muscle fat accumulation to insulin
resistance. Proc. Nutr. Soc.. 2004; 63:375–380. [PubMed: 15294058]
Pedersen B.K. Febbraio M.A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6.
Physiol. Rev.. 2008; 88:1379–1406. [PubMed: 18923185]
Bassel-Duby R. Olson E.N. Signaling pathways in skeletal muscle remodeling. Annu. Rev. Biochem..
2006; 75:19–37. [PubMed: 16756483]
Larsson L. Edstrom L. Lindegren B. Gorza L. Schiaffino S. MHC composition and enzymehistochemical and physiological properties of a novel fast-twitch motor unit type. Am. J. Physiol..
1991; 261:C93–C101. [PubMed: 1858863]
Thomas D.R. Loss of skeletal muscle mass in aging: examining the relationship of starvation,
sarcopenia and cachexia. Clin. Nutr.. 2007; 26:389–399. [PubMed: 17499396]
Wu H. Gallardo T. Olson E.N. Williams R.S. Shohet R.V. Transcriptional analysis of mouse skeletal
myofiber diversity and adaptation to endurance exercise. J. Muscle Res. Cell Motil.. 2003;
24:587–592. [PubMed: 14870974]
Benton C.R. Wright D.C. Bonen A. PGC-1alpha-mediated regulation of gene expression and
metabolism: implications for nutrition and exercise prescriptions. Appl. Physiol. Nutr. Metab..
2008; 33:843–862. [PubMed: 18923559]
C. Handschin, Regulation of skeletal muscle cell plasticity by the peroxisome proliferator-activated
receptor gamma coactivator 1alpha, J Recept Signal Transduct Res.
Abdul-Ghani M.A. DeFronzo R.A. Pathogenesis of insulin resistance in skeletal muscle. J. Biomed.
Biotechnol.. 2010:476279. [PubMed: 20445742]
Ryder J.W. Bassel-Duby R. Olson E.N. Zierath J.R. Skeletal muscle reprogramming by activation of
calcineurin improves insulin action on metabolic pathways. J. Biol. Chem.. 2003; 278:44298–
44304. [PubMed: 12941959]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 17
Sponsored Document
Sponsored Document
Sponsored Document
Tanner C.J. Barakat H.A. Dohm G.L. Pories W.J. MacDonald K.G. Cunningham P.R. Swanson M.S.
Houmard J.A. Muscle fiber type is associated with obesity and weight loss. Am. J. Physiol.
Endocrinol. Metab.. 2002; 282:E1191–E1196. [PubMed: 12006347]
J. Ren, L. Pulakat, A. Whaley-Connell, J.R. Sowers, Mitochondrial biogenesis in the metabolic
syndrome and cardiovascular disease, J. Mol. Med.
A. Fritah, J.H. Steel, D. Nichol, N. Parker, S. Williams, A. Price, L. Strauss, T.A. Ryder, M.A.
Mobberley, M. Poutanen, M. Parker, R. White, Elevated expression of the metabolic regulator
receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function,
Cardiovasc. Res. 86, 443–451.
Vuolteenaho O. Ruskoaho H. Gender matters: estrogen protects from cardiac hypertrophy. Trends
Endocrinol. Metab.. 2003; 14:52–54. [PubMed: 12591169]
Q. Liu, S. Bengmark, S. Qu, The role of hepatic fat accumulation in pathogenesis of non-alcoholic
fatty liver disease (NAFLD), Lipids Health Dis. 9, 42.
E. Vanni, E. Bugianesi, A. Kotronen, S. De Minicis, H. Yki-Jarvinen, G. Svegliati-Baroni, From the
metabolic syndrome to NAFLD or vice versa?, Dig. Liver Dis. 42, 320–330.
Donnelly K.L. Smith C.I. Schwarzenberg S.J. Jessurun J. Boldt M.D. Parks E.J. Sources of fatty acids
stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J.
Clin. Invest.. 2005; 115:1343–1351. [PubMed: 15864352]
Repa J.J. Liang G. Ou J. Bashmakov Y. Lobaccaro J.M. Shimomura I. Shan B. Brown M.S. Goldstein
J.L. Mangelsdorf D.J. Regulation of mouse sterol regulatory element-binding protein-1c gene
(SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev,. 2000; 14:2819–2830.
[PubMed: 11090130]
Lund E.G. Peterson L.B. Adams A.D. Lam M.H. Burton C.A. Chin J. Guo Q. Huang S. Latham M.
Lopez J.C. Menke J.G. Milot D.P. Mitnaul L.J. Rex-Rabe S.E. Rosa R.L. Tian J.Y. Wright S.D.
Sparrow C.P. Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an
alpha-selective and a dual agonist in mice deficient in each subtype. Biochem. Pharmacol.. 2006;
71:453–463. [PubMed: 16325781]
Knowler W.C. Barrett-Connor E. Fowler S.E. Hamman R.F. Lachin J.M. Walker E.A. Nathan D.M.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J.
Med.. 2002; 346:393–403. [PubMed: 11832527]
Bruce C.R. Thrush A.B. Mertz V.A. Bezaire V. Chabowski A. Heigenhauser G.J. Dyck D.J.
Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid
oxidation and alters muscle lipid content. Am. J. Physiol. Endocrinol. Metab.. 2006; 291:E99–
E107. [PubMed: 16464906]
Tontonoz P. Spiegelman B.M. Fat and beyond: the diverse biology of PPARgamma. Annu. Rev.
Biochem.. 2008; 77:289–312. [PubMed: 18518822]
Belfort R. Harrison S.A. Brown K. Darland C. Finch J. Hardies J. Balas B. Gastaldelli A. Tio F.
Pulcini J. Berria R. Ma J.Z. Dwivedi S. Havranek R. Fincke C. DeFronzo R. Bannayan G.A.
Schenker S. Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic
steatohepatitis. N. Engl. J. Med.. 2006; 355:2297–2307. [PubMed: 17135584]
Hammarstedt A. Sopasakis V.R. Gogg S. Jansson P.A. Smith U. Improved insulin sensitivity and
adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulinresistant subjects. Diabetologia. 2005; 48:96–104. [PubMed: 15624096]
de Souza C.J. Eckhardt M. Gagen K. Dong M. Chen W. Laurent D. Burkey B.F. Effects of
pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.
Diabetes. 2001; 50:1863–1871. [PubMed: 11473050]
Prentki M. Madiraju S.R. Glycerolipid metabolism and signaling in health and disease. Endocr. Rev..
2008; 29:647–676. [PubMed: 18606873]
Sathyanarayana P. Barthwal M.K. Kundu C.N. Lane M.E. Bergmann A. Tzivion G. Rana A.
Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of
mammalian MLK3. Mol. Cell. 2002; 10:1527–1533. [PubMed: 12504027]
Wang X. Devaiah S.P. Zhang W. Welti R. Signaling functions of phosphatidic acid. Prog. Lipid Res..
2006; 45:250–278. [PubMed: 16574237]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 18
Sponsored Document
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Jean-Baptiste G. Yang Z. Khoury C. Greenwood M.T. Lysophosphatidic acid mediates pleiotropic
responses in skeletal muscle cells. Biochem. Biophys. Res. Commun.. 2005; 335:1155–1162.
[PubMed: 16111655]
Sampson S.R. Cooper D.R. Specific protein kinase C isoforms as transducers and modulators of
insulin signaling. Mol. Genet. Metab.. 2006; 89:32–47. [PubMed: 16798038]
Adams J.M. 2nd, Pratipanawatr T. Berria R. Wang E. DeFronzo R.A. Sullards M.C. Mandarino L.J.
Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes.
2004; 53:25–31. [PubMed: 14693694]
P.M. Coen, J.J. Dube, F. Amati, M. Stefanovic-Racic, R.E. Ferrell, F.G. Toledo, B.H. Goodpaster,
Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II
myocytes concomitant with higher ceramide content, Diabetes 59, 80–88.
Stratford S. Hoehn K.L. Liu F. Summers S.A. Regulation of insulin action by ceramide: dual
mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol.
Chem.. 2004; 279:36608–36615. [PubMed: 15220355]
Muoio D.M. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly
accused. Biochim. Biophys. Acta. 1801:281–288.
Houstis N. Rosen E.D. Lander E.S. Reactive oxygen species have a causal role in multiple forms of
insulin resistance. Nature. 2006; 440:944–948. [PubMed: 16612386]
Nawrocki A.R. Rajala M.W. Tomas E. Pajvani U.B. Saha A.K. Trumbauer M.E. Pang Z. Chen A.S.
Ruderman N.B. Chen H. Rossetti L. Scherer P.E. Mice lacking adiponectin show decreased
hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated
receptor gamma agonists. J. Biol. Chem.. 2006; 281:2654–2660. [PubMed: 16326714]
Yamauchi T. Kadowaki T. The molecular mechanisms by which PPAR gamma/RXR inhibitors
improve insulin resistance. Nippon Rinsho. 2001; 59:2245–2254. [PubMed: 11712415]
Kiskinis E. Hallberg M. Christian M. Olofsson M. Dilworth S.M. White R. Parker M.G. RIP140
directs histone and DNA methylation to silence Ucp1 expression in white adipocytes. EMBO J..
2007; 26:4831–4840. [PubMed: 17972916]
Dlaskova A. Clarke K.J. Porter R.K. The role of UCP 1 in production of reactive oxygen species by
mitochondria isolated from brown adipose tissue. Biochim. Biophys. Acta. 1797:1470–1476.
Leonardsson G. Jacobs M.A. White R. Jeffery R. Poulsom R. Milligan S. Parker M. Embryo transfer
experiments and ovarian transplantation identify the ovary as the only site in which nuclear
receptor interacting protein 1/RIP140 action is crucial for female fertility. Endocrinology. 2002;
143:700–707. [PubMed: 11796527]
Tullet J.M. Pocock V. Steel J.H. White R. Milligan S. Parker M.G. Multiple signaling defects in the
absence of RIP140 impair both cumulus expansion and follicle rupture. Endocrinology. 2005;
146:4127–4137. [PubMed: 15919748]
Augereau P. Badia E. Fuentes M. Rabenoelina F. Corniou M. Derocq D. Balaguer P. Cavailles V.
Transcriptional regulation of the human NRIP1/RIP140 gene by estrogen is modulated by dioxin
signalling. Mol. Pharmacol.. 2006; 69:1338–1346. [PubMed: 16391242]
Kerley J.S. Olsen S.L. Freemantle S.J. Spinella M.J. Transcriptional activation of the nuclear receptor
corepressor RIP140 by retinoic acid: a potential negative-feedback regulatory mechanism.
Biochem. Biophys. Res. Commun.. 2001; 285:969–975. [PubMed: 11467847]
Carascossa S. Gobinet J. Georget V. Lucas A. Badia E. Castet A. White R. Nicolas J.C. Cavailles V.
Jalaguier S. Receptor-interacting protein 140 is a repressor of the androgen receptor activity.
Mol. Endocrinol.. 2006; 20:1506–1518. [PubMed: 16527872]
Graham J.D. Yager M.L. Hill H.D. Byth K. O'Neill G.M. Clarke C.L. Altered progesterone receptor
isoform expression remodels progestin responsiveness of breast cancer cells. Mol. Endocrinol..
2005; 19:2713–2735. [PubMed: 15976005]
Nichol D. Christian M. Steel J.H. White R. Parker M.G. RIP140 expression is stimulated by estrogenrelated receptor alpha during adipogenesis. J. Biol. Chem.. 2006; 281:32140–32147. [PubMed:
16923809]
Luo J. Sladek R. Carrier J. Bader J.A. Richard D. Giguere V. Reduced fat mass in mice lacking orphan
nuclear receptor estrogen-related receptor alpha. Mol. Cell. Biol.. 2003; 23:7947–7956.
[PubMed: 14585956]
Published as: Biochim Biophys Acta. 2011 August ; 1812(8): 919–928.
Rosell et al.
Page 19
Sponsored Document
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Tsai N.P. Lin Y.L. Wei L.N. MicroRNA mir-346 targets the 5′-untranslated region of receptorinteracting protein 140 (RIP140) mRNA and up-regulates its protein expression. Biochem. J..
2009; 424:411–418. [PubMed: 19780716]
Vo N. Fjeld C. Goodman R.H. Acetylation of nuclear hormone receptor-interacting protein RIP140
regulates binding of the transcriptional corepressor CtBP. Mol. Cell. Biol.. 2001; 21:6181–6188.
[PubMed: 11509661]
Wei L.N. Hu X. Chandra D. Seto E. Farooqui M. Receptor-interacting protein 140 directly recruits
histone deacetylases for gene silencing. J. Biol. Chem.. 2000; 275:40782–40787. [PubMed:
11006275]
Huq M.D. Khan S.A. Park S.W. Wei L.N. Mapping of phosphorylation sites of nuclear corepressor
receptor interacting protein 140 by liquid chromatography-tandem mass spectroscopy.
Proteomics. 2005; 5:2157–2166. [PubMed: 15846843]
Huq M.D. Wei L.N. Post-translational modification of nuclear co-repressor receptor-interacting
protein 140 by acetylation. Mol. Cell. Proteomics. 2005; 4:975–983. [PubMed: 15879431]
Mostaqul Huq M.D. Gupta P. Tsai N.P. White R. Parker M.G. Wei L.N. Suppression of receptor
interacting protein 140 repressive activity by protein arginine methylation. EMBO J.. 2006;
25:5094–5104. [PubMed: 17053781]
Huq M.D. Ha S.G. Barcelona H. Wei L.N. Lysine methylation of nuclear co-repressor receptor
interacting protein 140. J. Proteome Res.. 2009; 8:1156–1167. [PubMed: 19216533]
Huq M.D. Tsai N.P. Lin Y.P. Higgins L. Wei L.N. Vitamin B6 conjugation to nuclear corepressor
RIP140 and its role in gene regulation. Nat. Chem. Biol.. 2007; 3:161–165. [PubMed: 17277785]
Rytinki M.M. Palvimo J.J. SUMOylation modulates the transcription repressor function of RIP140. J.
Biol. Chem.. 2008; 283:11586–11595. [PubMed: 18211901]
Gupta P. Ho P.C. Huq M.M. Ha S.G. Park S.W. Khan A.A. Tsai N.P. Wei L.N. Retinoic acidstimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor
TR2 to suppress Oct4 expression. Proc. Natl Acad. Sci. USA. 2008; 105:11424–11429.
[PubMed: 18682553]
Gupta P. Huq M.D. Khan S.A. Tsai N.P. Wei L.N. Regulation of co-repressive activity of and HDAC
recruitment to RIP140 by site-specific phosphorylation. Mol. Cell. Proteomics. 2005; 4:1776–
1784. [PubMed: 16093479]
Ho P.C. Gupta P. Tsui Y.C. Ha S.G. Huq M. Wei L.N. Modulation of lysine acetylation-stimulated
repressive activity by Erk2-mediated phosphorylation of RIP140 in adipocyte differentiation.
Cell. Signal.. 2008; 20:1911–1919. [PubMed: 18655826]
J.H. Choi, A.S. Banks, J.L. Estall, S. Kajimura, P. Bostrom, D. Laznik, J.L. Ruas, M.J. Chalmers, T.M.
Kamenecka, M. Bluher, P.R. Griffin, B.M. Spiegelman, Anti-diabetic drugs inhibit obesitylinked phosphorylation of PPARgamma by Cdk5, Nature 466 451–456.
Acknowledgments
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This work was supported by the Welcome Trust number 079200/Z/06/Z, the BBSRC number 504327/and Genesis
Trust.
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Fig. 1.
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Actions of RIP140 in adipocytes. Nuclear RIP140 is recruited by nuclear receptors to
repress sets of genes that promote energy consumption. Glut4 gene is also transrepressed
and the action of Glut4 protein is inhibited by cytoplasmic RIP140, contributing to insulin
resistance. Cytoplasmic translocation of RIP140 is stimulated by PKCε-mediated
phosphorylation, followed by 14-3-3-dependent recruitment of PRMT1, arginine
methylation and export through exportin1. This sequence of post-translational modifications
is promoted under a high-fat diet. PKCε, protein kinase Cε; PRTM1, protein arginine methyl
transferase 1; HFD, high-fat diet.
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Fig. 2.
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In muscle cells RIP140 functions as a corepressor for nuclear receptors to repress genes
involved in oxidative metabolism. In macrophages RIP140 is a coactivator for NF-κBdependent pro-inflammatory genes. In hepatocytes RIP140 is both a corepressor and
coactivator for LXRα-dependent gene transcription to promote lipogenesis and reduce
gluconeogenesis.
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Fig. 3.
Actions of RIP140 in different metabolic tissue.
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