Download Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

Am J Physiol Cell Physiol 291: C203–C217, 2006;
doi:10.1152/ajpcell.00476.2005.
Invited Review
Orphan nuclear receptors: therapeutic opportunities in skeletal muscle
Aaron G. Smith and George E. O. Muscat
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
metabolism; cardiovascular disease
CARDIOVASCULAR DISEASE (CVD) represents one of the most
critical global health threats, and accounts for ⬎16.7 million
deaths every year. A cluster of pathologies that constitute CVC
include heart disease, vascular disease, atherosclerosis, myocardial infarction, stroke, and hypertension. Furthermore, the
links between CVD and the ever-increasing obesity epidemic
suggests a grave prognosis for human health in the early
decades of the 21st century. Such grim predictions are supported by the realization that CVD contributed to one-third of
global morbidity in 2001 (3, 4, 140).
Dyslipidemia associated with anomalous levels of the lipid
triad [i.e., elevated levels of triglycerides (TG) and low-density
lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol], hypertension, obesity, sedentary
lifestyle, diabetes, chronic inflammation, and smoking all constitute important independent risk factors for cardiovascular
disease. Importantly, diet, metabolism (genetic predisposition),
and physical activity directly influence these risk factors (3, 4,
140). Research indicates that ⬃62% of strokes and 49% of
heart attacks are caused by hypertension. High blood cholesterol (⬎5 mmol/l) accounts for ⬃18% of strokes and 50% of
heart disease. Aside from dietary and genetic factors, the
prevalence of cardiovascular disease is exacerbated by modern
Address for reprint requests and other correspondence: A. G. Smith, Institute
for Molecular Bioscience, Univ. of Queensland, St. Lucia 4072, Queensland,
Australia (e-mail: [email protected]).
http://www.ajpcell.org
sedentary lifestyles; current data suggest that ⬃60% of the
world’s population do not meet current physical activity guidelines (3, 4, 140).
Approximately 20% of the global population (up to 1 billion
adults) are deemed overweight and at least 300 million are
clinically obese. Obesity rates have tripled in North America,
Eastern Europe, the Middle East, Australia, and China. About
21% of coronary heart disease globally is attributable to an
elevated body mass index (⬎25) (4, 185). Obesity is the trigger
for the development of hypertension, dyslipidemia, and
diabetes, which ultimately leads to cardiovascular disease.
Furthermore, the increasing prevalence of diabetes in adults
(estimated at ⬃4.5% globally) leads to a 3- and 8-fold
higher coronary heart disease risk in men and women
respectively (185). Currently, 180 million people worldwide
suffer from diabetes, and at least 1 in 10 deaths among
adults between 35 and 64 years old is attributable to diabetes, primarily through the increased risk of cardiovascular
disease (122, 140, 185).
METABOLIC SYNDROME
Metabolic syndrome, or Syndrome X, represents a cluster of
metabolic abnormalities that all constitute known risk factors
for cardiovascular disease. The National Cholesterol Education
Program: Adult Treatment Panel III guidelines define metabolic syndrome as the presence of any three features listed in
Table 1 (1). The increased prevalence of metabolic syndrome
0363-6143/06 $8.00 Copyright © 2006 the American Physiological Society
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Smith, Aaron G., and George E. O. Muscat. Orphan nuclear receptors:
therapeutic opportunities in skeletal muscle. Am J Physiol Cell Physiol 291:
C203–C217, 2006; doi:10.1152/ajpcell.00476.2005.—Nuclear hormone receptors
(NRs) are ligand-dependent transcription factors that bind DNA and translate
physiological signals into gene regulation. The therapeutic utility of NRs is
underscored by the diversity of drugs created to manage dysfunctional hormone
signaling in the context of reproductive biology, inflammation, dermatology,
cancer, and metabolic disease. For example, drugs that target nuclear receptors
generate over $10 billion in annual sales. Almost two decades ago, gene products
were identified that belonged to the NR superfamily on the basis of DNA and
protein sequence identity. However, the endogenous and synthetic small molecules
that modulate their action were not known, and they were denoted orphan NRs.
Many of the remaining orphan NRs are highly enriched in energy-demanding major
mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and
kidney. This review focuses on recently adopted and orphan NR function in skeletal
muscle, a tissue that accounts for ⬃35% of the total body mass and energy
expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this
lean tissue is involved in cholesterol efflux and secretes that control energy
expenditure and adiposity. Consequently, muscle has a significant role in insulin
sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal
muscle plays a considerable role in the progression of dyslipidemia, diabetes, and
obesity. These are risk factors for cardiovascular disease, which is the the foremost
cause of global mortality (⬎16.7 million deaths in 2003). Therefore, it is not
surprising that orphan NRs and skeletal muscle are emerging as therapeutic
candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular
disease.
Invited Review
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METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
Table 1. Definitions of metabolic sndrome as outlined
by National Cholesterol Education Program:
Adult Treatment Panel III
Central obesity: waist circumference ⬎102 cm (men) or ⬎88 cm (women)
Impaired fasting glucose (⬎6.1 mmol/l)
Low HDL cholesterol (⬍1.0 mmol/l in men; ⬍1.3 mmol/l in women)
Hypertriglyceridemia (⬎1.7 mmol/l)
Hypertension: blood pressure ⬎135/85 mmHg (or medicated)
HDL, high-density lipoprotein.
SKELETAL MUSCLE CARBOHYDRATE AND
LIPID METABOLISM
Skeletal Muscle Metabolism
The three types of muscle tissues are skeletal, cardiac, and
smooth. Skeletal muscle is involved in movement, posture,
stability, metabolism, heat production, and cold tolerance.
Skeletal muscle fibers are classified by two major functional
characteristics: speed of contraction and the aerobic (oxidative)/anaerobic (glycolytic) production of ATP. The speed of
the fiber reflects how fast the fiber metabolizes ATP. Fast fibers
(also known as type IIb or white fibers) utilize anaerobic
glycolysis, are low in mitochondria and myoglobin, rich in
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Skeletal Muscle Dysfunction in Metabolic Disease
Skeletal muscle insulin resistance comprises perturbations in
both glucose and fatty acid metabolism. It is well established in
the literature that pathophysiological conditions that are associated with impaired insulin resistance, such as type 2 diabetes
and obesity, correlate with elevations in circulating FFAs (15,
147). Considerable evidence obtained in both animal and
human studies have linked accumulation of intra-myocellular
lipids with insulin resistance in obesity and type 2 diabetes (49,
75, 109, 133). Investigations aimed at identifying the mechanisms underlying this association have implied an imbalance
between fatty acid uptake and the rate of fatty acid oxidation.
The direct link between intra-myocellular lipid accumulation
and insulin resistance is supported by the observation that
insulin sensitivity can be restored by treatments that promote
depletion of accumulated triglycerides, such as low-fat diets,
fasting, exercise, and leptin administration (125, 163). The
significance of this is exemplified by NMR spectroscopy studies (86, 157) that measured intramyocellular lipids and found
that levels correlated more closely with insulin resistance that
other commonly used indexes, such as body mass index and
waist-to-hip ratios.
Impaired mitochondrial function that directs fatty acids toward storage, as opposed to oxidation, and reduced oxidative
enzyme activities may in large part contribute to muscle lipid
accumulation in obesity and type 2 diabetes mellitus (76, 77,
165, 166). Moreover, the activity of carnitine palmitoyl transferase 1 (CPT1), a key step in the regulation of muscle fatty
acid oxidation, has been shown to be reduced in insulin
resistant muscle from obese subjects (165). In addition to this,
shunting of fatty acids toward storage in skeletal muscle as
opposed to oxidation triglyceride accumulation in skeletal
muscle of obese and type 2 diabetic subjects was shown to be
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has arisen primarily as a result of the global obesity epidemic
with peripheral insulin resistance providing the most widely
accepted and unifying feature of the syndrome (40, 162). While
great inroads have been made in the identification of the relationship between the various clinical features of metabolic syndrome,
the underlying pathological mechanisms are not well understood.
Excessive circulating levels of saturated fatty acids is known
to be a major contributing factor to the development of insulin
resistance (40, 162). The development of insulin resistance in
response to increased dietary fatty acid intake is likely to be
exacerbated further by the ensuing inhibition of the antilipolytic effect of insulin action resulting in an increased
release of stored triglycerides into the circulation (84, 157).
Increased circulating fatty acids promotes insulin resistance by
inhibiting various components of insulin signaling pathways
such as protein kinase C in skeletal muscle (84) and insulin
receptor substrate phosphorylation in the liver (155). Increased
fatty acid delivery to the liver increases hepatic triglyceride
synthesis and promotes the production and secretion of ApoB
containing very low-density lipoprotein (VLDL) into the circulation contributing to the dyslipidemic features of Metabolic
Syndrome (97, 98). Defective glucose metabolism arises primarily from reduced ability of insulin to suppress hepatic
glucose production and promote glucose uptake by adipose and
muscle tissue. Subsequent compensatory mechanisms to maintain euglycemia result in the characteristic hyperinsulinemia
associated with metabolic syndrome (40, 157, 162). While
hyperinsulinemia will ultimately have feedback effects on
insulin secretion, prolonged exposure to circulating free fatty
acids (FFAs) are also implicated in perturbations in glucose
stimulated insulin secretion by pancreatic ␤-cells (92). Several
mechanisms have been proposed to underlie pancreatic lipotoxicity in metabolic syndrome (17, 69, 188). More recent
studies (93, 186) have suggested a relationship between elevated proinflammatory cytokines, such as TNF-␣ and the
pathogenesis of metabolic syndrome.
glycogen, and are suited to short-term intense activity. Slow
fibers (also known as type I or red fibers) utilize aerobic
metabolism, are rich in mitochondria and myoglobin, and are
suited to endurance activity. There is an intermediate fast fiber
type IIa, which combines fast twitch capacity with aerobic
fatigue-resistant metabolism and intermediate glycogen levels
(107).
Skeletal muscle is a “metabolically flexible” tissue and has
a paramount role in energy balance; for instance, it is the
primary tissue of insulin-stimulated glucose uptake (disposal),
and storage (4-fold the glycogen content of liver), regulates
ApoA1-dependent cholesterol efflux and strongly influences
metabolism via modulation of circulating and stored lipid flux
(57, 74, 78, 136). In fact, lipid catabolism supplies up to 70%
of the energy requirements in a fasted individual. During the
initial phase of aerobic exercise, skeletal muscle utilizes stored
glycogen; however, as exercise continues, glucose and stored
muscle triglycerides become important energy substrates (57,
148, 149). Prolonged exercise increasingly depends on fatty
acids and lipid mobilization from other tissues. Given the fact
that skeletal muscle can utilize both carbohydrate and lipid
energy substrates after appropriate mechanical and hormonal
cues and considering the relative mass of the tissue it is hardly
surprising that normal (and abnormal) skeletal muscle metabolism has a significant impact on insulin sensitivity, the blood
lipid profile and the pathogenesis of metabolic disease.
Invited Review
METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
SKELETAL MUSCLE AS AN ENDOCRINE ORGAN: MYOKINES
Obesity-linked insulin resistance is known to be associated
with a chronic systemic inflammatory response (61, 183). In
recent years, it has become apparent that adipose tissue functions as more than just a reservoir for energy storage in the
form of triglycerides but rather functions as a vital endocrine
organ regulating systemic metabolic homeostasis via controlled storage/release of fatty acids and the secretion of biologically active “adipokines,” such as adiponectin (70), resistin
(169), leptin (106), adipsin (184), and TNF-␣ (62). Similarly,
the potential endocrine function of skeletal muscle is being
recognized with the release of bioactive molecules now termed
“myokines” (42, 132). Identification of these factors offers
support for a skeletal muscle endocrine axis that is potentially
pivotal to metabolic homeostasis.
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Muscle tissue expresses and releases several cytokines into
the circulation, for example, IL-6, -8 and -15. The autocrine
actions of these factors are well documented; however, there is
accumulating evidence that these cytokines exert their effect in
other parts of the body. IL-15 is abundantly expressed in
skeletal muscle, is induced by acute exercise, and has anabolic
effects on skeletal muscle protein dynamics (141). Interestingly, administration of IL-15 in rats demonstrated a significant
reduction in adipose deposition (23). Studies (142) in adipogenic 3T3 cells revealed that despite little or no expression of
IL-15 mRNA, administration of IL-15 inhibited lipogenesis
and stimulated the release of adiponectin. Because skeletal
muscle expresses and secretes high levels of IL-15, such an
observation provides strong support for the hypothesis that a
skeletal muscle-adipose endocrine axis exists that modulates
lean body/adipose composition and insulin sensitivity.
Another cytokine released by skeletal muscle is IL-6 and has
been referred to as the “exercise factor” because its expression
and release was found to increase up to 100-fold during muscle
contraction and is postulated to underlie many of the metabolically beneficial effects of exercise (43). Circulating IL-6
stimulates AMPK activity, a fuel-sensing enzyme that is activated by changes in the energy state of the cell and in response
to adipokines, in adipose and lean tissue (80). IL-6 transcriptional regulation in skeletal muscle is influenced by glycogen
content via the p38 MAPK pathway that results in upregulated
expression in response to exercise-induced glycogen depletion
(26, 27). During exercise, IL-6 appears to play a glucoregulatory role via augmented hepatic glucose production and muscle
glucose uptake (43). IL-6 has been shown to be a potent
modulator of fatty acid metabolism via increased rates of fatty
acid oxidation and reesterification and attenuation of insulinmediated lipogenesis in both human subjects and isolated
rodent muscle samples (19, 173). More recently, IL-6-driven
increases in lipolysis were demonstrated in type 2 diabetic
patients without the induction of adverse side effects, such
as hypertriacylglyceridemia, suggesting a potential therapeutic utility of this cytokine in the treatment of metabolic
syndrome (135). Paradoxically, increased circulating IL-6
has been linked to type 2 diabetes, leading to speculation
that IL-6 may contribute to the induction or pathogenesis of
type 2 diabetes (137, 139, 152). However, firm evidence of
a causative link remains to be demonstrated. Furthermore,
IL-6-deficient transgenic mice are glucose intolerant, have
reduced endurance and energy expenditure, and develop
late-onset obesity (180).
Finally, myostatin, a member of the TGF-␤ superfamily, is
specifically expressed in vertebrate skeletal muscle. Mice lacking myostatin have a dramatic increase in skeletal muscle
growth and significantly reduced fat deposition with age (110,
111). Several mechanisms may account for the effect of myostatin on lipid metabolism, including a direct effect on adipocytes (81) or alternatively, anabolic effects in skeletal muscle
may produce a metabolic shift in energy consumption resulting
in a net reduction in adipose lipid storage. The latter hypothesis
is plausible, given the accumulating evidence that muscle fiber
composition has a favorable effect on the LDL/HDL cholesterol ratio (55) and the accepted tenet that muscle tissue has a
significantly higher metabolic rate than other major tissues.
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linked to elevated rates of fatty acid transport via increased
sarcolemma fat/cd36 (16). Another hypothesis contends that
hyperinsulinemia may increase skeletal muscle and liver lipid
content due to increased lipogenesis via elevated expression of
SREBP-1C (164). This hypothesis is further supported by the
recent observation that SCD-1 expression and activity is elevated in the skeletal muscle of obese humans contributing to
the abnormal skeletal muscle lipid partitioning seen in these
individuals (63).
Impaired glucose utilization by skeletal muscle in metabolic
disease is also linked to elevated circulating FFAs. As early as
the 1960s, it was noted that FFA oxidation disrupts glucose
catabolism via the inhibition of phosphofructokinase and pyruvate dehydrogenase. In this context, the Randle hypothesis
proposed that FFAs compete with glucose for mitochondrial
oxidation (144). Similarly, studies support the concept that
FFAs inhibit glucose transport and key phosphorylation events
(38, 147). Alternatively, mounting evidence points to direct
effects of increase circulating and intracellular lipid content to
perturbations in insulin signaling pathways (38, 147, 175).
Excess triglyceride in insulin resistant muscle has been shown
to alter insulin signaling via consequent increases in lipid
intermediates, such as fatty-acyl CoA, diacylglycerol, and
ceramides. Activation of protein kinase C by diacylglycerol
inhibits the tyrosine kinase activity of the insulin receptor
leading to reduced insulin action (159). Ceramides activate a
protein phosphatase that dephosphorylates AKT/protein kinase
B, subsequently inhibiting glut4 translocation and glycogen
synthesis (28, 100). Lipid accumulation in skeletal muscle has
also been shown to inhibit phosphorylation of Irs-1, thus
inhibiting the binding and activation of phosphatidylinositol
3-kinase, a pivotal step in the normal insulin signaling cascade
(38, 190).
The metabolic flexibility of skeletal muscle allows it to
utilize both carbohydrate and lipid energy sources given the
appropriate hormonal and mechanical signals (74, 76, 77).
While the precise mechanistic basis underlying abnormal skeletal muscle function in obesity and diabetes remains unclear, it
is obvious that biochemical perturbations in this tissue have a
profound effect on systemic metabolic homeostasis. Therapeutic targeting of the metabolic derangements in skeletal muscle
will undoubtedly promote improvement in systemic metabolic
homeostasis and ultimately attenuate the pathogenesis associated with the metabolic syndrome.
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METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
NUCLEAR RECEPTOR REGULATION OF CARBOHYDRATE
AND LIPID METABOLISM
NUCLEAR RECEPTOR FUNCTION: GENERAL CONCEPTS
A decade ago, gene products were identified that belonged to
the NR superfamily on the basis of nucleic acid sequence
identity. However, the endogenous molecules which regulate
their activity were unknown and thus they were called orphan
NRs. On the basis of members of the NR superfamily that have
been characterized, the orphans forecast an enormous, yet
unexploited opportunity for the discovery of novel signaling
pathways and therapeutic agents. The potential impact of such
a discovery cannot be overstated, because every known NR has
been implicated in disease (14, 51, 172). All members of the
NR superfamily display a highly conserved structural organization with an amino terminal region AB (that encodes activation function 1; AF-1), followed by the COOH region, which
encodes the DNA binding domain; a linker region D and the
COOH-terminal E region. The DE region encodes the ligand
binding domain (LBD), and a transcriptional domain, denoted
as AF-2 (Fig. 1) (4, 105). Nuclear receptors trans-activate the
expression of target genes via the binding of DNA consensus
elements within regulatory regions as either monomers, homodimers, or heterodimers with the retinoid X receptors. DNA
binding is mediated by a highly conserved zinc finger DNA
binding domain and in the case of heterodimerization consensus elements have been found as direct repeats, inverted repeats,
or palindromic repeats (4, 105). A subgroup of the NR superfamily controls metabolism in an organ-specific manner (45).
The transcriptional activity of nuclear receptors is regulated
by coordinated interaction with nuclear cofactors. As a general
rule, the interaction of receptors with ligands promotes a
Fig. 1. A: schematic representation of nuclear receptor
functional domains. The variable NH2-terminal domain
possesses AF-1 ligand independent activity (A/B), the
conserved DNA binding domain (C), variable linker
region (D), ligand binding and dimerization domain (E)
and the AF-2 ligand-dependent transactivation domain
(F). B: co-regulator binding of nuclear receptors. Many
nuclear receptors are associated with co-repressor proteins in the absence of ligand. Upon ligand binding,
co-repressors are displaced in favor of co-activator
proteins. CoR, coenzyme receptor; CoA, coenzyme A.
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The links between diets rich in free fatty acids and sugars
and the increasing prevalence of dyslipidemia, type II diabetes,
obesity, and cardiovascular disease are well established. Furthermore, it is becoming increasingly clear that the metabolic
regualtion of both lipid and carbohydrate homeostasis are
intrinsically connected. A pertinent example of this metabolic
interconnection is the regulation of triglyceride catabolism by
insulin, a signaling molecule known primarily as an essential
regulator of glucose disposal. Insulin regulates triglyceride
catabolism via inhibition of hormone sensitive lipase. The
significance of this regulatory mechanism is highlighted by the
demonstration that lipid accumulation and/or elevated lipoprotein lipase expression in nonadipose tissue (e.g., liver and
muscle) results in insulin resistance (82, 86). Perhaps paradoxically it has become evident that diets rich in unsaturated fatty
acids protect against metabolic disease prompting speculation
that dietary lipids function as signaling molecules that play
vital roles in controlling lipid homeostasis. The search for the
mechanisms by which various lipid molecules regulate lipid
homeostasis and the subsequent targets of such signaling have
become an intense area of investigation in recent years in an
effort to understand and control the increasing incidence of
metabolic disease in modern society.
Insights into the mechanisms regulating such processes have
significantly matured since the discovery that metabolism is, in
part, regulated by the nuclear hormone receptors (NRs) which
function as ligand (hormone)-regulated transcription factors
that bind DNA and control gene expression (14, 45). A ligand
or hormone can be considered any small molecule that can bind
to the receptor and affect its function. For example, steroids
(estrogen, testosterone, etc.), thyroid hormones, retinoids, dietary lipids, oxysterols, fatty and bile acids are signaling
molecules that bind to nuclear receptors and regulate gene
expression thereby controlling endocrine pathways directly
relevant to disease (14, 45). Essentially, NRs function as the
conduit between diet, metabolism (and environmental stimuli)
and gene expression mediating a unique physiological response
in a nutritionally dependent manner.
Invited Review
METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
ORPHAN NRs AS THERAPEUTIC TARGETS
The fundamental importance of NRs in human health is
underscored by the gamut of drugs created to treat disorders
associated with dysfunctional hormone signaling ranging from
cancer and diabetes to reproductive, cardiovascular and inflammatory diseases (28a, 51, 52, 172).
The plethora of orphan NRs has been the catalyst for the
development of a new paradigm, called “reverse endocrinology” mediated by functional genomics, high throughput
screening and combinatorial chemistry. Reverse endocrinology
is the process whereby the orphan NR is used to search for a
previously unknown ligand/hormone and signaling pathway
(85). In particular, recent studies on previously denoted orphans [e.g., PPAR-␣/␥/␦, LXR, FXR, CAR, SXR] have uncovered a myriad of new signaling pathways that regulate
metabolism, and drug tolerance, and provided new insights/
treatments into many human diseases (i.e., diabetes, dyslipidemia, obesity, and metabolic syndrome) (45, 50, 90). The
identification of low-affinity endogenous and/or high affinity
synthetic ligands for orphan receptors has created an orphan
receptor subclass often referred to as “adopted orphan” receptors (28a). Low-affinity natural agonists for this class of receptor are commonly dietary lipids and their derivatives.
Drugs targeting nuclear receptors, including the estrogen,
thyroid, and glucocorticoid receptors, and PPAR-␣ and
PPAR-␥ are among the most commonly prescribed drugs on
the market and generate annual revenues in excess of $10
billion (131). Despite the proven therapeutic effectiveness of
these pharmaceuticals many are accompanied by undesirable
side effects prompting intense efforts to identify and develop
new agents that retain the positive attributes of current drugs
while avoiding unwanted side effects. Development of tissue
and gene specific nuclear receptor ligands (selective modulators) is a key focus of such efforts with this concept best
exemplified by the selective estrogen receptor modulators,
such as tamoxifen and raloxifene (50, 68). The identification of
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endogenous and synthetic ligands to orphan NRs has generated
considerable excitement in recent years and highlights the
potential therapeutic opportunities given the wide range of
biological functions of these proteins. A pertinent example of
such promise was realized with the identification that the
anti-diabetic/insulin sensitizing thiazolidinediones (TZDs)
function largely as high-affinity ligands for PPAR-␥, whereas
the lipid lowering fibrate class of drugs signal via PPAR-␣ (91,
94). To date, several synthetic ligands have been identified for
other orphan nuclear receptors and are being intensively studied in laboratories, and in many cases, animal and clinical trials
are underway. While crystal structure analysis of orphan nuclear receptors suggest many will function as true orphan
receptors unable to accommodate molecules within their
LBDs, the identification of small molecules that bind to other
regions of the receptor and modulate coregulator interactions
and receptor function remain attractive avenues to explore (50,
114, 131, 160). In summary, the orphan receptors are key
functional regulators of metabolic homeostasis and provide a
scaffold with enormous scope and opportunity for the discovery of important new therapeutic agents.
REGULATION OF SKELETAL MUSCLE METABOLISM BY
ADOPTED AND ORPHAN NUCLEAR RECEPTORS
As discussed, skeletal muscle is a major mass peripheral
tissue accounts that for ⬎35% of the total body mass and
energy expenditure, and is the major site of fatty acid and
glucose oxidation. Moreover, this lean tissue mediates physical
activity and cholesterol efflux, and secretes myokines (myostatin, IL-6, -8, and -15) that control inflammation, energy
expenditure, and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, inflammation, and energy balance, conferring a significant role in the
progression of dyslipidemia, diabetes, and obesity. These are
risk factors for cardiovascular disease, the foremost cause of
global mortality. These risk factors are recognized by the
World Health Organization as being in the top 10 global health
problems and are directly influenced by diet, metabolism, and
lifestyle.
Many of the recently adopted orphan NRs and skeletal
muscle are rapidly emerging as critical therapeutic targets in
the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease. Along these lines it has been demonstrated
that “ligand-dependent” NRs in skeletal muscle enhance insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux, and decrease triglycerides (see
below).
Surprisingly, the function of the remaining orphan NRs in
skeletal muscle metabolism has not been examined. Nevertheless, given the data on the orphan NR subgroup, abundant
expression in skeletal muscle, and their potential utility as
therapeutic targets for the treatment of disease, the contribution
of this tissue to orphan NR action requires further investigation. Along these lines, emerging stories from cell culture and
animal models illustrate that the orphan NRs, including estrogen-related receptor (ERR)-␣, retinoic acid-related orphan receptor (ROR)-␣, Rev-erb (␣ and ␤), and Nur77 regulate lipid
absorption, lipolysis, inflammation (I␬B␣), and myokine expression (71, 88, 102, 104, 108).
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dissociation of co-repressor proteins and a recruitment of
coactivator proteins and associated complexes, due primarily
to structural changes in the LBD, eliciting a transcriptional
response and target gene expression (Fig. 1B). In addition to
ligand-induced activation, the function many nuclear receptors
is modulated by signaling cascades that phosphorylate the
receptor, further controlling activity in a ligand-independent or
ligand-dependent manner (34, 72, 161). In the case of true
orphan receptors, this level of regulation may prove to be
pivotal to the design of small molecules that target the function
of these receptors.
Genetic and pharmacological studies have demonstrated that
the liver X receptors (LXR)-␣ and -␤, farnesoid X receptor,
peroxisome proliferator-activated receptors (PPAR)-␣, -␤/␦,
and -␥, liver receptor homolog-1 and the small heterodimeric
partner regulate lipid, glucose, and energy homeostasis (45).
Concordantly, dysfunctional NR signaling results in dyslipidemia, diabetes, obesity, and inflammation. Recently, additional
orphan NRs have been implicated in the regulation of lipid and
carbohydrate metabolism, for example, Nur77, Rev-erb-␣ and
-␤, that control lipolysis, and lipid absorption. Moreover,
evidence for cross-talk between the ␤-adrenergic and the
Nur77 signaling pathways has appeared in the literature.
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METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
Clearly, improvements in skeletal muscle lipid and carbohydrate metabolism mediated by nuclear receptor function and
pharmacological activation will yield concomitant improvements in systemic metabolic homeostasis. numerous metabolic
genes regulated by nuclear receptors have been identified
ranging from transport molecules, enzymes involves in lipid
and carbohydrate anabolism/catabolism, lipid and carbohydrate storage, thermogenesis, and signaling pathways. For
brevity, the key genes presented and discussed in this review
are outlined in Table 2 with a brief explanation of their
respective functional roles. This review will focus on the
orphan and adopted nuclear receptors in the regulation of
skeletal muscle lipid and carbohydrate metabolism and the
implications for the treatment of metabolic disease (Fig. 2).
PPAR functions in skeletal muscle are emerging as critical
targets in the battle against obesity (39), metabolic syndrome X
(171), type II diabetes (58), and dyslipidemia (39, 54, 58). For
example PPAR-␣ (116), PPAR-␦ (171) (112, 134, 181), and
PPAR-␥ (58), have been shown to be involved in enhancing
insulin-stimulated glucose disposal rate, decreasing triglycerides, and increasing lipid catabolism, energy expenditure, cholesterol efflux and plasma HDL-C levels. Recently, two studies
that focused on PPAR-␦ action in skeletal muscle cells (39) and
tissue (171) demonstrated that this NR induces genes involved
in cholesterol efflux, lipid catabolism, and energy expenditure.
Moreover, PPAR␦ activation leads to a predominant type I/slow/
oxidative fiber phenotype, and dramatically increased endurance,
increased insulin sensitivity, and resistance to obesity (103, 181).
Table 2. Key metabolic genes discussed in this review as targets of nuclear hormone receptor signaling in skeletal muscle
ABCA1
ACS4
Adiponectin receptors
AMPK
ApoA1
ApoE
CD36
CEBP␣
CPT-1
⌬-6-Desaturase
FAS
FABP3
GLUT-4 and -5
Glycogenin
IRS-1
LPL
MCAD
PDK-2 and -4
PGC1
SCD-1 and -2
SREBP-1c
UCP1, -2 and -3
ATP binding cassette: transporters that transfer cholesterol to the HDL acceptors, i.e., reverse cholesterol efflux.
Acyl-CoA synthetase-4. Enhances uptake of fatty acids by catalyzing their activation to acyl-CoA esters for subsequent use in
catabolic fatty acid oxidation pathways.
Adiponectin receptors 1 and 2. Cell surface membrane receptors for adiponectin that regulate glucose uptake and fatty acid
oxidation
5⬘AMP-activated protein kinase. A fuel-sensing enzyme that responds to cellular stress by regulating carbohydrate and fat
metabolism
The major apolipoprotein of HDL.
Apolipoprotein E: facilitates cholesterol and lipid efflux.
Scavenger receptor involved in the uptake of oxidized LDL.
CCAAT/enhancer-binding protein transcription factor known to be important for adipogenesis.
Carnitine palmitoyl transferase-1. Transfers the long-chain fatty acyl group from CoA to carnitine, the initial reaction of
mitochondrial import of LCFAs and their subsequent oxidation.
Involved in desaturation of fatty acids via introduction of double bonds between defined carbons of the fatty acyl chain.
Fatty acid synthase. Involved in de novo fatty acid production.
Fatty acid translocase, and fatty acid binding protein. Facilitate uptake of LCFAs and LDLs.
Glucose transporters. GLUT4 facilitates glucose uptake in response to insulin stimulation. GLUT5 catalyzes uptake of fructose.
Initiates the synthesis of glycogen, the principal storage form of glucose in skeletal muscle.
Docking protein involved in binding and activating other signal transduction molecules after being phosphorylated by the insulin
receptor kinase.
Lipoprotein lipase. Hydrolysis of lipoprotein triglycerides into free fatty acids and responsible for the uptake of free fatty acids.
Medium chain acyl CoA dehydrogenase, a key enzyme involved in fatty acid oxidation.
Pyruvate dehydrogenase kinases: inhibiting the pyruvate dehydrogenase complex, thereby controlling glucose oxidation and
maintaining pyruvate for gluconeogenesis.
Co-activator of a number of nuclear receptors involved in adaptive thermogenesis.
Stearoyl CoA desaturase-1 and -2. Enzymes associated with adiposity, i.e., storage and esterification of cholesterol, and
responsible for cis saturation of stearoyl and palmitoyl-CoA, converting them to oleate and palmitoleate (monounsaturated fatty
acids of triglycerides).
Sterol regulatory element binding protein-1c, the hierarchical transcriptional activator of lipogenesis.
Uncoupling proteins. Mitochondrial proteins that uncouple metabolic fuel oxidation from ATP synthesis, regulating energy
expenditure.
LDL, low-density lipoprotein; CoA, coenzyme A; LCFA, long-chain fatty acid.
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PPARs
PPARs primarily function as systemic lipid sensors that
regulate a variety of homeostatic functions, including metabolism, inflammation and development. Three mammalian
PPAR subtypes, designated PPAR-␣ (NR1C1), PPAR-␥
(NR1C3), and PPAR-␦ (NR1C2) have been identified (12, 41,
90). PPAR activity is regulated by an array of dietary lipids
including saturated and unsaturated fatty acids and their respective metabolites derived through the lipoxygenase and
cyclooxygenase pathways. Furthermore, PPAR activity is targeted by selective synthetic compounds including hypolipidemic fibrates (PPAR-␣), the insulin-sensitizing TZDs
(PPAR-␥) (12, 41, 90), and the antisyndrome X phenoxy-acetic
acid compound GW-501516 currently in clinical trials (PPAR␦). Cell culture and animal studies over the last decade have
revealed discrete functions for the various PPAR subtypes in
the regulation of genes that control lipid and carbohydrate
metabolism in a range of tissues. PPAR-␣ and PPAR-␥ are
predominantly, though not exclusively, expressed in liver and
adipose tissue, respectively, whereas PPAR-␦ expression is
relatively ubiquitous, although it is abundantly expressed in
brain, intestine, skeletal muscle, spleen, macrophages, lung,
fat, and adrenals (12, 41, 90). Until recently, relatively little
was known about the specific function of PPAR-␦. Prostanoids,
produced by the conversion of polyunsaturated fatty acids,
have been proposed as potential endogenous ligands for
PPAR-␦. The development and analysis of a potent and selective PPAR-␦ agonist (GW-501516), a phenoxyacetic acid derivative, has generated intense interest by provided evidenced
for a role of this PPAR subtype in the coordination of glucose
Invited Review
METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
C209
tolerance, fatty acid oxidation, and energy expenditure in
adipose and skeletal muscle (128).
PPAR-␣
PPAR-␣ is known to regulate fatty acid oxidation gene
expression in the liver, a function which correlates with the
lipid lowering effect of the fibrate class of drugs (12, 41, 90).
PPAR-␣-specific agonists stimulate mitochondrial ␤-oxidation
in vivo in both liver and muscle via the upregulation of genes
such as mCPT1, medium chain acyl CoA dehydrogenase, and
MTE1 (113, 116, 168). Furthermore, PPAR-␣ activation promotes thermogenesis in skeletal muscle via the induction of
uncoupling proteins-1, -2, and -3 (20, 79). PPAR-␣-null mice
exhibit low rates of ␤-oxidation and lipid accumulation in
hepatic and cardiac tissues (36, 96). However, these animals
exhibited minimal alteration in the expression of PPAR-␣
target genes UCP-3, CPT-1, and PDK4 after a period of
starvation or exertion primarily due to a functional redundancy
with PPAR-␦ (116). Furthermore, while metabolism was significantly impaired in liver and cardiac muscle, in contrast,
skeletal muscle appeared refractory to the deleterious effects of
PPAR-␣ ablation. Myocardial lipid accumulation in PPAR-␣
null mice highlights the importance of PPAR-␣ in mitochondrial fatty acid uptake and oxidation in this tissue (36, 176).
PPAR-␣ plays a critical role in normal cardiac lipid homeostasis and its activity is downregulated during cardiac hypertrophy, resulting in diminished fatty acid oxidation and a reversion to glucose and lactate as primary energy sources (32, 153).
Ultimately, such this metabolic shift results in lipid accumulation and associated lipotoxicity of the myocardium (11).
PPAR-␥
PPAR-␥ is most abundantly expressed in adipose tissue,
intestine and macrophages and studies using rodent cell lines
demonstrate its essential role in normal fat cell development
(150, 151, 154). Mouse PPAR-␥ nulls die in utero due to
AJP-Cell Physiol • VOL
cardiac and placental defects; however, embryonic transfer of
mutant embryos onto wild-type placentas allowed the generation of a single live null animal, which exhibited no detectable
adipose tissue (9). Human patients with loss of function mutations in the PPAR-␥ gene present with a novel syndrome,
including lipodystrophy, insulin resistance, type 2 diabetes,
and hypertension (2, 13, 52, 156, 158). PPAR-␥ has generated
intense interest with the identification that the insulin sensitizing TZDs are high-affinity PPAR-␥ ligands (94). Subsequently
studies aimed at elucidating the functional mechanisms underlying the PPAR-␥ function have demonstrated a pivotal role for
PPAR-␥ in the regulation of systemic lipid and glucose (52,
145, 150, 151). While many studies have focused on the role of
PPAR-␥ in adipogenesis and the regulation of adipocyte metabolic function accumulating evidence suggests PPAR-␥ plays
important roles in the regulation of systemic homeostasis via
activities in other key tissues such as liver and skeletal muscle
(187). While low levels of detectable PPAR-␥ expression in
skeletal muscle had led to the long-held assumption that the
augmentation of insulin sensitivity by TZDs was facilitated
primarily via PPAR-␥ activity in adipose tissue, TZDs have
been shown to exert their insulin-sensitizing effects in skeletal
muscle independently of their activity in adipose tissue (21).
While the activity of PPAR-␥ in adipose tissue undoubtedly
contributes to systemic, and specifically skeletal muscle, metabolic homeostasis via storage of circulating fatty acids and the
release of adipokines (many of which act directly on muscle
cells), numerous studies offer support for a direct role for
PPAR-␥ in muscle cells. Studies to date support the contention
that augmentation of insulin sensitivity in skeletal muscle by
PPAR-␥ arises primarily via activation of FFA oxidation (25,
30). Furthermore, PPAR-␥ can directly activate components of
the insulin signaling pathway in skeletal muscle (3, 73, 83,
174). PPAR-␥ signaling activates expression of a number of
metabolic genes in isolated muscle tissue and muscle cell lines,
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Fig. 2. Schematic representation of nuclear receptors
involved in skeletal muscle lipid and carbohydrate homeostasis. Studies investigating normal and abnormal
function of several orphan nuclear receptors illustrate
the importance of these receptors in metabolic homeostasis. Specifically, regulation of metabolic homeostasis in skeletal muscle by these receptors may
have profound effects on systemic metabolic balance,
adiposity and the development of metabolic and cardiovascular disease. In this context, these receptors can be
considered a physiological conduit between diet, metabolism, activity, and gene expression. PPAR, peroxisome proliferator activator receptor; LXR, liver X receptor; ERR, estrogen-related receptor, ROR, retinoic
acid-related orphan receptor.
Invited Review
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METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
including UCP-2, UCP-3, IRS-1, ⌬-6-desaturase, and C/EBP␣
(53, 101, 167, 179) and promotes GLUT4 translocation (189).
More recently, muscle-specific disruption of PPAR-␥ expression in mice resulted in severe insulin resistance with
skeletal muscle remaining refractory to the insulin-sensitizing
effects of TZDs, despite normal TZD responses in liver and
adipose tissue and decreased plasma FFA levels (58). Paradoxically another muscle specific mouse knockout model was
similarly shown to be insulin resistant, despite apparently
normal skeletal muscle insulin sensitivity. In this study, it was
proposed that insulin resistance and increased adiposity arose
from a failure of insulin to suppress hepatic glucose production
(124).
Loss-of-function studies in the mouse have revealed a multitude of biological processes in which PPAR-␦ is active during
development. PPAR-␦-null embryos die at an early stage due
to a placental defect, with the few that survive exhibiting a
lower body weight than wild-type littermates, reduced body fat
mass, skin defects, and abnormal myelination (112, 134).
Paradoxically, this phenotype was absent in an adipocyte
specific PPAR-␦ null model, suggesting a complex regulation
of systemic lipid metabolism, as opposed to specific adipocyte
functions (8).
PPAR-␦ has generated a great deal of interest as a potential
therapeutic target in obesity after the identification of potent
synthetic phenoxy-acetic acid ligands. Treatment of insulinresistant and obese rhesus monkeys and Db/Db mice with
PPAR-␦ agonists lowered fasting insulin levels, raised serum
HDL cholesterol, and lowered fasting triglycerides. Although it
was unclear which tissue was the major target for this activity,
the classification of PPAR-␦ as sensor of dietary triglyceride in
native VLDLs released by lipoprotein lipase activity suggested
skeletal muscle was a potential target tissue (29, 95, 128).
Elevation of HDL cholesterol involved increases in the expression of ABCA1 in macrophages, and skeletal muscle and was
accompanied by an induction of ApoA1-specific cholesterol
efflux (to an even greater extent than agonists for PPAR-␣ or
PPAR-␥). Given the relative mass of skeletal muscle this
observation is entirely consistent with the profound effects of
this drug on systemic HDL-cholesterol (39, 177). Furthermore,
the PPAR-␦ agonist induced the expression of acyl-CoA synthetase (ACS), CPT1, UCP2, and UCP3 in rodent neonatal
cardiomyocytes, which correlated with an increase in fatty acid
oxidation (48). PPAR-␦ has been further implicated in the
regulation of skeletal muscle metabolism with reported modulation of expression of a range of genes involved in lipid
absorption [LPL, fatty acid binding protein 3 (FABP3), ACS4],
lipid catabolism (CPT1, PDK4), and energy expenditure
(UCP2 and -3) in cultured C2C12 muscle cells treated with
PPAR-␦ agonists (39). This study also demonstrated that
PPAR␦ agonists (but not PPAR-␣) primarily regulate the
CPT-1 promoter in skeletal muscle cells. Similarly, microarray
expression profiling in GW-501516-treated rat skeletal muscle
cells (L6 myotubes) and skeletal muscle of treated mice (171)
identified a large panel of genes involved lipid homeostasis
including CPT-1. The authors went on to demonstrate that
GW-501516 treatment of mice stimulates fatty acid oxidation
in skeletal muscle; in contrast, ␤-oxidation was not induced in
AJP-Cell Physiol • VOL
LXRs
Recent evidence suggests the Liver X Receptors (LXR␣ and
LXR␤) regulate lipid metabolism in skeletal muscle. Analysis
of gene expression changes in both rodent quadricep muscle
and cultured skeletal muscle myotubes treated with the synthetic LXR agonist T0901317 revealed an upregulation of key
genes involved in lipid and cholesterol efflux and lipogenesis
such as ABCA1, ApoE and SREBP-1c (119). While LXR
agonists have proven utility in the treatment of hypercholesterolemia their development into an efficacious treatment for
this condition has been impaired by the deleterious side effects
consequential to the activation of lipogenesis. Significantly, the
induction of the SREBP-1c target genes FAS, and SCD-1
involved in lipogenesis was observed in livers but not skeletal
muscle of rodents treated with LXR agonists. This observation
is believed to stem from the fact the LXR␤ is the predominant
isoform expressed in skeletal muscle as opposed to LXR␣ in
liver and prompted speculation that LXR␤ specific agonists
may retain the desired cholesterol lowering activity while
avoiding the undesirable hypertriglyceridaemia. The observation that synthetic LXR agonists increase ABCA1 mediated
cholesterol efflux in skeletal muscle cells underscores the
potential of this tissue as a target of reverse cholesterol transport and HDL cholesterol regulation (119).
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PPAR-␦
the liver. Starvation induces PPAR␦ mRNA expression in
murine gastrocnemius muscle with concomitant activation of
fatty acid translocase/CD36 (FAT/CD36), muscle carnitine
palmitoyl transferase (M-CPT1 or CPT-1␤) and heart FABP
(59).
PPAR-␦ is predominantly expressed in mitochondrial rich
type I (oxidative, slow twitch) relative to type II (glycolytic,
fast twitch) skeletal muscle. Endurance training promotes conversion into type I muscle, accompanied by an increased
expression of PPAR-␦ (103). Muscle-specific expression of
activated PPAR-␦ in mice leads to an increase in type I muscle
fibers. Concordantly, increased activity of enzymes involved in
oxidative (not glycolytic) metabolism has been reported. Expression analysis also revealed an induction of the genes
involved in increased oxidative metabolism, glucose tolerance,
preferential lipid utilization, energy expenditure (i.e., troponin-I slow, cytochrome c, UCP2, UCP3, and CPT1) (103), and
increased endurance (181).
Numerous studies demonstrated that GW-501516 treatment
and skeletal muscle-specific PPAR-␦ overexpression in mice
ameliorated diet induced obesity, enhanced metabolic rate,
lipid oxidation, reduced intramuscular triglycerides, and increased mitochondria in skeletal muscle. Moreover, anatomical
analysis revealed the resistance to increased body weight was
largely due to reduced mass of visceral and epidermal fat
depots. The drug treatment ameliorated the diet induced 1)
hypertrophy in epidermal white adipose, and brown fat, 2)
hepatic steatosis, and 3) accumulation of intramuscular lipid
droplets (103, 171, 181). Interestingly, these mice have profoundly increased endurance capabilities, and resistance to
fatigue relative to their wild-type littermates. Selective
PPAR-␦ agonists (i.e., GW-501516) are currently in clinical
trials for the treatment of dyslipidemia, insulin resistance, and
obesity.
Invited Review
METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
ESTROGEN-RELATED RECEPTOR
RORS AND REV-ERBS
RORs and Rev-erbs belong to the NR1F, and NR1D subgroups subgroups of nuclear hormone receptors, respectively.
These are closely related families of orphan nuclear receptors
that operate in opposing manners. Three ROR genes have been
identified; ROR␣ encodes four alternatively spliced isoforms
(ROR␣1, ROR␣2, ROR␣3, and ROR␣␣), which are predominantly expressed in blood, brain, skeletal muscle, and fat cells.
ROR␤ is expressed specifically in the brain and ROR␥ is found
at high levels in skeletal muscle and thymocytes (67). Two
Rev-erb genes have been identified: Rev-erb␣ and Rev-erb␤.
The Rev-erb␤ gene encodes two alternatively spliced isoforms,
Rev-erb␤1 and Rev-erb␤2. The mRNAs are expressed in most
tissues, although very abundant expression is seen in energydemanding tissues, including skeletal and cardiac muscle,
liver, kidney, and brown fat.
Analysis of the spontaneously generated “staggerer” (sg/sg)
mutant mouse, which carries a loss of function mutation in the
ROR-␣ gene, has been extremely informative on the role of
ROR-␣ in lipid homeostasis and skeletal muscle function. The
most obvious staggerer phenotype is ataxia associated with a
cerebellar atrophy, aberrant vascular physiology, hypersensitive inflammatory response, dyslipidemia, and enhanced susceptibility to atherosclerosis (104). In the context of lipid
homeostasis, the sg/sg mice exhibit a dyslipidemia, characterized by lower circulating plasma levels of HDL-C, ApoA1,
AII, and CIII and plasma triglycerides. Notably, ApoAI is a
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major constituent of HDL, whereas ApoCIII is a component of
HDL and VLDL that plays a role in regulation of triglyceride
levels and lipoprotein lipase activity (146, 178). This observation is supported by cell culture studies demonstrating that
ROR-␣, and Rev-erb-␣ activate and repress the expression of
ApoAI and CIII in cell culture, respectively (18, 66).
Futhermore, sg/sg mice have been shown to have a reduced
muscular strength, a finding supported by earlier work conducted in our laboratory, demonstrating that ROR-␣ potentiates skeletal muscle myogenesis, whereas the Rev-erbs antagonize muscle cell differentiation in culture (22, 37, 87). Ectopic
expression of a dominant negative form of ROR-␣ in skeletal
muscle cells attenuated ROR-dependent gene expression, repressed the endogenous levels of ROR-␣ and ROR-␥ mRNA,
and also resulted in attenuated expression of many genes
involved in lipogenesis and energy homeostasis, including
SREBP-1c, SCD1/2 and FAS, a finding consistent with the
lowered TG levels observed in sg/sg mice (88). Furthermore,
previous studies have demonstrated that MCPT-1 an established target for PPAR-␣ in cardiac muscle and PPAR-␦ in
skeletal muscle cells, is also directly regulated by ROR␣1
raising the suggesting a potential tissue-specific cross-talk
between PPAR-␣ and ROR-␣. Cell culture studies and analysis
of the sg/sg mouse highlights the importance of ROR-␣ in the
regulation of lipid homeostasis, and we hypothesize that
ROR-␣1 in skeletal muscle programs a cascade of gene expression designed to regulate lipid and energy homeostasis in this
tissue (88).
Similarly, mice homozygous (⫺/⫺) for the Rev-erb-␣ null
allele have a dyslipidemic phenotype and a 20% lower body
weight. Male Rev-erb-␣-deficient mice show elevated serum
VLDL triglyceride levels and increased serum and liver expression of apoCIII mRNA (146). Elevated ApoCIII and
VLDL triglycerides in Rev-erb-␣⫺/⫺ is in contrast to reduced
ApoCIII and triglycerides observed in ROR-␣ mutant sg/sg
mice and concurs with the negative regulation of ApoCIII by
Rev-erb-␣. Interestingly, homozygous Rev-erb-␣-null mice
display a significant shift from fast (type IIA) to slow (type I)
myosin heavy chain expression in the slow twitch, mitochondrial rich oxidative fibres which encodes the thick filament of
the sarcomere. This is in concordance with the selective expression of Rev-erb-␣ in type IIB glycolytic and intermediate
type IIA oxidative fibers (138). This suggests that this orphan
NR regulates muscle fiber type, which will have concomitant
effects on insulin sensitivity and aerobic/anaerobic metabolism.
Ectopic expression of a dominant negative mutant Rev-erb␤⌬E (lacking the LBD) in skeletal muscle cells attenuated a
range of genes involved in fatty acid/lipid absorption including
CD36, FABP3, and FABP4 (143). Increased expression of
SREBP-1c and SCD1 was also observed and is consistent with
elevated TG levels in Rev-erb-␣⫺/⫺ mice. Moreover, a dramatic decrease in the myostatin expression and elevated IL-6
expression further highlights a potential role of this orphan
receptor in the regulation of muscle mass, adiposity, and
inflammation (143). Modulation of these myokines coupled
with observed changes in genes controlling muscle lipid absorption and metabolism suggest that Rev-erb-␤ activity plays
and important role in muscle growth and lipid homeostasis
(143).
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Estrogen-related receptors (␣, ␤, and ␥) are orphan receptors
with close homology to the estrogen receptor that have implicated roles in the regulation of cellular energy metabolism.
Accordingly ERRs are abundantly expressed in tissues with a
high capacity for fatty acid ␤-oxidation (47, 65). Homozygous
knock-out ERR␣⫺/⫺ mice were found to have a significant
reduction in fat mass and a commensurate resistance to high fat
induced obesity (102). This phenotype was attributable to the
altered expression of genes involved in lipid metabolism and
adipocyte development. Somewhat paradoxically, a synthetic
ERR␣ agonist was found to increase energy expenditure and
thus antagonize the development of obesity (71).
ERR regulation of cellular metabolism appears to involve
interactions with the PGC1 co-regulator. PGC1 has been
shown to be a potent co-activator of ERR␣ with a synthetic
inhibitor of ERR␣ significantly attenuating PGC1␣ mediated
regulation of oxidative phosphorylation and mitochondrial respiration in skeletal and cardiac muscle cells (115). ERR␣ has
also been found to activate PPAR␣ in skeletal muscle cells
subsequently regulating an array of genes involved in fatty acid
uptake, fatty acid oxidation, and oxidative phosphorylation
(64). Recent evidence that an ERR␣-dependent PGC1␣ program mediates the induction of mitofusin-2 helps explain the
link between exercise and PGC1␣/ERR␣ mediated modulation
of mitochondrial function (24). Mitofusin-2 is a key regulator
of mitochondrial biogenesis and is pivotal to the increase in
mitochondrial size, content and oxidative capacity in response
to exericse. In light of established links between insulin resistance and impaired mitochondrial function synthetic modulation of ERR function may prove to be an effective therapeutic
target in the treatment of metabolic disease.
C211
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METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
These studies underscore the potential therapeutic utility of
ROR-␣1, and Rev-erb agonists, that is further highlighted by
genetic and biochemical studies demonstrating the anti-atherogenic and anti-inflammatory properties of ROR-␣, and proinflammatory properties of Rev-erb␣. The mechanism involves
the modulation of the NF-␬B signaling pathway and regulation
of p65 translocation, and of I␬B␣ activity. Moreover, we
propose that the atherogenic and dyslipidemic phenotype of the
sg/sg mouse is related to aberrant ROR␣ function in skeletal
muscle and surmise that ROR␣1 agonists may have therapeutic
utility in the treatment of hypercholesterolemia and atherosclerosis.
NR4A FAMILY
AJP-Cell Physiol • VOL
CHICKEN OVALBUMIN UPSTREAM PROMOTERTRANSCRIPTION FACTOR
The chicken ovalbumin upstream promotor (COUP)-transcription factors (TFs) are most related to the retinoid X
receptor/retinoid acid receptor, and are generally considered to
be repressors of other nuclear receptors, such as PPARs,
retinoic acid, thyroid hormone, and vitamin D receptors (130).
COUP-TFs are involved in the regulation of several fundamental biological processes, such as neurogenesis, organogenesis,
and metabolic homeostasis. COUP-TFs can modulate the activity of genes that are fundamental in the orchestration of
glucose and lipid metabolism, such as bile acid synthesis
(CYP7A-cholesterol 7a-hydroxylase) (31), ketogenesis (mitochondrial HMG-CoA synthase) (56), cholesterol transport
(cholesterol ester transfer gene and apolipoprotein AI) (46,
121), fatty-acid ␤-oxidation (medium-chain acyl CoA dehydrogenase) (35), and glucose homeostasis and insulin sensitivity (10). Moreover, COUP-TF can inhibit preadipocyte differentiation, and its ortholog in Drosophila (svp) is required for
fat cell differentiation (60). Previous studies (7) in muscle cell
cultures have demonstrated a role for COUP-TFs in muscle
development showing COUP-TFII inhibits the expression and
function of MyoD. Despite COUP-TFII involvement in muscle
differentiation and its implication in the regulation of carbohydrate and lipid metabolism in other tissues the specific
contribution of COUP-TFs in skeletal muscle metabolic homeostasis remains unexplored.
In conclusion, it is increasingly obvious that orphan and
adopted nuclear receptors are key regulators of lipid and
carbohydrate homeostasis in skeletal muscle. The efficacy of a
number of pharmacological agents that target a number of
these adopted orphan receptors such as PPAR-␥ (TZD) and
PPAR-␣ (fibrates) underscores the immense potential of orphan nuclear receptors as therapeutic targets in the treatment of
metabolic and cardiovascular disease. The relative mass and
metabolic flexibility of skeletal muscle, and the observed
metabolic and biochemical perturbations in diabetic and obese
individuals, attests to the importance of this tissue in systemic
metabolic homeostasis. For this reason, NRs and skeletal
muscle are valid targets in the battle to ameliorate metabolic
perturbations associated with metabolic syndrome, obesity, and
cardiovascular disease. Despite recent advances in our understanding of NR function in metabolic homeostasis, considerable future effort is required to realise the potential of NR
agonists in the battle against cardiovascular disease.
Dyslipidemia, insulin resistance, blood glucose levels (and
glucose tolerance), diabetes, inflammation, and obesity are all
serious risk factors for cardiovascular and metabolic disease.
NRs and skeletal muscle are validated targets in the battle to
ameliorate metabolic perturbations; however, the real promise
and potential of NR agonists in the battle against cardiovascular disease has not yet been realized.
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The NR4A subgroup of orphan nuclear receptors comprises
three members Nurr1, Nur77, and NOR-1, which largely function as immediate-early genes, whose expression and activation is regulated in a cell-type specific manner in response to a
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Invited Review
METABOLIC DISEASE, RECEPTOR, AND MUSCULAR LINKS
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