Adv Physiol Educ 30: 145–151, 2006;
doi:10.1152/advan.00052.2006.
PGC-1␣: a key regulator of energy metabolism
Huiyun Liang1,2 and Walter F. Ward2,3
1
Department of Cellular and Structural Biology, 2Barshop Institute for Longevity and
Aging Studies, and 3Department of Physiology, Audie Murphy Veterans Administration
Medical Center and University of Texas Health Science Center, San Antonio, Texas
Submitted 22 June 2006; accepted in final form 27 July 2006
Liang, Huiyun, and Walter F. Ward. PGC-1␣: a key regulator of
energy metabolism. Adv Physiol Educ 30: 145–151, 2006; doi:
10.1152/advan.00052.2006.—Peroxisome proliferator-activated re-
ceptor-␥ coactivator (PGC)-1␣ is a member of a family of transcrip-
tion coactivators that plays a central role in the regulation of cellular
energy metabolism. It is strongly induced by cold exposure, linking
this environmental stimulus to adaptive thermogenesis. PGC-1␣ stim-
ulates mitochondrial biogenesis and promotes the remodeling of
muscle tissue to a fiber-type composition that is metabolically more
oxidative and less glycolytic in nature, and it participates in the
regulation of both carbohydrate and lipid metabolism. It is highly
likely that PGC-1␣ is intimately involved in disorders such as obesity,
diabetes, and cardiomyopathy. In particular, its regulatory function in
lipid metabolism makes it an inviting target for pharmacological
intervention in the treatment of obesity and Type 2 diabetes.
adaptive thermogenesis; transcription coactivator; proliferator perox-
isome-activated receptor; glucose metabolism; diabetes
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)-␥ coac-
tivator (PGC)-1␣ is a transcription coactivator that interacts
with a broad range of transcription factors that are involved in
a wide variety of biological responses including adaptive
thermogenesis, mitochondrial biogenesis, glucose/fatty acid
metabolism, fiber type switching in skeletal muscle, and heart
development (Table 1). A transcription coactivator is defined
as a protein or protein complex that increases the probability of
a gene being transcribed by interacting with transcription
factors but does not itself bind to DNA in a sequence-specific
manner (48). The PPARs (PPAR-␣, PPAR-␦, and PPAR-␥) are
members of a relatively large family of nuclear receptors, all of
which are subject to transcriptional coactivation by PGC-1␣.
PPAR-␥ is essential for adipogenesis and differentiation (31),
whereas PPAR-␣ and PPAR-␦ play important roles in the
control of fatty acid oxidation (61). In addition, PPAR-␥ is the
target of thiazolidinediones (TZDs), which are drugs that are
widely utilized for increasing insulin sensitivity in diabetic
patients (50, 59).
The PGC-1␣ gene is located on chromosome 5 in mice
(chromosome 4 in humans) and encodes a protein containing
797 (mouse) or 798 amino acids (human). PGC-1␣ has two
putative nuclear localization signals and is located in the cell
nucleus (49). It is expressed at high levels in tissues where
mitochondria are abundant and oxidative metabolism is active,
such as brown adipose tissue (BAT), the heart, and skeletal
muscle. PGC-1␣ expression is also high in the brain and
kidney, whereas the expression level is low in the liver and
Address for reprint requests and other correspondence: W. F. Ward, Dept. of
Physiology, Univ. of Texas Health Science Center, 7703 Floyd Curl Dr., San
Antonio, TX 78229-3900 (e-mail: wardw@uthscsa.edu).
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Staying Current
very low in white adipose tissue (WAT) (49). It is noteworthy
that PGC-1␣ does not exhibit histone acetyltransferase (HAT)
activity itself, but the conformational change it induces after
docking on specific transcription factors increases the affinity
of the transcription complex to additional coactivators possess-
ing HAT activity, such as steroid receptor coactivator-1 and
cAMP response-binding element (CREB)-binding protein and
p300. The end result is acetylation of histone proteins, which
produces conformation alterations that increase the accessibil-
ity of DNA to the transcription complex (46). Although there
are three members of the PGC-1 family [PGC-1␣, PGC-1␤,
and PGC-1-related coactivator (48)], we will focus on PGC-1␣
in this review. There is currently a great interest in PGC-1␣
because rapidly growing evidence strongly suggests that it is a
powerful regulator of energy metabolism under conditions of
both health and disease (12).
PGC-1␣ and Adaptive Thermogenesis
PGC-1␣ was originally discovered as a cold-inducible tran-
scription coactivator of adaptive thermogenesis, a physiologi-
cal process through which energy is dissipated as heat in
response to environmental conditions such as cold stress and
overfeeding (8, 51). BAT and skeletal muscle are the two
major organs involved in this process. While rats and mice
have prominent brown fat depots, this isn’t the case in larger
mammals, including humans, although there may be brown fat
cells dispersed among the adipocytes of WAT (49). Thus, in
larger mammals, skeletal muscle is generally thought to be the
major thermogenic tissue. The primary physiological function
of WAT is energy storage, whereas the primary function of
BAT is energy dissipation, largely in the form of heat. In fact,
BAT produces ⬃60% of the heat generated by nonshivering,
adaptive thermogenesis. Spurred on in part by the prevalence
of human obesity, interest in adaptive thermogenesis has in-
creased because of the possibility that it may provide a phys-
iological defense against obesity (68). This has also led to
increased attention being directed toward the regulation of
adipose tissue differentiation. It was known that the transcrip-
tion factor PPAR-␥ is an important regulator of adipocyte
differentiation, but, surprisingly, it is unable, by itself, to
induce brown fat differentiation (45). It was during the search
for the solution to this puzzle that PGC-1␣ was discovered
(49). PGC-1␣ binds to PPAR-␥ and coactivates PPAR-␥ to
stimulate the transcription of genes involved in the brown
adipocyte differentiation process (49).
The adaptive thermogenic program in both brown fat and
skeletal muscle involves the stimulation of mitochondria bio-
genesis, increased fatty acid oxidation, and the uncoupling of
oxidative phosphorylation. In response to cold exposure,
145
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146 PGC-1␣: A KEY REGULATOR OF ENERGY METABOLISM

Table 1. Selected list of transcription factors for which
PGC-1␣ functions as a coactivator
Transcription Factor Function
NRF1 Mitochondria biogenesis
NRF2 Mitochondria biogenesis
ERR-␣/␤/␥ Mitochondria biogenesis
PPAR-␣ Fatty acid oxidation
PPAR-␦ Fatty acid oxidation
TR-␤ CPT-I induction
FXR Triglyceride metabolism
LXR-␣/␤ Lipoprotein secretion
GR Gluconeogenesis
HNF-4␣ Gluconeogenesis
FOXO1 Gluconeogenesis
PPAR-␥ Brown adipocyte differentiation;
UCP1 induction
PGC-1␣, proliferator peroxisome-activated receptor (PPAR)-␥ coactivator-
1␣; NRF, nuclear respiratory factor; ERR, estrogen-related receptor; TR,
thyroid receptor; CPT-I, carnitine palmitoyltransferase-I; FXR, farnesoid X
receptor; LXR, liver X receptor; GR, glucocorticoid receptor; HNF, hepatic
nuclear factor; FOXO1, forkhead box O1; UCP1, uncoupling protein-1. [Mod-
ified from Ref. 23.]
PGC-1␣ expression is increased, with the induction being
mediated through the sympathetic nervous system’s ␤3-adren-
ergic receptor/cAMP pathway (49). Increased PGC-1␣ induces
the transcription of nuclear respiratory factor (NRF)1 and
NRF2, leading to the increased expression of mitochondrial
transcription factor A (mtTFA) (68) as well as other nuclear-
encoded mitochondria subunits of the electron transport chain
complex such as ␤-ATP synthase, cytochrome c, and cyto-
chrome c oxidase IV (56, 57). mtTFA translocates to the
mitochondrion, where it stimulates mitochondrial biogenesis as
manifested by stimulation of mitochondrial DNA replication
and mitochondria gene expression (14, 24). PGC-1␣ also
interacts with other nuclear hormone receptors such as
PPAR-␣, retinoic acid receptor, and thyroid receptor in BAT to
enhance the expression of brown fat-specific uncoupling pro-
tein 1 (UCP1) (6, 9, 58). UCP1 action leads to dissipation of
the proton gradient and the uncoupling of oxidative phosphor-
ylation, thereby increasing heat production. Under these con-
ditions, there is a marked increase in the rate of energy
metabolism. The essential role of PGC-1␣ in adaptive thermo-
genesis is convincingly demonstrated by the observation that
the PGC-1␣-deficient mice are unable to withstand a cold
stress (4°C) for longer than 6 h due to a continuous decrease of
core body temperature. Wild-type control mice, on the other
hand, were able to tolerate the cold stress by keeping their core
body temperature at ⬃36.5°C, after an initial drop of ⬃1.5°C
(26, 29).
PGC-1␣ and Skeletal Muscle Fiber Conversion
Skeletal muscle fibers are classified into three types: type I,
type IIa, and type IIb. Slow-twitch type I and fast-twitch type
IIa fibers contain more mitochondria and exhibit relatively
higher rates of oxidative metabolism. In contrast, type IIb
fibers have fewer mitochondria and are metabolically glyco-
lytic. It is now well established that PGC-1␣ induces a remod-
eling of skeletal muscle fiber composition. In general, the ratio
of glycolytic type IIb fibers to the more oxidative type I and
type IIa fibers decreases. The expression of PGC-1␣ in skeletal
muscle is readily inducible by both short-term exercise and
endurance training in rodent models and human subjects (5, 15,
41, 52). Our understanding of the biological role of PGC-1␣ in
skeletal muscle structure and function has been greatly im-
Reference proved through the use of gain of function and loss of function
68 mouse models. In a gain of function transgenic model, PGC-1␣
36 is overexpressed in a skeletal muscle-specific manner under the
35 control of the muscle creatine kinase (MCK) promoter (28).
62 PGC-1␣ overexpression results in the conversion of fast-twitch
64
67, 72 type IIb muscle fibers to type IIa and slow-twitch type I fibers
71 by 20% and 10%, respectively, in plantaris muscle. In addition,
30 there is an activation of genes involved in mitochondrial
23 oxidative metabolism. The conversion to slow-twitch fibers is
39
47
also evidenced by the redder muscle color and the expression
16, 20 of contractile proteins characteristic of slow-twitch fibers such
as slow troponin I and myoglobin. As would be predicted,
based on these alterations, muscles isolated from the MCK-
PGC-1␣ transgenic mouse show increased resistance to elec-
trically stimulated fatigue (28). Consistent with this, Morten-
son et al. (39) recently reported that overexpression of PGC-1␣
in primary rat skeletal muscle cells leads to enhanced levels of
mRNA for the slow oxidative-associated myosin heavy chain
(MHC) isoform (MHCIb) and decreased mRNA levels for
the fast glycolytic-associated MHC isoforms (MHCIIX and
MHCIIB) (39). In contrast, PGC-1␣-deficient mice exhibit
decreased mitochondrial number and decreased respiratory
capacity in slow-twitch muscle as well as reduced exercise
capacity and a reduced fatigue resistance index (26).
The upstream signaling involved in the activation of
PGC-1␣ are unclear at present, but several pathways have been
implicated, such as the calcineurin A and CaMK, p38 MAPK,
and AMP-activated protein kinase pathways (1, 67, 73). Al-
though the relative importance of these kinases in controlling
PGC-1␣ is yet to be determined, there appears to be a consid-
erable amount of evidence suggesting that the calcineurin and
CaMK pathways play important roles in the regulation of
PGC-1␣ expression. During exercise, the combination of in-
creased neuromuscular input and increased contractile activity
induces the expression of several transcription factors, e.g.,
myocyte-specific enhancer factor (MEF)2 and CREB (10, 17).
These induction processes appear to be mediated by cal-
cineurin and CaMK (67). Increased expression of MEF2 leads
to increased MEF2 binding to the promoter region of the
PGC-1␣ gene, increasing PGC-1␣ expression. PGC-1␣ can
then bind directly to MEF2 to coactivate the transcription of
those genes involved in the determination of slow-twitch fiber
types and mitochondrial oxidative metabolism (10, 27). Fi-
nally, it should be pointed out that recent work from Holloszy’s
laboratory (13) suggests that calcineurin may not be required
for exercise-induced increases in PGC-1␣ and a range of
mitochondrial proteins. Obviously, further work is needed to
elucidate the roles of calcineurin and calcium signaling path-
ways in the regulation of PGC-1␣.
PGC-1␣ and Heart Development
The heart, an organ with a very high and dynamic demand
for ATP, derives most of the required ATP from fatty acid
oxidation. In the developing mouse heart, as the energy source
turns toward mitochondria fatty acid oxidation after birth, there
is a large burst of mitochondria biogenesis and oxidative
metabolism that is preceded by a dramatically increased ex-
pression of PGC-1␣ (25). Short-term fasting, another condition

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PGC-1␣: A KEY REGULATOR OF ENERGY METABOLISM
that produces an increased reliance on mitochondrial fatty acid
oxidation, also activates myocardial PGC-1␣ (25). Under in
vitro conditions, ectopic expression of PGC-1␣ in cultured
cardiac myocytes has been shown to drive mitochondrial bio-
genesis, and oxidative phosphorylation in these mitochondria
is tightly coupled with ATP production (25). In contrast, in
adipocyte and C2C12 mouse myoblast cell lines, PGC-1␣
expression leads to the uncoupling of oxidative phosphoryla-
tion, resulting in decreased ATP formation and increased heat
production (68). When the heart undergoes hypertrophy in
response to pressure overload or cyclin T1-induced activation
of Cdk9, PGC-1␣ expression is markedly decreased, and this
reduction of PGC-1␣ levels is associated with a conversion
from fatty acid oxidation to glycolytic metabolism (54, 55, 55).
To further investigate the role of PGC-1␣ in the heart, two
independent lines of PGC-1␣-deficient mouse models have
been established (26, 29). Although myocardial mitochondrial
volume density didn’t change significantly in either PGC-1␣
knockout model, the expression of genes of oxidative phos-
phorylation was markedly blunted in the PGC-1␣-deficient
heart. This was accompanied with reduced mitochondrial en-
zymatic activities and decreased levels of ATP and phospho-
creatine (2). The PGC-1␣-deficient heart also exhibits a dimin-
ished response to exercise and ␤-adrenergic stimulation in vivo
(26). Consistent with this, it has been reported that there is a
decreased ability to increase both the heart rate and rate of
change of pressure in response to chemical or electrical stim-
ulation in a isolated perfused heart preparation of PGC-␣-
deficient mice (2). In addition, starting from 7 to 8 mo of age,
PGC-1␣-deficient mice exhibit significant cardiac dysfunction
(2). In this context, it has been recently reported that PGC-1␣-
deficient mice underwent accelerated heart failure when chal-
lenged by transverse aortic constriction (3). These data indicate
that PGC-1␣ is essential for the heart to be able to meet the
increased demands for both ATP and work output in response
to physiological stimuli. Surprisingly, the in vivo gain of
function studies, carried out using two independent transgenic
mouse models that overexpress PGC-1␣ specifically in the
heart (MHC-PGC-1␣ mice and tet-on PGC-1␣ mice), revealed
modest to dramatic mitochondria biogenesis associated with
cardiomyopathy (25, 53). The development of this cardiomy-
opathy is thought to be associated with mitochondrial ultra-
structural abnormalities and the disruption of sarcomere struc-
ture by overwhelmingly increased mitochondria biogenesis
(25, 53).
PGC-1␣ and Glucose Metabolism
Maintenance of plasma glucose homeostasis is vital for the
survival of mammalian organisms, and, as a result, glucose
levels are tightly regulated in response to nutrient conditions
and hormonal signals. Insulin suppresses plasma glucose level
by the inhibition of glucose production in the liver and by
promotion of glucose disposal into skeletal muscle and white
fat tissue. Conversely, glucagon and glucocorticoids increase
glucose levels through the activation of gluconeogenesis, in
addition to the activation of glycogenolysis, in the liver and
reduction of glucose utilization in skeletal muscle. Under
normal, fed conditions, PGC-1␣ is expressed at very low levels
in the liver (49). However, fasting produces a robust increase
of PGC-1␣ expression, which, in turn, stimulates hepatic
gluconeogenesis and fatty acid oxidative metabolism (19, 69).
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147
During fasting, the expression of PGC-1␣ is activated by
glucagon and catecholamines via the stimulation of the cAMP
pathway and the CREB transcription factor. PGC-1␣ then
coactivates a variety of transcription factors such as hepatic
nuclear factor-4␣, glucocorticoid receptor, and forkhead box
O1 (FOXO1). These transcription factors bind to the promoter
regions of those genes encoding key gluconeogenic enzymes
such as phosphoenolpyruvate carboxykinase (PEPCK) and
glucose-6-phosphatase (G-6-Pase).
Tissue culture studies have revealed that forced overexpres-
sion of PGC-1␣ in primary hepatocytes is sufficient to drive the
expression of key gluconeogenic genes (69). In contrast,
knockdown of PGC-1␣ expression by short interfering RNA in
the mouse liver dramatically reduced the expression of PEPCK
and G-6-Pase (22). The essential role of PGC-1␣ in the control
of hepatic gluconeogenesis has been further reinforced by
studies in the PGC-1␣-deficient mouse model (26, 29). One
strain of PGC-1␣ knockout mice exhibited fasting hypoglyce-
mia in response to impaired gluconeogenic gene expression
and hepatic glucose production (26, 29). Although the expres-
sion of PGC-1␣ target genes involved in gluconeogenesis was
not altered in another strain of PGC-1␣-deficient mice, the
hepatic glucose production was reduced secondary to dimin-
ished fatty acid ␤-oxidation and tricarboxylic acid cycle flux
(7). Interestingly, after short-term starvation, one line of PGC-
1␣-deficient mice developed hepatic steatosis due to a combi-
nation of reduced mitochondrial fatty acid oxidation capacity
and an increased expression of lipogenic genes (26). Fasting
also induces PPAR-␣ expression, which, when coactivated by
PGC-1␣, results in the expression of genes involved in hepatic
fatty acid oxidation. The gene expression changes that have
been described, under conditions of nutrient deprivation, cause
a shift in fuel usage from glucose utilization to fatty acid
oxidation, which contributes to the conservation of glucose for
use by the central nervous system (19, 69).
Under fed conditions, skeletal muscle is a major site for
glucose disposal. Skeletal muscle takes up glucose using glu-
cose transporters (GLUTs) located in the cell membrane. There
are two types of skeletal muscle GLUTs: constitutive, insulin-
insensitive GLUT1 and GLUT3 and insulin-sensitive GLUT4.
PGC-1␣ has been shown to increase the expression of GLUT
4 in cultured muscle cells and skeletal muscle (5, 33, 33).
Whereas MEF2C has been shown to mediate PGC-1␣-induced
GLUT4 expression in cultured muscle cells (33), the MEF2A
isoform appears to be responsible for GLUT4 upregulation
under other conditions (4, 37). Surprisingly, PGC-1␣ has not
been shown to increase glucose uptake in skeletal muscle in
vivo, although it induced an increased glucose uptake into
skeletal muscle cells (33). In addition, it has been reported that
GLUT4 expression is downregulated in a muscle-selective
PGC-1␣ transgenic mouse model (34). Resolution of the role
of PGC-1␣ in the regulation of skeletal muscle glucose uptake
thus requires further investigation.
It is now well established that insulin also stimulates the
recruitment of GLUT4 to the cell membrane of insulin-sensi-
tive tissues. A very important area of future research is the
elucidation of the interaction between insulin and PGC-1␣ in
the regulation of glucose metabolism, an interaction about
which there is very little known at the present time. There is
some evidence suggesting that insulin has a suppressive effect
on the expression of PGC-1␣, i.e., PGC-1␣ promotor activity
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148 PGC-1␣: A KEY REGULATOR OF ENERGY METABOLISM
is inhibited by insulin (19). Consistent with this, hepatic
PGC-1␣ expression levels have been reported to be increased
in animal models exhibiting insulin deficiencies (69). On the
other hand, there is evidence showing a suppressive effect of
insulin downstream of PGC-1␣. The mechanism for this effect
may involve the transcription factor FOXO1. Activation of the
insulin signaling pathway leads to phosphorylation of FOXO1,
inhibiting its translocation to the nucleus and increasing its
susceptibility to degradation. Because PGC-1␣ requires
FOXO1 to bind to the promotor regions of gluconeogenic
genes, this action of insulin could have a suppressive effect on
PGC-1␣ action (47).
PGC-1␣ and Type 2 Diabetes
Type 2 diabetes is the most common metabolic disease in the
world, reaching epidemic proportions. Although there are mul-
tiple complicated genetic elements involved in the pathogene-
sis of Type 2 diabetes, lifestyle and age seem to be the two
major risk factors triggering the disease. A sedentary lifestyle
and overeating can contribute to excessive weight gain and
obesity, with the latter being closely associated with insulin
resistance. Insulin resistance is considered to be present when
the biological effects of insulin are less than expected for both
glucose disposal in skeletal muscle and suppression of glucose
production by the liver (11). When the insulin level is not
sufficient to overcome this insulin-resistant state, Type 2 dia-
betes ensues. In this regard, there is there is increasing evi-
dence suggesting that mitochondrial dysfunction plays a role in
the pathogenesis of insulin resistance and Type 2 diabetes. For
example, it has been reported that the activities of both mito-
chondrial oxidative enzymes and mitochondria complex I are
decreased in Type 2 diabetic patients (21, 63). In keeping with
the observations that both obesity and mitochondrial dysfunc-
tion are risk factors for the development of insulin resistance,
obese individuals have been reported to have smaller mito-
chondria that exhibit a compromised bioenergetic capacity
(21). Insulin resistance also develops with age, and, in this
case, a potentially important defect has been found in the
mitochondrial fatty acid oxidation pathway. There appears to
be a reduction in the rate of fatty acid oxidation, leading to the
accumulation of intracellular triglycerides in elderly patients
compared with matched young controls (43). Furthermore, the
accumulation of triglycerides has been directly correlated with
the development of insulin resistance in skeletal muscle and the
liver. Thus, a specific type of mitochondrial dysfunction, i.e.,
decreased fatty acid oxidation, may play a significant role in
the development of insulin resistance in both aging and obesity
(43). It is interesting to note that triglycerides can also accu-
mulate in pancreatic ␤-cells, resulting in decreased rates of
insulin secretion, which would further exacerbate the problem
of glucose disposal (32, 60). As noted above, the accumulation
of intracellular triglycerides could be the result of a deficiency
in fatty acid oxidation related to mitochondrial dysfunction. As
a result, the cause of insulin resistance may well be due to
mitochondrial dysfunction rather than the accumulation of
triglycerides, a mechanistic concept that will be important to
establish in gaining an understanding of the etiology of Type 2
diabetes.
It has been hypothesized that a close relationship exists
among PGC-1␣ function, insulin sensitivity, and Type 2 dia-
betes, which is most likely related to the essential roles of
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PGC-1␣ in mitochondria biogenesis and glucose/fatty acid
metabolism. Evidence supporting this hypothesis has been
found in a number of studies. For example, it has been
observed that expression of PGC-1␣ is downregulated in mus-
cles of Type 2 diabetic subjects (36, 42, 44). In addition, a
common polymorphism of the PGC-1␣ gene (Gly482Ser),
expressing reduced PGC-1␣ activity, has been linked to an
increased risk of Type 2 diabetes (18, 40). These observations
would suggest that either reduced levels or compromised
activity of PGC-1␣ can be associated with the development of
insulin resistance and Type 2 diabetes (Fig. 1). In this context,
it is interesting to note that TZDs, an important class of
antidiabetic drugs, also act to increase insulin sensitivity coin-
cident with the activation of PGC-1␣ (66). The effects of TZDs
are likely mediated through the ability of PGC-1␣ to activate
mitochondria biogenesis and increase mitochondrial function.
As described above, PGC-1␣ stimulates the conversion of
muscle fiber type toward more oxidative type I and IIa fibers,
favoring fatty acid oxidative metabolism (28). The promotion
of fatty acid oxidative metabolism would be expected to lead to
a reduction of fat accumulation in muscle, which, in turn, could
increase insulin sensitivity because there is a close relationship
between triglyceride accumulation and insulin resistance (43).
One manifestation of increased insulin sensitivity would be
increased glucose uptake by insulin-sensitive tissues. PGC-1␣
has, as previously noted, been reported to activate the expres-
sion of insulin-sensitive GLUT4 in skeletal muscle (5, 33).
Taken together, the evidence presented supports a role for
PGC-1␣ in preventing insulin resistance and Type 2 diabetes
mellitus.
However, it should be pointed out that PGC-1␣ expression
has been reported to be increased in the liver of both Type 1
and Type 2 diabetic mouse models, in contrast to the reported
decrease in PGC-1␣ expression observed in the muscle of
human Type 2 diabetic subjects described above (48). Further-
more, PGC-1␣ has been shown to inhibit the insulin signaling
pathway in the liver (22), inhibit glucose utilization in cultured
myotubes (65), and suppress ␤-cell energy metabolism and
insulin release in mice (70). Increased hepatic PGC-1␣ expres-
sion could be expected to stimulate hepatic glucose output,
Fig. 1. Potential role of decreased peroxisome proliferator-activated recep-
tor-␥ coactivator (PGC)-1␣ expression in skeletal muscle as it relates to the
development of the metabolic phenotype of insulin resistance and Type 2
diabetes mellitus. [Revised from Ref. 34.]

PGC-1␣: A KEY REGULATOR OF ENERGY METABOLISM
and, when coupled with the reported inhibitory effect of
PGC-1␣ on insulin signaling and secretion, the combined
effects would be to contribute to the hyperglycemic state, a
prodiabetes effect. This prodiabetic effect of PGC-1␣ has been
further supported by the manifestation of improved insulin
sensitivity in PGC-1␣-deficient mouse models (22, 26, 29).
Moreover, another recent report (38) has indicated that
PGC-1␣ expression is normal in insulin-resistant subjects de-
spite severe impairments in mitochondrial function. These
apparently paradoxical actions of PGC-1␣ in different tissues
are intriguing. The underlining mechanisms for the interactions
between these tissues are currently unknown and deserve
further intensive investigations.
Summary
As an inducible transcription coactivator, PGC-1␣ is en-
riched in metabolically active tissues. It is intimately involved
in adaptive thermogenesis, skeletal muscle fiber type switch-
ing, glucose/fatty acid metabolism, and heart development.
Among these varied biological responses, a common mecha-
nism of action appears to be the promotion of oxidative
metabolism accompanying the stimulation of mitochondria
biogenesis. Furthermore, there is growing evidence that
PGC-1␣ plays a role in disorders such as obesity, diabetes, and
cardiomyopathy. Because of the involvement of PGC-1␣ in so
many important biological processes, in conjunction with the
rapid improvement in our understanding of its mechanisms of
action, it has become an inviting target for the design of
pharmacological interventions for treatment of these disorders.
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