PPARs modulate cardiac metabolism and mitochondrial function in diabetes
Lee et al. Journal of Biomedical Science
PPARs modulate cardiac metabolism and mitochondrial function in diabetes
Ting-Wei Lee 0
Yu-Hsun Kao 0 1
Yi-Jen Chen 0
0 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , 250 Wu-Xing Street, Taipei 11031 , Taiwan
1 Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University , Taipei , Taiwan
Diabetic cardiomyopathy is a major complication of diabetes mellitus (DM). Currently, effective treatments for diabetic cardiomyopathy are limited. The pathophysiology of diabetic cardiomyopathy is complex, whereas mitochondrial dysfunction plays a vital role in the genesis of diabetic cardiomyopathy. Metabolic regulation targeting mitochondrial dysfunction is expected to be a reasonable strategy for treating diabetic cardiomyopathy. Peroxisome proliferator-activated receptors (PPARs) are master executors in regulating glucose and lipid homeostasis and also modulate mitochondrial function. However, synthetic PPAR agonists used for treating hyperlipidemia and DM have shown controversial effects on cardiovascular regulation. This article reviews our updated understanding of the beneficial and detrimental effects of PPARs on mitochondria in diabetic hearts.
Cardiomyopathy; Diabetes mellitus; Mitochondria; Metabolism; Peroxisome proliferator-activated receptors
Diabetes mellitus (DM) is one of the most common
chronic diseases, and its prevalence continues to
increase worldwide [1, 2]. Cardiovascular disease is the
leading cause of morbidity and mortality in patients with
DM. Diabetic cardiomyopathy is recognized as a distinct
disease entity, since diabetic patients have an increased
incidence of heart failure in the absence of hypertension,
coronary artery disease, or valvular heart disease [3–5].
Diabetic cardiomyopathy is characterized by cardiac lipid
accumulation, myocardial fibrosis, and increased
myocardial cell death, all of which lead to left ventricular
remodeling and hypertrophy, diastolic dysfunction, and
ultimately systolic impairment . The pathophysiology
of diabetic cardiomyopathy is complex and yet to be
fully elucidated. Altered cardiac metabolism and
mitochondrial dysfunction are proposed mechanisms
underling diabetic cardiomyopathy .
Peroxisome proliferator-activated receptors (PPARs)
are nuclear hormone receptors and major executors of
modulating glucose and lipid homeostasis . There are
three PPAR isoforms (PPAR-α, PPAR-β/PPAR-δ, and
PPAP-γ), which differ in distribution, function, and
ligand specificity. Accumulating evidence suggests that
PPARs play crucial roles in cardiovascular disease .
PPAR isoforms are differentially expressed in the atria
and ventricles of diabetic hearts because of the increased
inflammatory cytokines and oxidative stress .
Moreover, we found increases in protein and messenger (m)
RNA expressions of PPAR-γ, but decreases in protein
and mRNA expressions of PPAR-α and PPAR-δ in
hypertensive hearts. Diabetic spontaneously hypertensive
rats were associated with greater reductions in cardiac
PPAR-α and PPAR-δ, but higher increases in PPAR-γ
mRNA and protein levels than were spontaneously
hypertensive rats . Diabetic cardiomyopathy is
associated with an increase in cardiac PPAR-γ and a decrease
in PPAR-α, resulting in altered glucose transportation,
increased cardiac lipid accumulation, and progressive
diabetic cardiomyopathy [7, 10–12]. Calcitriol and
histone deacetylase inhibitor improved diabetic
cardiomyopathy by modulating cardiac PPAR expressions and
regulating fatty acid metabolism [13, 14]. Mitochondria
are the center of fatty acid and glucose metabolism and
are thus likely to be impacted by metabolic
derangements in DM. Proper mitochondrial function is critical
for maintaining optimal cardiac performance. Several
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
mouse models of mitochondrial defects are relevant to
human cardiomyopathy . Patients with inherited
mitochondrial disorders frequently manifest cardiac
dysfunction, such as dilated or hypertrophic
cardiomyopathy and conduction defects . This review elucidates
our current understanding of different PPARs and their
agonists on mitochondrial function in diabetic hearts.
Cardiac metabolism in normal and diabetic hearts
Fatty acids and glucose are principle substrates for
myocardial energy metabolism. Under physiological
conditions, fatty acid β-oxidation constitutes the major energy
source in the heart. In contrast, glycolysis predominates
during pathological stimuli, such as during ischemia and
heart failure [17, 18]. The cardiac oxygen consumption
for adenosine triphosphate (ATP) production is greater
when utilizing fatty acids than when using glucose.
However, there is increased fatty acid β-oxidation and
reduced glucose oxidation in diabetic hearts. The
increased fatty acid utilization in diabetic hearts is
associated with reduced cardiac efficiency, which is a hallmark
of diabetic cardiomyopathy [19–21]. Diabetic hearts are
more vulnerable to ischemic injury due to their
constrained fuel substrate flexibility. In DM, high circulating
lipid levels increase fatty acid delivery to cardiomyocytes
due to insulin resistance. Cardiac glucose uptake is
mainly controlled by insulin-mediated recruitment of
glucose transporter type four (GLUT4) from the
intracellular compartment to plasma membranes. High fatty
acid concentrations in diabetic hearts may impair insulin
signal transduction, thereby decreasing GLUT4
translocation and reducing glucose uptake . In contrast,
expressions of fatty acid transporters are increased in
diabetic hearts. The enhanced cluster of differentiation
36 (CD36) and fatty acid-binding proteins can promote
fatty acid uptake, and increased fatty acids activate
PPAR-α, which facilitates cardiac fatty acid metabolism.
Activation of cardiac PPAR-α not only increases
expressions of genes involved in fatty acid β-oxidation but also
suppresses glucose utilization [19, 20]. Myocardial fatty
acid uptake and oxidation are increased, and glucose
uptake and oxidation are reciprocally suppressed in mice
with cardiac-specific overexpression of PPAR-α, which
exhibited cardiac dysfunction that mimics diabetic
cardiomyopathy . Moreover, augmented fatty acid
βoxidation causes accumulation of citrate in the cytosol.
High concentrations of citrate inhibit the action of
phosphofructokinase 1 (the rate-limiting enzyme) in
glycolysis. Pyruvate, the product of glycolysis, is transported to
mitochondria and decarboxylated to acetyl-CoA by
pyruvate dehydrogenase. Both increased fatty acid
βoxidation and PPAR-α activation lead to suppression of
pyruvate dehydrogenase, which impairs glucose
oxidation . Our previous study found that diabetic hearts
expressed more fatty acid transporters and metabolic
enzymes, including CD36, carnitine palmitoyltransferase 1
(CPT-1), and phosphorylated acetyl CoA carboxylase. In
addition, diabetic cardiomyopathy is associated with
activation of enzymes controlling the formation of triglycerides,
such as diacylglycerol acyltransferase (DGAT) [13, 14]. The
shuttling of excessive fatty acids into triglyceride synthesis
serves to minimize the generation of toxic lipid
metabolites. However, chronic metabolic derangement results in
cardiac lipid accumulation and produces diabetic
cardiomyopathy. Alternations of cardiac metabolism in DM are
summarized in Table 1.
Mitochondrial dysfunction in diabetic hearts
Mitochondria act as the powerhouse of cells because
they generate most of the cell’s supply of ATP.
Cardiomyocytes contain a relatively large amount of
mitochondria (approximately 40% of the cardiomyocyte volume is
comprised of mitochondria), because the heart has a
high and continuous demand for ATP . In response
to diverse physiological and nutritional conditions, it is
critical to control the metabolic activity of mitochondria
to meet cellular energy requirements.
A substantial body of evidence has demonstrated that
there is significantly impaired mitochondrial function in
diabetic cardiomyopathy. Excessive fatty acid uptake in
diabetic hearts results in an altered mitochondrial
architecture and reduced expressions of genes involved in
mitochondrial oxidative phosphorylation . Moreover,
PPAR-α activates genes involved in fatty acid uptake and
β-oxidation, but does not increase expressions of genes
associated with the tricarboxylic acid cycle or
mitochondrial oxidative phosphorylation. Thus, the upregulated
mitochondrial fatty acid uptake and β-oxidation may
exceed the capacity of downstream mitochondrial
respiration and lead to an accumulation of toxic lipid
Table 1 Altered cardiac metabolism in diabetes
Alteration of cardiac metabolism
Alterations in fatty acid
utilization [13, 14, 19, 20]
Decreases glucose oxidation
High fatty acid oxidation suppresses
PFK1 through accumulation of
citrate in the cytosol
High fatty acid oxidation inhibits
PDH through activation of PDK
Increases the expression of fatty
PPAR-α activation promotes the
expressions of genes that regulate
fatty acid β-oxidation
GLUT4, glucose transporter type 4; PFK1, phosphofructokinase 1; PDH, pyruvate
dehydrogenase; PDK, pyruvate dehydrogenase kinase
metabolites, which further worsens insulin resistance. In
addition, increased fatty acid β-oxidation augments
delivery of electrons to the mitochondrial electron transport
chain and results in an elevated mitochondrial inner
membrane potential, which stimulates reactive oxygen
species (ROS) generation [19, 20]. ROS directly impair
mitochondria and/or oxidize lipids to yield reactive lipid
peroxidation, as a result of inducing oxidative damage to
mitochondrial proteins that are associated with energy
metabolism and oxidative phosphorylation. Moreover,
ROS can activate mitochondrial uncoupling, and
subsequently reduce cardiac efficiency [19–21, 23]. Excessive
fatty acids lead to the generation of ceramide. Ceramide
triggers apoptosis through nitric oxide- and
peroxynitritemediated opening of mitochondrial permeability
transition pores and release of cytochrome c. Ceramide also
suppresses mitochondrial respiration through directly
inhibiting the activity of mitochondrial electron transport
chain complex III [19, 24]. Incomplete fat oxidation and
accumulated toxic fatty acid intermediates lead to
mitochondrial dysfunction through hyperpolarization of the
mitochondrial inner membrane potential, mitochondrial
uncoupling, and generation of ROS [21, 23, 25].
Upregulation of mitochondrial uncoupling proteins is
another potential explanation for the reduced
mitochondrial efficiency in diabetic hearts. Uncoupling proteins
cause proton leaks across mitochondrial membranes
from ATP synthesis, thereby decreasing the generation
of mitochondrial superoxide. Increased mitochondrial
uncoupling is presumably an adaptive mechanism;
however, sustained activation of mitochondrial uncoupling
may adversely affect cardiomyocyte ATP production and
contractile function in DM [21, 25, 26]. Mitochondrial
calcium handling was proposed to represent a
mechanism for coordinating the ATP supply and demand for
cardiomyocyte contractions . Mitochondrial calcium
uptake may also act as a spatial buffering system, which
regulates the activity of calcium-dependent processes
and signaling . The mitochondrial transmembrane
potential is not only required for ATP synthesis, but also
plays a crucial role in driving calcium accumulation in
mitochondria. Disruption of the mitochondrial
membrane potential in the diabetic heart leads to altered
mitochondrial calcium handling which contributes to
the development of diabetic cardiomyopathy .
Mitochondrial DNA encodes proteins for the electron
transport chain, which is localized in the mitochondrial
inner membrane and drives ATP production through
oxidative phosphorylation. The damage to mitochondrial
DNA leads to impairment of mitochondrial respiration
and ATP synthesis. Because dysfunctional mitochondria
are a major source of ROS production, mitochondrial
DNA is a vulnerable target of ROS damage [23, 29].
Several investigations have implied that cardiomyocyte
apoptosis promotes the development of diabetic
cardiomyopathy. Diabetic mice showed enhanced apoptotic
signaling in the heart that was associated with changes
in the mitochondrial membrane potential and the
opening in mitochondrial permeability transition pores .
Findings from mitochondrial proteomic studies in diabetic
hearts supported the role of mitochondrial-induced
apoptosis in diabetic cardiomyopathy . Furthermore,
cardiac fibrosis is a major feature of diabetic cardiomyopathy.
Apoptotic cardiomyocytes are replaced by fibrotic tissues.
Myocardial fibrosis contributes to increased stiffness and
decreased compliance of the ventricular wall, resulting in
left ventricle dysfunction. Mitochondrial dysfunction
augments ROS production, which is thought to be a crucial
driving force for cardiac fibrosis [6, 32–34].
A number of studies provided evidence for
mitochondrial alternations in hearts of patients with DM. Diastolic
dysfunction in association with a reduction in myocardial
energy metabolism was demonstrated using magnetic
resonance techniques in asymptomatic normotensive
patients with well—controlled DM . Mitochondria in
atrial tissues of diabetic patients revealed a sharply
decreased capacity for respiration and increased
mitochondrial hydrogen peroxide emissions, suggesting an increase
in oxidative stress . An association of worsened
cardiac mitochondrial respiration with a reduced
mitochondrial calcium retention capacity with decreased contractile
performance in heart tissues of diabetic patients was
shown before the onset of clinical cardiomyopathy .
PPARs regulate myocardial energy metabolism
PPAR-α was first cloned in 1990 and so named because
it was activated by the lipid-lowering drug, fibrate, which
causes hepatic peroxisome proliferation in rodents .
PPAR-α is the principal regulator modulating energy and
lipid homeostasis through transcriptional regulation of
fatty acid metabolic enzymes. PPAR-α is abundantly
expressed in tissues with a high capacity for
mitochondrial fatty acid oxidation, such as the liver and heart.
Figure 1 shows that PPAR-α regulates lipid metabolism
by controlling expressions of enzymes that are directly
involved in fatty acid uptake (CD36), triglyceride
synthesis (DGAT), and β-oxidation (CPT-1, acyl-CoA
dehydrogenase) [12, 21, 25]. Several studies indicated that
diabetic hearts were associated with increased expression
of PPAR-α because of high levels of circulating fatty
acids . However, our previous study demonstrated a
significant decline in PPAR-α and an increase in PPAR-γ
protein levels in diabetic hearts despite an increase in
cardiac fatty acid oxidation. These findings indicated
that hyperglycemia is associated with a compensatory
response for preserving the contractile function through
activation of inflammatory cytokines . Mouse models
Fig. 1 Peroxisome proliferator-activated receptor (PPAR)-α regulates fatty acid utilization and β-oxidation in cardiac metabolism. Stars indicate
transporters and enzymes involved in fatty acid metabolism which are regulated by PPAR-α. FATP, fatty acid transport protein; FABP, fatty acid
binding protein; ACS, acyl-CoA synthetase; CPT-I, carnitine palmitoyltransferase-I; CPT-II, carnitine palmitoyltransferase II; TCA, tricarboxylic acid;
GLUT4, glucose transporter four; MPC, mitochondrial pyruvate carrier; and PDH, pyruvate dehydrogenase. Modified from 
lacking PPAR-α were protected against the development
of diabetes-induced cardiac hypertrophy. In contrast,
transgenic overexpression of PPAR-α in diabetic hearts
displayed severe cardiomyopathy and was accompanied
by myocardial triglyceride accumulation [40, 41].
PPAR-δ is expressed in multiple tissues and shares
certain similarities with PPAR-α in regulating cardiac lipid
metabolism. Cardiac-specific deletion of PPAR-δ down
regulates constitutive myocardial fatty acid oxidation,
and induces myocardial lipid accumulation and cardiac
hypertrophy in mice . Fatty acids and
PPAR-δselective ligands increase fatty acid oxidation through
transcriptional activation in both neonatal and adult
cardiomyocytes [43, 44]. However, the PPAR-δ-selective
ligand does not modify the expression of PPAR-α in
cultured cardiomyocytes. PPAR-δ activation can partially
restore the blunted expressions of genes encoding
cardiac fatty acid oxidation enzymes in PPAR-α-knockout
mice. These findings suggest that PPAR-δ-regulated
cardiac fatty acid metabolism might not wholly interact
with PPAR-α [44, 45]. Moreover, there was increasing
myocardial glucose utilization without myocardial lipid
accumulation or cardiac dysfunction in transgenic mice
with cardiac-specific overexpression of PPAR-δ.
Accordingly, PPAR-α and PPAR-δ may exert distinct cardiac
metabolic regulatory actions .
PPAR-γ plays a crucial role in regulating lipid storage
and adipogenesis. PPAR-γ is expressed at levels far below
those of PPAR-α and PPAR-δ in the heart. PPAR-γ ligands
do not affect the fatty acid oxidation rate or metabolic
gene expression in cardiomyocytes . It was suggested
that PPAR-γ modulates cardiac energy metabolism
through its effects on extra cardiac tissues. Activation of
PPAR-γ promotes glucose uptake and triglyceride
synthesis in adipose tissues. Reductions in circulating glucose
and fatty acid levels caused by PPAR-γ activation may
directly modulate cardiac PPAR-α and PPAR-δ activities
. Cardiac-specific PPAR-γ-overexpressing transgenic
mice developed dilated cardiomyopathy with increased
myocardial lipid and glycogen stores and upregulated
cardiac expressions of genes associated with fatty acid
utilization and glucose metabolism . The mechanism
underlying cardiomyopathy in PPAR-γ-overexpressing
transgenic mice was hypothesized to be combined lipid
and glucose toxicity .
Adenosine monophosphate-activated protein kinase
(AMPK) and PPAR-γ co-activator (PGC)-1α are two
major signaling molecules that regulate mitochondrial
biogenesis. AMPK upregulates mitochondrial biogenesis
through activation of PGC-1α, which is a master
metabolic regulator that coordinates gene expressions in
association with mitochondrial biogenesis and respiratory
function . Lee et al. showed that diabetic hearts have a
lower ratio of phosphorylated AMPK2α to total AMPK2α
and greater expression of PGC-1α compared to those of
control rats [13, 14]. The up regulation of PGC-1α enables
diabetic hearts to enhance their mitochondrial oxidative
capacity . Therefore, up regulation of PPAR-α and
PGC-1α may initially be adaptive responses in diabetic
hearts [21, 25, 50]. However, sustained increases in fatty
acid β-oxidation are detrimental to cardiac mitochondria
and further promote the development of diabetic
cardiomyopathy [21, 23, 25].
PPARs modulate mitochondrial function
Effects of PPAR-α on mitochondria
Transgenic mice with cardiac-specific overexpression of
PPAR-α had disorganized mitochondria, altered
mitochondrial cristae density and architecture, and decreased
expressions of genes involved in mitochondrial
metabolism, including the tricarboxylic acid cycle and oxidative
phosphorylation . The cristae of mitochondria
increased in number and density in cardiomyocytes of
PPAR-α-null mice . These findings suggest that
abnormal expression of PPAR-α is linked to an altered
mitochondrial structure and metabolic function.
Fibrates are synthetic PPAR-α agonists that are used as
lipid-lowering agents. Several laboratory findings
suggested that fibrates modulate mitochondrial function
with potential beneficial or deleterious effects (Table 2).
Ureido-fibrate-5 is a potent PPAR-α agonist and exerts a
marked triglyceride-lowering effect by stimulating
mitochondrial CPT-1-mediated fatty acid β-oxidation in both
the liver and muscles . In addition, fibrates also have
Table 2 Effects of peroxisome proliferator-activated receptor
(PPAR)-α agonists on mitochondria
Potential beneficial effects
Fenofibrate [54, 55, 56, 58]
Reduces mitochondrial membrane
potential depolarization and apoptosis
Reduces mitochondrial membrane
potential depolarization and apoptosis
Induces mitochondrial CPT I expression
Inhibits mitochondrial respiratory chain
complex I activity
an effect on glucose homeostasis. Fenofibrate improved
insulin sensitivity not only by lowering serum lipid levels
but also by enhancing mitochondrial fatty acid
βoxidation in skeletal muscles of fructose-fed rats .
Two weeks of fenofibrate treatment (5 mg/kg)
ameliorated insulin resistance accompanied by an improved
mitochondrial oxidative capacity in pediatric burn
patients . Mitochondrial oxidative stress was implicated
in the pathogenesis of Batten disease, a rare and fatal
autosomal recessive neurodegenerative disorder.
Fenofibrate and gemfibrozil (1 μM) reduced mitochondrial
membrane potential depolarization, thereby inhibiting
the apoptosis of lymphoblast cells in Batten disease .
Pretreatment of female rats with gemfibrozil prior to
global cerebral ischemia-reperfusion resulted in
neuroprotection by modulating mitochondrial biogenesis and
apoptosis . Activation of PPAR-α with WY-14,643,
an experimental ligand, or fenofibrate protects mice
from acetaminophen-induced hepatotoxicity. This
protective effect is mediated by up regulating the PPAR-α
target gene that encodes mitochondrial uncoupling
protein 2, which serves to prevent mitochondria from
oxidative stress through decreasing the generation of
mitochondrial ROS . However, fibrates may cause
mitochondrial dysfunction. A 24-h fenofibrate exposure
(100 μM) impaired mitochondrial function in rat skeletal
muscles through inhibiting the activity of mitochondrial
respiratory chain complex I . Gemfibrozil and
WY14,643 at toxicologically relevant concentrations altered
mitochondrial bioenergetics through inducing the
mitochondrial permeability transition which caused
inhibition of oxidative phosphorylation and ATP synthesis in
mitochondria in the rat liver . Chronic treatment
with WY-14,643 impaired myocardial contractile
function while decreasing mitochondrial respiratory function
and increasing mitochondrial uncoupling in rats .
Effects of PPAR-γ on mitochondria
Overexpression of cardiac PPAR-γ via the cardiac
αmyosin heavy chain promoter produced a distorted
architecture of the mitochondrial inner matrix and disrupted
cristae in PPAR-γ transgenic mice . Transgenic mice
overexpressing PPAR-γ2 had significantly increased
expression of mitochondrial uncoupling protein one,
elevated levels of PGC-1α, and reduced mitochondrial ATP
concentrations in the subcutaneous fat . Cardiac
expression of the gene encoding manganese superoxide
dismutase as a mitochondrial antioxidant was suppressed in
cardiac-specific PPAR-γ-knockout mice .
Thiazolidinediones (TZDs) are synthetic PPAR-γ
agonists and are used to treat DM. In addition to glucose
metabolism, TZDs also exert several beneficial effects
including lipid-lowering and anti-inflammation actions.
However, troglitazone and rosiglitazone were respectively
CPT I, carnitine palmitoyltransferase I
withdrawn from the market due to hepatotoxicity and
increased cardiovascular risk. Our previous study showed
that rosiglitazone can upregulate PPAR-γ mRNA and
protein expressions, which might explain the harmful effects
of the PPAR-γ agonist in DM given that PPAR-γ is already
overexpressed in diabetic hearts . In addition, we also
found that rosiglitazone significantly changed cardiac
calcium regulatory and electrophysiological characteristics,
thereby enhancing arrhythmogenicity in DM with
hypertension . Numerous investigations have suggested that
TZDs have important effects on mitochondrial function
and biogenesis (Table 3). Expressions of genes in
mitochondrial respiratory complexes I ~ IV were significantly
down regulated in subcutaneous adipose tissues of
diabetic patients and were restored in response to
rosiglitazone treatment. Rosiglitazone also increased the relative
amount of mitochondria in diabetic patients compared to
control groups . Pioglitazone treatment significantly
increased the mitochondrial DNA copy number and
expressions of factors involved in mitochondrial biogenesis
and genes involved in the fatty acid oxidation pathway in
adipocytes of patients with DM . PPAR-γ also plays a
crucial role in energy homeostasis observed in Huntington’s
Table 3 Effects of peroxisome proliferator-activated receptor
(PPAR)-γ agonists on mitochondria
Potential beneficial effects
Rosiglitazone [65, 67, 68, 73, 74]
Pioglitazone [66, 73–75]
and Pioglitazone [69, 70]
Maintains mitochondrial potential
to promote cell survival
Increases mitochondrial biogenesis
Increase genes involved in the
fatty acid oxidation
Controls maximal mitochondrial
Changes membrane permeability
Inhibits mitochondrial complex I
activity and cell respiration
disease, which is characterized by mutant Huntingtin
protein aggregates in the brain. Rosiglitazone protected a
neuroblastoma cell line from a mutant Huntingtin
proteinevoked mitochondrial deficiency . Rosiglitazone can
promote T lymphocyte survival by allowing cells to
maintain the mitochondrial membrane potential following
growth factor withdrawal or glucose restriction at doses
that induce optimal PPAR-γ transcriptional activity. This
suggests that PPAR-γ activation may potentially augment
immune responses of diabetic patients . However,
TZDs demonstrated varying degrees of hepatotoxicity in an
in vitro model, with troglitazone exhibiting the highest
mitochondrial toxicity, followed by rosiglitazone and then
pioglitazone. TZD-induced hepatotoxicity may involve
alterations in mitochondrial respiratory function, changes in
membrane permeability, and mitochondrial structural
damage . An in vitro study demonstrated that both
rosiglitazone and pioglitazone at supra-physiological
concentrations (100 μM) directly inhibited mitochondrial
respiratory chain complex I activity and cell respiration in rat
skeletal muscles . In addition, PPAR-γ activation is
associated with fluid retention, heart failure, and bone loss,
thereby limiting the clinical use of TZDs.
Substantial evidence has shown that TZDs exert direct
and rapid PPAR-γ-independent effects on mitochondrial
respiration, thereby leading to changes in glycolytic
metabolism and fuel substrate specificity [71, 72]. It was
shown that clinically relevant concentrations of TZDs
acutely, specifically, and partially inhibit mitochondrial
pyruvate carrier activity, thereby improving cellular
glucose handling in human myocytes . Laboratory
studies revealed that TZDs have a recognition site in the
inner mitochondrial membrane that is comprised of a
protein complex, which is involved in mitochondrial
pyruvate importation . Pioglitazone was shown to
specifically bind to a protein named mitoNEET, which is
an iron-containing outer mitochondrial membrane
protein, that is involved in controlling maximal
mitochondrial respiratory rates . Therefore, these findings
suggest that development of novel molecules designed
to maintain this mitochondrial interaction while
specifically avoiding significant interactions with PPAR-γ is very
appropriate for clinical treatments.
Impaired mitochondrial biogenesis and function
associated with derangement of cardiac metabolism play vital
roles in the pathogenesis of diabetic cardiomyopathy.
Therefore metabolic regulation targeting mitochondrial
dysfunction may show therapeutic potential for treating
diabetic cardiomyopathy. Synthetic PPAR-α and PPAR-γ
agonists not only regulate expressions of genes involving
lipid and glucose metabolism, but also modulate
mitochondrial function and therefore appear to be promising
treatments for diabetic cardiomyopathy. However,
unfavorable effects of PPAR activation on cardiac
mitochondria were also observed. Additional studies are
required to develop optimal pharmacological approaches
to improve mitochondrial function in diabetic hearts.
AMPK: Adenosine monophosphate-activated protein kinase; ATP: Adenosine
triphosphate; CD36: Cluster of differentiation 36; CPT-1: Carnitine
palmitoyltransferase 1; DGAT: Diacylglycerol acyltransferase; DM: Diabetes
mellitus; GLUT4: Glucose transporter type 4; PGC-1α: PPAR-γ co-activator-1α;
PPAR: Peroxisome proliferator-activated receptor; ROS: Reactive oxygen
species; TZD: Thiazolidinedione
This work was supported by grants from the Ministry of Science and Technology
of Taiwan (MOST 104-2314-B-038-032 and 105-2314-B-038-019-MY2) and Taipei
Medical University, Wan Fang Hospital (105-wf-phd-03 and 105-swf-09).
Ethics approval and consent to participate
“Not applicable” (The present paper is a review article that does not involve
human subjects but describes published data).
1. Whiting DR , Guariguata L , Weil C , Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030 . Diabetes Res Clin Pract . 2011 ; 94 : 311 - 21 .
2. Calton EK , James AP , Pannu PK , Soares MJ . Certain dietary patterns are beneficial for the metabolic syndrome: reviewing the evidence . Nutr Res . 2014 ; 34 : 559 - 68 .
3. Chen K , Lindsey JB , Khera A , Lemos JAD , Ayers CR , Goyal A , et al. Independent associations between metabolic syndrome, diabetes mellitus and atherosclerosis: observations from the Dallas Heart Study . Diab Vasc Dis Res . 2008 ; 5 : 96 - 101 .
4. Roberts AW , Clark AL , Witte KK . Review article: left ventricular dysfunction and heart failure in metabolic syndrome and diabetes without overt coronary artery disease - do we need to screen our patients? Diab Vasc Dis Res . 2009 ; 6 : 153 - 63 .
5. de Simone G , Devereux RB , Chinali M , Lee ET , Galloway JM , Barac A , et al. Diabetes and incident heart failure in hypertensive and normotensive participants of the Strong Heart Study . J Hypertens . 2010 ; 28 : 353 - 60 .
6. Ernande L , Derumeaux G . Diabetic cardiomyopathy: myth or reality? Arch Cardiovasc Dis . 2012 ; 105 : 218 - 25 .
7. Lee TW , Lee TI , Chang CJ , Lien GS , Kao YH , Chao TF , et al. Potential of vitamin D in treating diabetic cardiomyopathy . Nutr Res . 2015 ; 35 : 269 - 79 .
8. Barger PM , Kelly DP . PPAR signaling in the control of cardiac energy metabolism . Trends Cardiovasc Med . 2000 ; 10 : 238 - 45 .
9. Puddu GM , Cravero E , Arnone G , Muscari A , Puddu P. Molecular aspects of atherogenesis: new insights and unsolved questions . J Biomed Sci . 2005 ; 12 : 839 - 53 .
10. Lee TI , Kao YH , Chen YC , Pan NH , Chen YJ . Oxidative stress and inflammation modulate peroxisome proliferator-activated receptors with regional discrepancy in diabetic heart . Eur J Clin Invest . 2010 ; 40 : 692 - 9 .
11. Lee TI , Kao YH , Chen YC , Pan NH , Lin YK , Chen YJ . Cardiac peroxisomeproliferator-activated receptor expression in hypertension co-existing with diabetes . Clin Sci (Lond) . 2011 ; 121 : 305 - 12 .
12. Lee TI , Kao YH , Chen YC , Huang JH , Hsiao FC , Chen YJ . Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy . Diabetes Res Clin Pract . 2013 ; 100 : 330 - 9 .
13. Lee TI , Kao YH , Chen YC , Tsai WC , Chung CC , Chen YJ . Cardiac metabolism, inflammation, and peroxisome proliferator-activated receptors modulated by 1,25-dihydroxyvitamin D3 in diabetic rats . Int J Cardiol . 2014 ; 176 : 151 - 7 .
14. Lee TI , Kao YH , Tsai WC , Chung CC , Chen YC , Chen YJ . HDAC inhibition modulates cardiac PPARs and fatty acid metabolism in diabetic cardiomyopathy . PPAR Res . 2016 ; 2016 : Article ID : 5938740 .
15. Russell LK , Finck BN , Kelly DP . Mouse models of mitochondrial dysfunction and heart failure . J Mol Cell Cardiol . 2005 ; 38 : 81 - 91 .
16. Neubauer S. The failing heart - an engine Out of fuel . N Engl J Med . 2007 ; 356 : 1140 - 51 .
17. Ashrafian H , Frenneaux MP , Opie LH . Metabolic mechanisms in heart failure . Circulation . 2007 ; 116 : 434 - 48 .
18. Marin-Garcia J , Goldenthal MJ , Moe GW . Mitochondrial pathology in cardiac failure . Cardiovasc Res . 2001 ; 49 : 17 - 26 .
19. An D , Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy . Am J Physiol Heart Circ Physiol . 2006 ; 291 : H1489 - 506 .
20. Bugger H , Abel ED. Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome . Clin Sci (Lond) . 2008 ; 114 : 195 - 210 .
21. Duncan JG . Mitochondrial dysfunction in diabetic cardiomyopathy . Biochim Biophys Acta . 1813 ; 2011 : 1351 - 9 .
22. Finck BN , Lehman JJ , Leone TC , Welch MJ , Bennett MJ , Kovacs A , et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus . J Clin Invest . 2002 ; 109 : 121 - 30 .
23. Teshima Y , Takahashi N , Nishio S , Saito S , Kondo H , Fukui A , et al. Production of reactive oxygen species in the diabetic heart . Roles of mitochondria and NADPH oxidase. Circ J . 2014 ; 78 : 300 - 6 .
24. Gudz TI , Tserng KY , Hoppel CL . Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide . J Biol Chem . 1997 ; 272 : 24154 - 8 .
25. Schilling JD . The mitochondria in diabetic heart failure: from pathogenesis to therapeutic promise . Antioxid Redox Signal . 2015 ; 22 : 1515 - 26 .
26. Boudina S , Han YH , Pei S , Tidwell TJ , Henrie B , Tuinei J , et al. UCP3 regulates cardiac efficiency and mitochondrial coupling in high Fat-Fed mice but Not in leptin-deficient mice . Diabetes . 2012 ; 61 : 3260 - 9 .
27. Szabadkai G , Duchen MR . Mitochondria: the Hub of cellular Ca2+ signaling . Physiology (Bethesda) . 2008 ; 23 : 84 - 94 .
28. Parekh AB . Store-operated Ca (2+) entry: dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane . J Physiol . 2003 ; 547 : 333 - 48 .
29. Puddu P , Puddu GM , Cravero E , De Pascalis S , Muscari A. The emerging role of cardiovascular risk factor-induced mitochondrial dysfunction in atherogenesis . J Biomed Sci . 2009 ; 16 : 112 .
30. Williamson CL , Dabkowski ER , Baseler WA , Croston TL , Alway SE , Hollander JM . Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location . Am J Physiol Heart Circ Physiol . 2010 ; 298 : H633 - H42 .
31. Dabkowski ER , Baseler WA , Williamson CL , Powell M , Razunguzwa TT , Frisbee JC , et al. Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes . Am J Physiol Heart Circ Physiol . 2010 ; 299 : H529 - H40 .
32. Zhang X , Chen C. A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy . Endocrine . 2012 ; 41 : 398 - 409 .
33. Goyal B , Mehta A. Diabetic cardiomyopathy: Pathophysiological mechanisms and cardiac dysfuntion . Hum Exp Toxicol . 2013 ; 32 : 571 - 90 .
34. Li CJ , Lv L , Li H , Yu DM. Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid . Cardiovasc Diabetol . 2012 ; 11 : 73 .
35. Diamant M , Lamb HJ , Groeneveld Y , Endert EL , Smit JW , Bax JJ , et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus . J Am Coll Cardiol . 2003 ; 42 : 328 - 35 .
36. Anderson EJ , Kypson AP , Rodriguez E , Anderson CA , Lehr EJ , Neufer PD . Substratespecific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart . J Am Coll Cardiol . 2009 ; 54 : 1891 - 8 .
37. Montaigne D , Marechal X , Coisne A , Debry N , Modine T , Fayad G , et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients . Circulation . 2014 ; 130 : 554 - 64 .
38. Issemann I , Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators . Nature . 1990 ; 347 : 645 - 50 .
39. Lee TI , Kao YH , Chen YC , Chen YJ . Proinflammatory cytokine and ligands modulate cardiac peroxisome proliferator-activated receptors . Eur J Clin Invest . 2009 ; 39 : 23 - 30 .
40. Finck BN , Han X , Courtois M , Aimond F , Nerbonne JM , Kovacs A , et al. A critical role for PPARα-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content . Proc Natl Acad Sci U S A . 2003 ; 100 : 1226 - 31 .
41. Finck BN . The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart . Curr Opin Clin Nutr Metab Care . 2004 ; 7 : 391 - 6 .
42. Cheng L , Ding G , Qin Q , Huang Y , Lewis W , He N , et al. Cardiomyocyterestricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy . Nat Med . 2004 ; 10 : 1245 - 50 .
43. Gilde AJ , van der Lee KA , Willemsen PH , Chinetti G , van der Leij FR , van der Vusse GJ , et al. Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism . Circ Res . 2003 ; 92 : 518 - 24 .
44. Cheng L , Ding G , Qin Q , Xiao Y , Woods D , Chen YE , et al. Peroxisome proliferator-activated receptor delta activates fatty acid oxidation in cultured neonatal and adult cardiomyocytes . Biochem Biophys Res Commun . 2004 ; 313 : 277 - 86 .
45. Huss JM , Kelly DP . Nuclear receptor signaling and cardiac energetics . Circ Res . 2004 ; 95 : 568 - 78 .
46. Burkart EM , Sambandam N , Han X , Gross RW , Courtois M , Gierasch CM , et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart . J Clin Invest . 2007 ; 117 : 3930 - 9 .
47. Son NH , Park TS , Yamashita H , Yokoyama M , Huggins LA , Okajima K , et al. Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice . J Clin Invest . 2007 ; 117 : 2791 - 801 .
48. Madrazo JA , Kelly DP . The PPAR trio: regulators of myocardial energy metabolism in health and disease . J Mol Cell Cardiol . 2008 ; 44 : 968 - 75 .
49. Kuznetsov AV , Javadov S , Sickinger S , Frotschnig S , Grimm M. H9c2 and HL1 cells demonstrate distinct features of energy metabolism, mitochondrial function and sensitivity to hypoxia-reoxygenation . Biochim Biophys Acta . 1853 ; 2015 : 276 - 84 .
50. Duncan JG , Fong JL , Medeiros DM , Finck BN , Kelly DP . Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-α/PGC-1α gene regulatory pathway . Circulation . 2007 ; 115 : 909 - 17 .
51. Duncan JG , Bharadwaj KG , Fong JL , Mitra R , Sambandam N , Courtois MR , et al. Rescue of cardiomyopathy in peroxisome proliferator-activated receptoralpha transgenic mice by deletion of lipoprotein lipase identifies sources of cardiac lipids and peroxisome proliferator-activated receptor-alpha activators . Circulation . 2010 ; 121 : 426 - 35 .
52. Watanabe K , Fujii H , Takahashi T , Kodama M , Aizawa Y , Ohta Y , et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with agedependent cardiac toxicity . J Biol Chem . 2000 ; 275 : 22293 - 9 .
53. Minnich A , Tian N , Byan L , Bilder G . A potent PPARα agonist stimulates mitochondrial fatty acid β-oxidation in liver and skeletal muscle . Am J Physiol Endocrinol Metab . 2001 ; 280 : E270 - E9 .
54. Furuhashi M , Ura N , Murakami H , Hyakukoku M , Yamaguchi K , Higashiura K , et al. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and betaoxidation in skeletal muscle . J Endocrinol . 2002 ; 174 : 321 - 9 .
55. Cree MG , Zwetsloot JJ , Herndon DN , Qian T , Morio B , Fram R , et al. Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate . Ann Surg . 2007 ; 245 : 214 - 21 .
56. Hong M , Song KD , Lee HK , Yi S , Lee YS , Heo TH , et al. Fibrates inhibit the apoptosis of Batten disease lymphoblast cells via autophagy recovery and regulation of mitochondrial membrane potential . In Vitro Cell Dev Biol Anim . 2016 ; 52 : 349 - 55 .
57. Mohagheghi F , Ahmadiani A , Rahmani B , Moradi F , Romond N , Khalaj L. Gemfibrozil pretreatment resulted in a sexually dimorphic outcome in the Rat models of global cerebral ischemia-reperfusion via modulation of mitochondrial Pro-survival and apoptotic cell death factors as well as MAPKs . J Mol Neurosci . 2013 ; 50 : 379 - 93 .
58. Patterson AD , Shah YM , Matsubara T , Krausz KW , Gonzalez FJ. PPARα- dependent induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity . Hepatology . 2012 ; 56 : 281 - 90 .
59. Brunmair B , Lest A , Staniek K , Gras F , Scharf N , Roden M , et al. Fenofibrate impairs Rat mitochondrial function by inhibition of respiratory complex I . J Pharmacol Exp Ther . 2004 ; 311 : 109 - 14 .
60. Zhou S , Wallace KB . The effect of peroxisome proliferators on mitochondrial bioenergetics . Toxicol Sci . 1999 ; 48 : 82 - 9 .
61. Zungu M , Young ME , Stanley WC , Essop MF . Chronic treatment with the peroxisome proliferator-activated receptor alpha agonist Wy-14,643 attenuates myocardial respiratory capacity and contractile function . Mol Cell Biochem . 2009 ; 330 : 55 - 62 .
62. Zhou Y , Yang J , Huang J , Li T , Xu D , Zuo B , et al. The formation of brown adipose tissue induced by transgenic over-expression of PPARgamma2 . Biochem Biophys Res Commun . 2014 ; 446 : 959 - 64 .
63. Ding G , Fu M , Qin Q , Lewis W , Kim HW , Fukai T , et al. Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage . Cardiovasc Res . 2007 ; 76 : 269 - 79 .
64. Lee TI , Chen YC , Kao YH , Hsiao FC , Lin YK , Chen YJ . Rosiglitazone induces arrhythmogenesis in diabetic hypertensive rats with calcium handling alteration . Int J Cardiol . 2013 ; 165 : 299 - 307 .
65. Håkansson J , Eliasson B , Smith U , Enerbäck S. Adipocyte mitochondrial genes and the forkhead factor FOXC2 are decreased in type 2 diabetes patients and normalized in response to rosiglitazone . Diabetol Metab Syndr . 2011 ; 3 : 32 .
66. Bogacka I , Xie H , Bray GA , Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo . Diabetes . 2005 ; 54 : 1392 - 9 .
67. Chiang MC , Chern Y , Huang RN . PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease . Neurobiol Dis . 2012 ; 45 : 322 - 8 .
68. Wang YL , Frauwirth KA , Rangwala SM , Lazar MA , Thompson CB . Thiazolidinedione activation of peroxisome proliferator-activated receptor γ Can enhance mitochondrial potential and promote cell survival . J Biol Chem . 2002 ; 277 : 31781 - 8 .
69. Hu D , Wu CQ , Li ZJ , Liu Y , Fan X , Wang QJ , et al. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: an in vitro model in mitochondria . Toxicol Appl Pharmacol . 2015 ; 284 : 134 - 41 .
70. Brunmair B , Staniek K , Gras F , Scharf N , Althaym A , Clara R , et al. Thiazolidinediones , like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes . 2004 ; 53 : 1052 - 9 .
71. Feinstein DL , Spagnolo A , Akar C , Weinberg G , Murphy P , Gavrilyuk V , et al. Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key ? Biochem Pharmacol . 2005 ; 70 : 177 - 88 .
72. Colca JR , Tanis SP , McDonald WG , Kletzien RF . Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases . Expert Opin Investig Drugs . 2014 ; 23 : 1 - 7 .
73. Divakaruni AS , Wiley SE , Rogers GW , Andreyev AY , Petrosyan S , Loviscach M , et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier . Proc Natl Acad Sci U S A . 2013 ; 110 : 5422 - 7 .
74. Colca JR , McDonald WG , Cavey GS , Cole SL , Holewa DD , Brightwell-Conrad AS , et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)-relationship to newly identified mitochondrial pyruvate carrier proteins . PLoS One . 2013 ; 8 : e61551 .
75. Wiley SE , Murphy AN , Ross SA , van der Geer P , Dixon JE . MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity . Proc Natl Acad Sci U S A . 2007 ; 104 : 5318 - 23 .