Department of Biomedical Sciences, University of Prince Edward Island, 550
University Avenue, Charlottetown, Prince Edward Island, Canada C1A 4P3.
Hyperproinsulinemia is observed in type 2 diabetic patients. We hypothesized
that the induction of uncoupling protein-2 (UCP2) would impair processing of
proinsulin to mature insulin and potentially contribute to hyperproinsulinemia,
based on the evidence that hormone processing is an ATP-dependent process and
UCP2 up-regulation can suppress cellular ATP production. UCP2 was
overexpressed (UCP2-OE) by twofold in INS-1 cells by means of plasmid
transfection. Although UCP2-OE reduced glucose-stimulated insulin secretion
and cellular ATP content, no effects on proinsulin processing, as measured by
western blotting, were observed. To increase the demand for insulin, we then
cultured UCP2-OE and control INS-1 cells in medium containing 20 mM KCl for 24
h. High K(+) markedly reduced glucose-stimulated insulin secretion from
control cells, indicating inability of cells to meet secretory demand.
Independent of UCP2 expression, high K(+) reduced preproinsulin mRNA
expression but had no effect on ATP content despite increasing ATP synthase
expression. In UCP2-OE cells, high K(+)decreased total cellular insulin
species content and increased the ratio of proinsulin to insulin, indicating
an impairment of processing. We conclude that UCP2-OE can negatively impact
proinsulin processing, possibly by ATP-dependent alteration of the granule
environment or reduction of Ca(2+)availability, particularly when cells are
chronically stimulated to secrete insulin.
Increasing uncoupling protein-2 in pancreatic beta cells
does not alter glucose-induced insulin secretion but decreases production of
reactive oxygen species.
Department of Cell Physiology and Metabolism, Centre Medical Universitaire, 1
rue Michel Servet, CH 1211, Geneva 4, Switzerland, francoise.assimacopoulos@medecine.unige.ch.
AIMS/HYPOTHESIS: Levels of uncoupling protein-2 (UCP2) are regulated in the
pancreatic beta cells and an increase in the protein level has been associated
with mitochondrial uncoupling and alteration in glucose-stimulated insulin
secretion. However, it is not clear whether an increase in uncoupling protein-2
per se induces mitochondrial uncoupling and affects ATP generation and insulin
secretion. MATERIALS AND METHODS: Transgenic mice with beta cell-specific
overexpression of the human UCP2 gene and INS-1 cells with
doxycycline-inducible overproduction of the protein were generated and the
consequences of increased levels of UCP2 on glucose-induced insulin secretion
and on parameters reflecting mitochondrial uncoupling were determined. RESULTS:
In transgenic mice, an increase in beta cell UCP2 protein concentration did
not significantly modify plasma glucose and insulin levels. Glucose-induced
insulin secretion and elevation in the ATP/ADP ratio were unaltered by an
increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did
not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio,
or glucose oxidation. Increased levels of UCP2 did not modify the
mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels
decreased cytokine-induced production of reactive oxygen species. CONCLUSION/INTERPRETATION:
The results obtained in transgenic mice and in the beta cell line do not
support the hypothesis that an increase in UCP2 protein per se uncouples the
mitochondria and decreases glucose-induced insulin secretion. In contrast, the
observation that increased UCP2 levels decrease cytokine-induced production of
reactive oxygen species indicates a potential protective effect of the protein
on beta cells, as observed in other cell types.
PMID: 17131143 [PubMed - as supplied by publisher]
3: id: 17090928
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The mitochondrion is a major organelle contributing to energy metabolism but
also a main site of reactive oxygen species (ROS) production.
Lipopolysaccharide (LPS)-induced ROS signaling is a critical event in
macrophage activation. We report here that part of LPS-mediated ROS signaling
comes from mitochondria inside a signal amplification loop that enhances
mitogen-activated protein kinase (MAPK) activation. More precisely, we
identified the inner mitochondrial membrane uncoupling protein 2 (UCP2) as a
physiological brake on ROS signaling. Stimulation of murine bone
marrow-derived macrophages by LPS quickly downregulated UCP2 through the JNK
and p38 pathways. UCP2 downregulation was shown to be necessary to increase
mitochondrial ROS production in order to potentiate MAPK activation.
Consistent with this, UCP2-deficient macrophages exhibit an enhanced
inflammatory state characterized by increased nitric oxide production and
elevated migration ability. Additionally, we found that absence of UCP2
renders macrophages more resistant to NO-induced apoptosis.
PMID: 17073824 [PubMed - as supplied by publisher]
Okayama University Graduate School of Medicine and Dentistry.
UCP2 is an important regulator of intracellular ROS production. We determined
the effects of calorie restriction (CR) on the dynamic aspects of
mitochondrial reactive oxygen species (ROS) production, uncoupling protein 2 (UCP2)
and NO-cGMP pathway in the cardiovascular tissues of type II diabetic Otsuka
Long-Evans Tokushima Fatty (OLETF) rats. Some rats were on restricted diets
(30% reduction from free intake) from age 29 to 42 weeks. Blood glucose,
hemoglobin A1c, plasma levels of free fatty acid, triacylglycerol, and
plasminogen activator inhibitor-1 in OLETF rats were significantly higher than
those in non-diabetic control (LETO) rats at 29 weeks. Mitochondrial ROS
production and UCP2 protein expression significantly increased in the heart
and aorta of OLETF rats compared with that in LETO rats. A fibrogenic growth
factor, transforming growth factor (TGF)-beta1 in the coronary vessels,
endothelial NO synthase (eNOS), and aortic nitrotyrosine were increased in
OLETF rats at 42 weeks. In contrast, an index of the NO-cGMP pathway,
phosphorylated vasodilator-stimulated phosphoprotein and SOD activity in the
aorta was significantly diminished. The relationship between UCP2 and ROS
production in the cardiovascular function of diabetic rats being fed a CR diet
is unknown. These abnormalities in OLETF rats were reversed to normal levels
by CR. CR significantly improved the NO-cGMP pathway via normalizing ROS
generation in OLETF rats. Decrease of UCP2 expression by CR may be a
compensatory mechanism to counteract decreased intracellular oxidative stress.
The data suggest that CR may prevent cardiovascular tissues from oxidative
stress provoked by diabetes mellitus.
PMID: 17068205 [PubMed - as supplied by publisher]
Department of Molecular Life Science, Tokai University School of Medicine,
Kanagawa, Japan.
Many studies suggest that mitochondrial dysfunction is involved in the
pathophysiology of schizophrenia. We performed a case-control study using tag
SNPs in the mitochondrial uncoupling protein genes, UCP2, UCP4, and BMCP1/UCP5,
to investigate their association with schizophrenia. These neuronal UCPs are
expressed in various brain tissues and may exert a neuroprotective effect
against increased oxidative stress. We found modest associations between
schizophrenia and the four tag SNPs, rs660339 (odds ratio (OR) = 1.330; P =
0.0043) and rs649446 (OR = 0.739; P = 0.0069) in UCP2, and rs10807344 (OR =
0.622; P = 0.0029) and rs2270450 (OR = 0.704; P = 0.0043) in UCP4, all of
which were statistically significant even after correcting for multiple
comparisons. Moreover, we found a statistically significant synergistic
interaction between UCP2 and UCP4 by using the multifactor dimensionality
reduction (MDR) method. The synergistic interaction was also confirmed by the
logistic regression analysis, where the maximal OR was obtained when the risk
alleles at rs660339 and rs10807344 were simultaneously homozygous. Individuals
possessing homozygous risk alleles at these two loci have a 7.6-fold risk of
developing schizophrenia compared with those of minimal OR. Our findings
suggest that UCP2 and UCP4 have a modest but important involvement in the
genetic etiology of schizophrenia. This is the first report of the association
between schizophrenia and neuronal UCPs. (c) 2006 Wiley-Liss, Inc.
PMID: 17066476 [PubMed - as supplied by publisher]
7: id: 17052202
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Department of Genetics and Institute of Diabetes, Obesity and Metabolism,
University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia,
PA 19104-6145, USA.
Foxa1 (formerly hepatic nuclear factor 3alpha) belongs to the family of Foxa
genes that are expressed in early development and takes part in the
differentiation of endoderm-derived organs and the regulation of glucose
homeostasis. Foxa1-/- pups are growth retarded and hypoglycemic but glucose
intolerant in response to an intraperitoneal glucose challenge. However, the
mechanism of glucose intolerance in this model has not been investigated. Here,
we show that Foxa1-/- islets exhibit decreased glucose-stimulated insulin
release in islet perifusion experiments and have significantly reduced
pancreatic insulin and glucagon content. Moreover, Foxa1-/- beta-cells exhibit
attenuated calcium influx in response to glucose and glyburide, suggesting an
insulin secretion defect either at the level or upstream of the ATP-sensitive
K+ channel. Intracellular ATP levels after incubation with 10 mmol/l glucose
were about 2.5 times lower in Foxa1-/- islets compared with controls. This
diminished ATP synthesis could be explained by increased expression of the
mitochondrial uncoupling protein uncoupling protein 2 (UCP2) in
Foxa1-deficient islets, resulting in partially uncoupled mitochondria.
Chromatin immunoprecipitation assays indicate that UCP2 is a direct
transcriptional target of Foxa1 in vivo. Thus, we have identified a novel
function for Foxa1 in the regulation of oxidative phosphorylation in
pancreatic beta-cells.
PMID: 17003337 [PubMed - indexed for MEDLINE]
9: id: 17003268
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Short-term, increasing dietary protein and fat moderately
affect energy expenditure, substrate oxidation and uncoupling protein gene
expression in rats.
Groups of Stable Isotopes and of Energy Metabolism, German Institute of Human
Nutrition in Potsdam-Rehbrucke (DIfE), D-14558 Nuthetal, Germany.
Macronutrient composition of diets can influence body-weight development and
energy balance. We studied the short-term effects of high-protein (HP) and/or
high-fat (HF) diets on energy expenditure (EE) and uncoupling protein (UCP1-3)
gene expression. Adult male rats were fed ad libitum with diets containing
different protein-fat ratios: adequate protein-normal fat (AP-NF): 20% casein,
5% fat; adequate protein-high fat (AP-HF): 20% casein, 17% fat; high
protein-normal fat (HP-NF): 60% casein, 5% fat; high protein-high fat (HP-HF):
60% casein, 17% fat. Wheat starch was used for adjustment of energy content.
After 4 days, overnight EE and oxygen consumption, as measured by indirect
calorimetry, were higher and body-weight gain was lower in rats fed with HP
diets as compared with rats fed diets with adequate protein content (P<.05).
Exchanging carbohydrates by protein increased fat oxidation in HF diet fed
groups. The UCP1 mRNA expression in brown adipose tissue was not significantly
different in HP diet fed groups as compared with AP diet fed groups.
Expression of different homologues of UCPs positively correlated with
nighttime oxygen consumption and EE. Moreover, dietary protein and fat
distinctly influenced liver UCP2 and skeletal muscle UCP3 mRNA expressions.
These findings demonstrated that a 4-day ad libitum high dietary protein
exposure influences energy balance in rats. A function of UCPs in energy
balance and dissipating food energy was suggested. Future experiments are
focused on the regulation of UCP gene expression by dietary protein, which
could be important for body-weight management.
PMID: 16979329 [PubMed - as supplied by publisher]
12: id: 16971137
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Department of Obstetrics, Gynecology & Reproductive Services, Yale University
School of Medicine, New Haven, CT 06510, USA.
Uncoupling protein 2 (UCP2) is known to promote neuroprotection in many forms
of neurological pathologies including Parkinson's disease. Here, we examined
the hypothesis that UCP2 also mediates aspects of normal nigrostriatal
dopamine (DA) function. Mice lacking UCP2 exhibited reduced dopamine turnover
in the striatum as measured by the 3,4-dihydoxyphenylacetic acid/dopamine (DOPAC/DA)
ratio, reduced tyrosine hydroxylase immunoreactivity (TH IR) in the substantia
nigra pars compacta (SNc) and reticulata, striatum and nucleus accumbens.
UCP2-knockout (KO) mice also had reduced dopamine transporter immunoreactivity
(DAT IR) in the SNc but not other brain regions examined. In order to
determine if these biochemical deficits are transcribed into behavioural
deficits, we examined locomotor function in UCP2-KO mice compared to wild-type
(WT) controls. UCP2-KO mice exhibited significantly reduced total movement
distance, movement velocity and increased rest time compared to wild-type
controls. These results suggest that UCP2 is an important mitochondrial
protein that helps to maintain normal nigrostriatal dopamine neuronal function
and a reduction in UCP2 levels may predispose individuals to environmental
causes of Parkinson's disease.
PMID: 16882005 [PubMed - indexed for MEDLINE]
16: id: 16872578
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The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University,
SE-106 91 Stockholm, Sweden. barbara.cannon@wgi.su.se
A physiological function of the original uncoupling protein, UCP1, is well
established: UCP1 is the molecular background for nonshivering thermogenesis.
The functions of the "novel" UCPs, UCP2 and UCP3, are still not established.
Recent discussions imply that all UCPs may play a role in protection against
reactive oxygen species (ROS). Here we examine critically the evidence that
UCP1, UCP2 and UCP3 are stimulated by ROS (superoxide) or ROS products (4-hydroxy-2-nonenal),
and that the UCPs actually diminish oxidative damage. We conclude that,
concerning UCP1, it is unlikely that it has such a role; concerning UCP2/UCP3,
most evidence for physiologically significant roles in this respect is still
circumstantial.
Expression modification of uncoupling proteins and MnSOD in
retinal endothelial cells and pericytes induced by high glucose: the role of
reactive oxygen species in diabetic retinopathy.
Department of Ophthalmology, Shanghai First People's Hospital, 85 Wu Jin Road,
Shanghai 200080, PR China.
Uncoupling proteins (UCPs) are mitochondrial transporters present in the inner
membrane of mitochondria. They belong to the family of anion mitochondrial
carriers. UCPs could act as proton carriers activated by metabolites and
create a shunt between complexes of the respiratory chain and ATP synthase.
The increased leakiness of the mitochondrial inner membrane to protons may be
to minimize superoxide production by limiting the maximum Deltamu(H+). The
purpose of this study was to detect UCP expression in retinal capillary cells
and their modification in high levels of glucose. The role of reactive oxygen
species (ROS) of mitochondria and UCPs in pathogenesis of diabetic retinopathy
was investigated. Bovine retinal capillary endothelial cells and pericytes
were cultured with selective culture media, respectively. Passage cells were
cultured in three different glucose concentrations (5, 23, 30 mM) until
passage four. ROS changes in mitochondria of these cells in different glucose
concentrations were detected with scanning laser confocal microscopy (SLCM).
The mitochondria membrane potential (Deltapsi), cell death rate and apoptosis
rate were measured with flowing cytometry. UCP expression in retinal capillary
cells was detected by immunocytochemistry. Expression and modification of
MnSOD and uncoupling proteins (UCPs) in different concentrations of glucose
were detected by means of semi-quantitative RT-PCR. ROS in mitochondria of
both endothelial cells and pericytes increased as the glucose concentration of
media increased. Deltapsi and cell death rate of endothelial cells increased
also. ROS was correlated to Deltapsi and cell death rate positively in
endothelial cells. No difference in Deltapsi and cell death rate among
different glucose levels was found in pericytes. Apoptosis rate of endothelial
cells and pericytes in high glucose levels was higher than that in lower
glucose levels. UCP1 and UCP2 were expressed in cultured retinal capillary
cells whereas UCP3 was not. At high levels of glucose, expression of UCP1,
UCP2 and MnSOD increased to accommodate ROS production compensatively. The
compensative mechanism disappeared when glucose concentration was too high (30
mM). The results of this study showed that increasing mitochondrial ROS could
be induced by high glucose concentration. Those proteins related to
antioxidation mechanism, such as MnSOD and UCPs, could exert compensative
action to a certain extent. This compensative action was insufficient when the
glucose concentration was too high.
PMID: 16750827 [PubMed - indexed for MEDLINE]
20: Stem Cells.
2006 Sep;24(9):2110-9. Epub 2006 May 25.
Department of Biomedical Sciences, College of Veterinary Medicine 2052, Iowa
State University, Ames, 50011, USA.
Although the potential value of transplanted and endogenous neural stem cells
(NSCs) for the treatment of the impaired central nervous system (CNS) has
widely been accepted, almost nothing is known about their sensitivity to the
hostile microenvironment in comparison to surrounding, more mature cell
populations. Since many neuropathological insults are accompanied by oxidative
stress, this report compared the alertness of antioxidant defense mechanisms
and cell survival in NSCs and postmitotic neural cells (PNCs). Both primary
and immortalized cells were analyzed. At steady state, NSCs distinguished
themselves in their basal mitochondrial metabolism from PNCs by their lower
reactive oxygen species (ROS) levels and higher expression of the key
antioxidant enzymes uncoupling protein 2 (UCP2) and glutathione peroxidase (GPx).
Following exposure to the mitochondrial toxin 3-nitropropionic acid, PNC
cultures were marked by rapidly decreasing mitochondrial activity and
increasing ROS content, both entailing complete cell loss. NSCs, in contrast,
reacted by fast upregulation of UCP2, GPx, and superoxide dismutase 2 and
successfully recovered from an initial deterioration. This recovery could be
abolished by specific antioxidant inhibition. Similar differences between NSCs
and PNCs regarding redox control efficiency were detected in both primary and
immortalized cells. Our first in vivo data from the subventricular stem cell
niche of the adult mouse forebrain corroborated the above observations and
revealed strong baseline expression of UCP2 and GPx in the resident,
proliferating NSCs. Thus, an increased "vigilance" of antioxidant mechanisms
might represent an innate characteristic of NSCs, which not only defines their
cell fate, but also helps them to encounter oxidative stress in diseased CNS.
Centre For Cardiovascular Genetics, Royal Free and University College London
Medical School, The Rayne Institute, 5 University Street, London WC1E 6JJ,
U.K. d.gable@ucl.ac.uk
The impact of the UCP2 -866G>A and UCP3 -55C>T variants on prospective risk of
type 2 diabetes was examined over 15 years in 2,936 healthy middle-aged men (mean
age 56 years). Conversion to diabetes (n = 169) was associated with higher BMI,
blood pressure, cholesterol, triglycerides and C-reactive protein. The hazard
ratio (HR) for diabetes of a BMI >30 kg/m(2) was 3.96 (95% CI 2.87-5.47).
Homozygosity for the UCP2A or UCP3T alleles accelerated the onset of diabetes,
with significant differences in risk of diabetes at 10 years (HR [95% CI]
UCP2AA vs. GA+GG 1.94 [1.18-3.19], P = 0.009; UCP3TT vs. CC+ CT 2.06
[1.06-3.99], P = 0.03) but less so at 15 years (UCP2AA 1.42 [0.92-2.19], P =
0.1; UCP3TT 1.57 [0.87-2.04], P = 0.13). Men who were homozygous for both
UCP2AA and UCP3TT (1.5% of men) had a risk for diabetes at 10 years of 4.20
(1.70-10.37), P = 0.002. These genotype effects were additive with obesity,
and men with a BMI >30 kg/m(2) and this genotype combination had a 10-year
risk of diabetes of 19.23 [5.63-63.69], P < 0.0001. Functional promoter
variants UCP2 and UCP3 increase the prospective risk of diabetes. Although the
mechanism of the UCP2 effect is likely to be caused by increased expression in
the pancreas and subsequent reduced insulin secretion, the mechanism of the
UCP3 effect is currently unknown. Both effects are exacerbated by obesity.
Laboratory of Bioenergetics, Department of Life Sciences, Institute of
Chemistry B6c, University of Liege, Sart Tilman, B-4000 Liege, Belgium. f.sluse@ulg.ac.be
Uncoupling proteins (UCPs) are mitochondrial inner membrane proteins
sustaining an inducible proton conductance. They weaken the proton
electrochemical gradient built up by the mitochondrial respiratory chain.
Brown fat UCP1 sustains a free fatty acid (FA)-induced purine nucleotide (PN)-inhibited
proton conductance. Inhibition of the proton conductance by PN has been
considered as a diagnostic of UCP activity. However, conflicting results have
been obtained in isolated mitochondria for UCP homologues (i.e., UCP2, UCP3,
plant UCP, and protist UCP) where the FFA-activated proton conductance is
poorly sensitive to PN under resting respiration conditions. Our recent work
clearly indicates that the membranous coenzyme Q, through its redox state,
represents a regulator of the inhibition by PN of FFA-activated UCP1
homologues under phosphorylating respiration conditions. Several physiological
roles of UCPs have been suggested, including a control of the cellular energy
balance as well as the preventive action against oxidative stress. In this
paper, we discuss new information emerging from comparative proteomics about
the impact of UCPs on mitochondrial physiology, when recombinant UCP1 is
expressed in yeast and when UCP2 is over-expressed in hepatic mitochondria
during steatosis.
Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center,
Lund, Sweden. Gustav.Mattiasson@med.lu.se
The uncoupling proteins (UCPs) are attracting an increased interest as
potential therapeutic targets in a number of important diseases. UCP2 is
expressed in several tissues, but its physiological functions as well as
potential therapeutic applications are still unclear. Unlike UCP1, UCP2 does
not seem to be important to thermogenesis or weight control, but appears to
have an important role in the regulation of production of reactive oxygen
species, inhibition of inflammation, and inhibition of cell death. These are
central features in, for example, neurodegenerative and cardiovascular disease,
and experimental evidence suggests that an increased expression and activity
of UCP2 in models of these diseases has a beneficial effect on disease
progression, implicating a potential therapeutic role for UCP2. UCP2 has an
important role in the pathogenesis of type 2 diabetes by inhibiting insulin
secretion in islet beta cells. At the same time, type 2 diabetes is associated
with increased risk of cardiovascular disease and atherosclerosis where an
increased expression of UCP2 appears to be beneficial. This illustrates that
therapeutic applications involving UCP2 likely will have to regulate
expression and activity in a tissue-specific manner.
NO-1886 (ibrolipim), a lipoprotein lipase-promoting agent,
accelerates the expression of UCP3 messenger RNA and ameliorates obesity in
ovariectomized rats.
Department of Pharmacology, Hokkaido College of Pharmacy, Hokkaido 047-0264,
Japan.
The synthetic compound NO-1886 (ibrolipim, [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic
acid diethyl ester, CAS 133208-93-2) is a lipoprotein lipase (LPL)-promoting
agent that decreases plasma triglycerides, increases high-density lipoprotein
cholesterol levels, and prevents fat accumulation in high fat-fed rats.
However, the effect of NO-1886 on body weight, fat accumulation, and energy
expenditure in ovariectomized (OVX) rats is not clear. The primary aim of this
study was to ascertain whether NO-1886 ameliorated obesity in OVX rats and to
examine the effects on fatty acid oxidation-related enzymes. NO-1886 decreased
accumulation of visceral fat and suppressed the increase in body weight
resulting from the ovariectomy. NO-1886 decreased the respiratory quotient and
increased expression of the fatty acid translocase messenger RNA (mRNA) in the
liver, soleus muscle, and mesenteric fat. NO-1886 also increased the
expression of fatty acid-binding protein mRNA in the liver and soleus muscle
and the expression of the uncoupling protein 3 (UCP3) mRNA in the heart,
soleus muscle, and mesenteric fat, but not in the brown adipose tissue.
Furthermore, NO-1886 did not affect UCP1 and UCP2 in brown adipose tissue.
Therefore, amelioration of obesity by NO-1886 in OVX rats is possibly because
of an the increased expression of fatty acid oxidation-related enzymes and
UCP3, both of which are related to fatty acid transfer and fat use. Our study
indicates that the LPL-promoting agent NO-1886 may be potentially beneficial
in the treatment of obesity and obesity-linked health problems in
postmenopausal women.
Division of Endocrinology and Metabolism, Department of Medicine, University
of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
OBJECTIVE: We studied the association between polymorphisms in the UCP genes
and diabetes complications in patients with type 1 diabetes. RESEARCH DESIGN
AND METHODS: We analyzed 227 patients with type 1 diabetes using PCR and
subsequent cleavage by restriction endonucleases for the promoter variants
A-3826G in the UCP1 gene, G-866A in the UCP2 gene, and C-55T in the UCP3 gene.
RESULTS: No effect of the A-3826G polymorphism in the UCP1 gene on diabetes
complications was found. Patients who were heterozygous or homozygous for the
G-866A polymorphism in the UCP2 gene or the C-55T polymorphism in the UCP3
gene had a significantly reduced prevalence of diabetic neuropathy (UCP2: odds
ratio 0.44 [95% CI 0.24-0.79], P = 0.007; UCP3: 0.48 [0.25-0.92], P = 0.031),
whereas there was no association with other diabetes complications. This
effect was stronger when G-866A and C-55T occurred in a cosegregatory manner (UCP2
and UCP3: 0.28 [0.12-0.65], P = 0.002). Furthermore, a multiple logistic
regression model showed an age- and diabetes duration-independent effect of
the cosegregated polymorphisms on the prevalence of diabetic neuropathy (P =
0.013). CONCLUSIONS: Our data indicate that both the G-866A polymorphism in
the UCP2 gene and the C-55T polymorphism in the UCP3 gene are associated with
a reduced risk of diabetic neuropathy in type 1 diabetes. Thus, the results
presented here support the hypothesis that higher expression of uncoupling
protein might prevent mitochondria-mediated neuronal injury and, ultimately,
diabetic neuropathy.
Dept. of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido
University, Sapporo 060-0818, Japan.
Mitochondrial uncoupling protein-1 (UCP1) has been thought to be a key
molecule for thermogenesis during cold exposure and spontaneous hyperphagia
and thereby in the autonomic regulation of energy expenditure and adiposity.
However, UCP1 knockout (KO) mice were reported to be cold intolerant but
unexpectedly did not get obese even after hyperphagia, implying that UCP1 may
not be involved in the regulation of adiposity. Treatment of obese animals
with beta3-adrenergic agonists is known to increase lipid mobilization, induce
UCP1, and, finally, reduce body fat content. To obtain direct evidence for the
role of UCP1 in the anti-obesity effect of beta3-adrenergic stimulation, in
the present study, UCP1-KO and wild-type (WT) mice were fed on cafeteria diets
for 8 wk and then given a beta3-adrenergic agonist, CL-316,243 (CL), or saline
for 2 wk. A single injection of CL increased whole body oxygen consumption and
brown fat temperature in WT mice but not in KO mice, and it elicited almost
the same plasma free fatty acid response in WT and KO mice. WT and KO mice
increased similarly their body and white fat pad weights on cafeteria diets
compared with those on laboratory chow. Daily treatment with CL resulted in a
marked reduction of white fat pad weight and the size of adipocytes in WT mice,
but not in KO mice. Compared with WT mice, KO mice expressed increased levels
of UCP2 in brown fat but decreased levels in white fat and comparable levels
of UCP3. It was concluded that the anti-obesity effect of beta3-adrenergic
stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and
thereby to UCP1-dependent degradation of fatty acids released from white
adipose tissue.
Faculte de Medecine Necker-Enfants Malades, CNRS-UPR 9078, 156 rue de
Vaugirard, 75730, Paris, Cedex 15, France.
Mammals and birds are endotherms and respond to cold exposure by the means of
regulatory thermogenesis, either shivering or non-shivering. In this latter
case, waste of cell energy as heat can be achieved by uncoupling of
mitochondrial respiration. Uncoupling proteins, which belong to the
mitochondrial carrier family, are able to transport protons and thus may
assume a thermogenic function. The mammalian UCP1 physiological function is
now well understood and gives to the brown adipose tissue the capacity for
heat generation. But is it really the case for its more recently discovered
isoforms UCP2 and UCP3? Additionally, whereas more and more evidence suggests
that non-shivering also exists in birds, is the avian UCP also involved in
response to cold exposure? In this review, we consider the latest advances in
the field of UCP biology and present putative functions for UCP1 homologues.
Department of Medicine, Division of Medical Sciences, University of
Birmingham, Queen Elizabeth Hospital, UK.
The roles of uncoupling proteins (UCPs) are discussed. Particular attention
has been paid to the roles of UCP2 to UCP5 as agents mediating thermogenesis,
and to the concept of limited or "mild" uncoupling as a means of reducing
oxidative stress. The role of the endocrine system, thyroid hormones and
catecholamines, in regulating expression of UCPs is also discussed.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale
University School of Medicine, 333 Cedar Street, FMB 339, New Haven,
Connecticut 06510, USA.
Mitochondrial uncoupling mediated by uncoupling protein 1 (UCP1) is
classically associated with non-shivering thermogenesis by brown fat. Recent
evidence indicates that UCP family proteins are also present in selected
neurons. Unlike UCP1, these proteins (UCP2, UCP4 and BMCP1/UCP5) are not
constitutive uncouplers and are not crucial for non-shivering thermogenesis.
However, they can be activated by free radicals and free fatty acids, and
their activity has a profound influence on neuronal function. By regulating
mitochondrial biogenesis, calcium flux, free radical production and local
temperature, neuronal UCPs can directly influence neurotransmission, synaptic
plasticity and neurodegenerative processes. Insights into the regulation and
function of these proteins offer unsuspected avenues for a better
understanding of synaptic transmission and neurodegeneration.
BIOTRAM (Transporteurs Mitochondriaux et Metabolisme) CNRS UPR9078, Faculte de
Medecine Rene Descartes Paris 5, site Necker, 156 rue de Vaugirard 75730
Paris, France.
The proton-transport activity of UCP1 (uncoupling protein 1) triggers
mitochondrial uncoupling and thermogenesis. The exact role of its close
homologues, UCP2 and UCP3, is unclear. Mounting evidence associates them with
the control of mitochondrial superoxide production. Using CHO (Chinese-hamster
ovary) cells stably expressing UCP3 or UCP1, we found no evidence for
respiration uncoupling. The explanation lies in the absence of an appropriate
activator of UCP protonophoric function. Accordingly, the addition of retinoic
acid uncouples the respiration of the UCP1-expressing clone, but not that of
the UCP3-expressing ones. In a glucose-containing medium, the extent of the
hyperpolarization of mitochondria by oligomycin was close to 22 mV in the five
UCP3-expressing clones, contrasting with the variable values observed with the
15 controls. Our observations suggest that, when glycolysis and mitochondria
generate ATP, and in the absence of appropriate activators of proton transport,
UCPs do not transport protons (uncoupling), but rather other ions of
physiological relevance that control mitochondrial activity. A model is
proposed using the known passive transport of pyruvate by UCP1.
Department of Neurology, Washington University School of Medicine, St. Louis,
MO, USA.
Mitochondrial uncoupling proteins (UCPs), a subfamily of the mitochondrial
transporter family, are related by sequence homology to UCP1. This protein,
which is located in the inner mitochondrial membrane, dissipates the proton
gradient between the intermembrane space and the mitochondrial matrix to
uncouple electron transport from ATP synthesis. UCP1 (thermogenin) was first
discovered in brown adipose tissue and is responsible for non-shivering
thermogenesis. Expression of mRNA for three other UCP isoforms, UCP2, UCP4,
and BMCP1/UCP5, has been found at high levels in brain. However, the
physiological function(s) of UCPs in the brain have not been determined,
although it has recently been postulated that UCPs regulate free radical flux
from mitochondria by physiologically modulating mitochondrial membrane
potential. In the CNS, this hypothesis has been studied primarily for UCP2.
UCP2 message has been shown to be up-regulated in the CNS by stress signals
such as kainate administration or ischemia, and overexpression of UCP2 has
been reported to be neuroprotective against oxidative stress in vivo and in
vitro, although the exact mechanism has not been fully established. In this
review, studies on UCPs in the nervous system will be reviewed, and the
potential roles of these intriguing proteins in acute and chronic diseases of
the nervous system will be discussed.
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge, United Kingdom. martin.brand@mrc-dunn.cam.ac.uk
Evidence for the physiological functions of UCP2 and UCP3 is critically
reviewed. They do not mediate adaptive thermogenesis, but they may be
significantly thermogenic under specific pharmacological conditions. There is
strong evidence that the mild regulated uncoupling they cause attenuates
mitochondrial ROS production, protects against cellular damage, and diminishes
insulin secretion. Evidence that they export fatty acids physiologically is
weak. UCP2 and UCP3 are important potential targets for treatment of aging,
degenerative diseases, diabetes, and perhaps obesity.
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK.
The mitochondrial uncoupling proteins UCP2 and UCP3 may be important in
attenuating mitochondrial production of reactive oxygen species, in insulin
signalling (UCP2), and perhaps in thermogenesis and other processes. To
understand their physiological roles, it is necessary to know what reactions
they are able to catalyse. We critically examine the evidence for proton
transport and anion transport by UCP2 and UCP3. There is good evidence that
they increase mitochondrial proton conductance when activated by superoxide,
reactive oxygen species derivatives such as hydroxynonenal, and other alkenals
or their analogues. However, they do not catalyse proton leak in the absence
of such acute activation. They can also catalyse export of fatty acid and
other anions, although the relationship of anion transport to proton transport
remains controversial.
Increased uncoupling protein-2 mRNA abundance and
glucocorticoid action in adipose tissue in the sheep fetus during late
gestation is dependent on plasma cortisol and triiodothyronine.
Centre for Reproduction and Early Life, Institute of Clinical Research,
University of Nottingham NG7 2UH, UK.
The endocrine regulation of uncoupling protein-2 (UCP2), an inner
mitochondrial protein, in fetal adipose tissue remains unclear. The present
study aimed to determine if fetal plasma cortisol and triiodothyronine (T3)
influenced the mRNA abundance of UCP2, glucocorticoid receptor (GR) and
11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) and 2 (11betaHSD2) in
fetal adipose tissue in the sheep during late gestation. Perirenal-abdominal
adipose tissue was sampled from ovine fetuses to which either cortisol (2-3 mg
kg(-1) day(-1)) or saline was infused for 5 days up to 127-130 days gestation,
or near term fetuses (i.e. 142-145 days gestation) that were either
adrenalectomised (AX) or remained intact. Fetal plasma cortisol and T3
concentrations were higher in the cortisol infused animals and lower in AX
fetuses compared with their corresponding control group, and increased with
gestational age. UCP2 and GR mRNA abundance were significantly lower in AX
fetuses compared with age-matched controls, and increased with gestational age
and by cortisol infusion. Glucocorticoid action in fetal adipose tissue was
augmented by AX and suppressed by cortisol infusion, the latter also
preventing the gestational increase in 11betaHSD1 mRNA and decrease in
11betaHSD2 mRNA. When all treatment groups were combined, both fetal plasma
cortisol and T3 concentrations were positively correlated with UCP2, GR and
11betaHSD2 mRNA abundance, but negatively correlated with 11betaHSD1 mRNA
abundance. In conclusion, plasma cortisol and T3 are both required for the
late gestation rise in UCP2 mRNA and differentially regulate glucocorticoid
action in fetal adipose tissue in the sheep during late gestation.
PMID: 15961419 [PubMed - indexed for MEDLINE]
35: Clin Chem.
2005 Aug;51(8):1451-6. Epub 2005 Jun 10.
Division of Epidemiology, School of Public Health, University of Minnesota,
Minneapolis, MN 55454, USA.
BACKGROUND: Uncoupling proteins (UCPs) reduce ATP generation with concomitant
increased release of heat. The activities of UCPs have been related to obesity
and energy metabolism. METHODS: We investigated the association of the
commonly observed UCP2 Ala55Val (V) polymorphism with diabetes mellitus and
impaired fasting glucose (IFG) among 3684 participants in the Coronary Artery
Risk Development in Young Adults (CARDIA) study. RESULTS: The V frequency was
approximately 45% in blacks and 42% in whites. Those with the Val/Val (VV)
genotype had a higher incidence of diabetes than those having the Ala/Ala (AA)
genotype (5.8% vs 3.3%; P = 0.02). Similarly, the incidences of diabetes in
participants without abdominal obesity were 2.8% and 1.0% (P = 0.03) in the VV
and AA groups, and 12.4% and 8.3% (P = 0.15) in participants with abdominal
obesity. The incidence of IFG was higher in VV vs AA only in those without
abdominal obesity (12.9% vs 9.2%). These trends persisted in minimally and
fully adjusted models, and in strata of blacks and whites and men and women.
The homeostasis model assessment for insulin resistance was highest in VV in
the combined group of those with IFG or untreated diabetes, but not in those
with normal fasting glucose. CONCLUSION: The VV genotype of the UCP2
polymorphism was positively related to diabetes. It may involve increased
insulin resistance in those with impaired glucose homeostasis.
Department of Internal Medicine 1, School of Medicine, Faculty of Medicine,
Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan.
To examine the involvement of ghrelin in obesity, we investigated the effects
of treatment with peripherally administered ghrelin on food intake, adiposity,
and expression of uncoupling protein (UCP) mRNA in brown (BAT) and white (WAT)
adipose tissue in mice. Acute bolus administration of ghrelin at a dose of 120
nmol/kg increased cumulative food intake over 4 and 24 h as compared to
controls (p<0.05 for each), whereas 12 nmol/kg/day ghrelin showed no
remarkable effect (p>0.1). Chronic repeated treatment with 12 nmol/kg/day
ghrelin for 7 days increased body weight and adiposity assessed by the weight
of adipose tissue, triglyceride content in WAT (p<0.05 for each versus control).
In addition, the same treatment decreased and increased mRNA expression of BAT
UCP1 and WAT UCP2, respectively (p<0.05 for each). In conclusion, ghrelin can
regulate body weight, adiposity and UCPs mRNA expression in mice. The present
results provide evidence for a new regulatory loop involving ghrelin and UCP,
and add novel insights into the regulatory mechanisms of obesity.
Unite de Recherches Avicoles, Institut National de la Recherche Agronomique,
37380 Nouzilly, France. collin@tours.inra.fr
Thyroid hormones (THs) have long been known to be involved in the control of
thermoregulation in birds and mammals. In particular, they are reported to
play a role in the regulation of heat production. The underlying mechanisms
could be the stimulation of the nuclear and mitochondrial transcription of
several genes involved in energy metabolism and/or a direct action on the
activity of components of the mitochondrial respiratory chain. Attention has
recently been focussed on a subfamily of mitochondrial anion carriers called
uncoupling proteins (UCPs). These proteins are suspected to be involved in a
partial dissipation of the mitochondrial proton electrochemical gradient that
would uncouple phosphorylations from oxidations and hence produce heat.
However, the involvement of uncoupling mechanisms in thermogenesis and
particularly in the thermogenic effect of TH is still unclear. The thermogenic
role of UCP1, specifically expressed in brown adipose tissue, and its
regulation by TH in rodents is quite well recognised, but the involvement in
heat production of its mammalian homologues UCP2, ubiquitously expressed, and
UCP3, muscle and adipose tissue-specific, as well as the role of the muscular
avian UCP (avUCP), are to be further investigated. The expression of the UCP2
and UCP3 genes was shown to be enhanced by TH in muscle of several rodent
species, and to be increased in situations where thermogenesis is stimulated,
whereas results are more contrasted in pig. There is now increasing evidence
that the physiological role of the mammalian UCP3 and UCP2 is rather related
to lipid oxidation and/or prevention of reactive oxygen species accumulation
than to heat production by uncoupling. The expression of avUCP was also
recently demonstrated to be strongly regulated by thyroid status in chicken,
and overexpressed in experimental conditions favouring high triiodothyronine
concentrations and thermogenesis. However, its real uncoupling activity and
contribution to thermogenesis remain to be established.
Centre National de la Recherche Scientifique Unit 9078, Faculty of Medicine
Necker-Enfants Malades, Paris, France.
Metabolic energy expenditure negatively regulates energy balance. Metabolic
and catabolic pathways contribute to energy expenditure. Catabolic pathways
split C-containing molecules into small molecules and generate reduced
coenzymes and ATP. For a given amount of substrate, any increase in energy
expenditure requires either increased ATP hydrolysis or decreased ATP
synthesis. In skeletal muscles substrate utilisation is coupled to ATP
production, whereas ATP hydrolysis is activated during physical exercise and
increases energy expenditure. In brown adipose tissue activation of cells
during exposure to cold increases substrate utilisation in such a way that
glucose and fatty acid oxidation detach from the orthodox coupling to ATP
synthesis and result in thermogenesis. The unique mechanism of uncoupling
respiration that occurs in brown adipocyte mitochondria represents an
attractive strategy for promoting energy expenditure and decreasing the fat
content of the body. Moreover, ectopic expression of brown fat uncoupling
protein (UCP) 1 in mouse skeletal muscle and induction of UCP1 in mouse or
human white adipocytes promote fatty acid oxidation and resistance to obesity.
In normal conditions UCP2 and UCP3 do not seem to contribute substantially to
energy expenditure. Whether the induction of UCP1, the induction of other UCP
or chemical mild uncoupling represent promising strategies for attenuating
nutrient efficiency and counteracting obesity should be considered.
Neuroendocrine & Obesity Biology Unit, Liverpool Centre for Nutritional
Genomics, School of Clinical Sciences, University of Liverpool, UK. p.trayhurn@liverpool.ac.uk
Obesity is a multidisciplinary area, the 'biology' of which encompasses: (1)
the fundamental mechanisms of energy balance and its regulation; (2) the
biological basis for the development of obesity; (3) adipose tissue function;
(4) the biological description of the obese state; (5) the pathological
consequences of obesity; (6) the physiological basis for treatment strategies.
At a mechanistic level, important developments in recent years include the
identification of novel neuroendocrine factors in the control of appetite (such
as cocaine- and amphetamine-regulated transcript, the orexins, the
endocannabinoids) and the discovery of new peripheral signals (such as leptin,
ghrelin). Despite the identification of additional uncoupling proteins (UCP2,
UCP3), mitochondrial uncoupling in brown adipose tissue through UCP1 remains
the only major mechanism for adaptive thermogenesis. White adipose tissue (WAT)
has now moved centre stage in energy balance and obesity research, and there
are three main reasons: (1) it is the organ which defines obesity; (2) it is
the source of a critical endocrine signal in the control of body weight; (3)
it secretes a range of diverse protein factors, termed adipokines, some of
which are directly implicated in the pathologies associated with obesity. WAT
is now recognised as a key endocrine organ, communicating both with the brain
and peripheral tissues through the adipokines. Obesity is characterised by
mild inflammation, and WAT may be the main locus of the inflammatory state,
producing cytokines, chemokines, acute-phase proteins and angiogenic factors.
It has been suggested that inflammation in obesity is principally an adaptive
response to hypoxia in clusters of adipocytes within the expanding adipose
mass.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State
University, Moscow 119992, Russia. mokhova@genebee.msu.su
This paper considers stages of the search (initiated by V. P. Skulachev) for a
receptor protein for fatty acids that is involved in their uncoupling effect.
Based on these studies, mechanism of the ADP/ATP antiporter involvement in the
uncoupling induced by fatty acids was proposed. New data (suppression by
carboxyatractylate of the SDS-induced uncoupling, pH-dependence of the ADP/ATP
and the glutamate/aspartate antiporter contributions to the uncoupling, etc.)
led to modification of this hypothesis. During discussion of the uncoupling
effect of fatty acids caused by opening of the Ca(2+)-dependent pore, special
attention is given to the effects of carboxyatractylate added in the presence
of ADP. The functioning of the uncoupling protein UCP2 in kidney mitochondria
is considered, as well as the diversity observed by us in effects of 200
microM GDP on decrease in Deltapsi under the influence of oleic acid added
after H(2)O(2) (in the presence of succinate, oligomycin, malonate). A
speculative explanation of the findings is as follows: 1) products of lipid
and/or fatty acid peroxidation (PPO) modify the ADP/ATP antiporter in such a
way that its involvement in the fatty acid-induced uncoupling is suppressed by
GDP; 2) GDP increases the PPO concentration in the matrix by suppression of
efflux of fatty acid hydroperoxide anions through the UCP and/or of efflux of
PPO anions with involvement of the GDP-sensitive ADP/ATP antiporter; 3) PPO
can potentiate the oleate-induced decrease in Deltapsi due to inhibition of
succinate oxidation.
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess
Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston,
Massachusetts 02215, USA.
Uncoupling protein(UCP)1 is an integral membrane protein that is located in
the mitochondrial inner membrane of brown adipocytes. Its physiological role
is to mediate a regulated, thermogenic proton leak. UCP2 and UCP3 are recently
identified UCP1 homologues. They also mediate regulated proton leak, and might
function to control the production of superoxide and other downstream reactive
oxygen species. However, their role in normal physiology remains unknown.
Recent studies have shown that UCP2 has an important part in the pathogenesis
of type-2 diabetes. The obscure roles of the UCP homologues in normal
physiology, together with their emerging role in pathophysiology, provide
exciting potential for further investigation.
