Upregulation Of Uncoupling Protein Research Articles

Administration of a murine diet supplemented with conjugated linoleic acid increases the expression and activity of hepatic uncoupling proteins

Daily intake of conjugated linoleic acid (CLA) has been shown to reduce body fat accumulation and to increase body metabolism; this latter effect has been often associated with the up-regulation of uncoupling proteins (UCPs). Here we addressed the effects of a CLA-supplemented murine diet (~2% CLA mixture, cis-9, trans-10 and trans-10, cis-12 isomers; 45% of each isomer on alternating days) on mitochondrial energetics, UCP2 expression/activity in the liver and other associated morphological and functional parameters, in C57BL/6 mice. Diet supplementation with CLA reduced both lipid accumulation in adipose tissues and triacylglycerol plasma levels, but did not augment hepatic lipid storage. Livers of mice fed a diet supplemented with CLA showed high UCP2 mRNA levels and the isolated hepatic mitochondria showed indications of UCP activity: in the presence of guanosine diphosphate, the higher stimulation of respiration promoted by linoleic acid in mitochondria from the CLA mice was almost completely reduced to the level of the stimulation from the control mice. Despite the increased generation of reactive oxygen species through oxi-reduction reactions involving NAD(+)/NADH in the Krebs cycle, no oxidative stress was observed in the liver. In addition, in the absence of free fatty acids, basal respiration rates and the phosphorylating efficiency of mitochondria were preserved. These results indicate a beneficial and secure dose of CLA for diet supplementation in mice, which induces UCP2 overexpression and UCP activity in mitochondria while preserving the lipid composition and redox state of the liver.

Genipin Inhibits Mitochondrial Uncoupling Protein 2 Expression and Ameliorates Podocyte Injury in Diabetic Mice

Diabetic nephropathy (DN) is one of the most common causes of end stage renal disease (ESRD) in China, which requires renal replacement therapy. Recent investigations have suggested an essential role of podocyte injury in the initial stage of DN. This study investigated the potential therapeutic role of genipin, an active extract from a traditional Chinese medicine, on progression of DN in diabetic mice induced by intraperitoneally injection of streptozocin (STZ). In diabetic mice, orally administration of genipin postponed the progression of DN, as demonstrated by ameliorating body weight loss and urine albumin leakage, attenuating glomerular basement membrane thickness, restoring the podocyte expression of podocin and WT1 in diabetic mice. The protective role of genipin on DN is probably through suppressing the up-regulation of mitochondrial uncoupling protein 2 (UCP2) in diabetic kidneys. Meanwhile, through inhibiting the up-regulation of UCP2, genipin restores podocin and WT1 expression in cultured podocytes and attenuates glucose-induced albumin leakage through podocytes monolayer. Therefore, these results revealed that genipin inhibited UCP2 expression and ameliorated podocyte injury in DN mice.

Deep sequencing-based transcriptome profiling analysis of Oryzias melastigma exposed to PFOS

Oryzias melastigma is a newly emerging marine fish model. However, the application of this model has been restricted because of the lack of genomic information. Perfluorooctane sulfonate (PFOS), a persistent organic pollutant, is widely distributed in the estuarine/marine environment. The toxicological effects of PFOS on organisms, especially on marine fish species, remain largely unknown. In this study, the transcriptome of O. melastigma was sequenced using newly developed sequencing technology (Illumina RNA-seq). A total of 145,394 unigenes were obtained with 565bp of unigene N50. These genes were further enriched in various molecular pathways involved in the toxicological response. We also investigated the transcriptional response of O. melastigma embryos after PFOS exposure from 2 days post fertilization (dpf) to 6 dpf by digital gene expression (DGE) technology. The differentially expressed genes were related to neurobehavioral defects, mitochondrial dysfunction and the metabolism of proteins and fats. A further quantitative RT-PCR study showed the down-regulation of ATP synthase and the up-regulation of uncoupling protein 2 (UCP2), which indicated mitochondrial dysfunction. In all, the transcriptome data represent the most comprehensive expressed gene catalog for O. melastigma and will serve as an important reference for various marine fish that are yet to be sequenced. The transcriptome profiling of O. melastigma embryos after exposure to PFOS are also expected to improve our current understanding of the molecular toxicology of PFOS.

Activation of the AMP-Activated Protein Kinase by Eicosapentaenoic Acid (EPA, 20:5 n-3) Improves Endothelial Function In Vivo

The aim of the present study was to test the hypothesis that the cardiovascular-protective effects of eicosapentaenoic acid (EPA) may be due, in part, to its ability to stimulate the AMP-activated protein kinase (AMPK)-induced endothelial nitric oxide synthase (eNOS) activation. The role of AMPK in EPA-induced eNOS phosphorylation was investigated in bovine aortic endothelial cells (BAEC), in mice deficient of either AMPKα1 or AMPKα2, in eNOS knockout (KO) mice, or in Apo-E/AMPKα1 dual KO mice. EPA-treatment of BAEC increased both AMPK-Thr172 phosphorylation and AMPK activity, which was accompanied by increased eNOS phosphorylation, NO release, and upregulation of mitochondrial uncoupling protein-2 (UCP-2). Pharmacologic or genetic inhibition of AMPK abolished EPA-enhanced NO release and eNOS phosphorylation in HUVEC. This effect of EPA was absent in the aortas isolated from either eNOS KO mice or AMPKα1 KO mice fed a high-fat, high-cholesterol (HFHC) diet. EPA via upregulation of UCP-2 activates AMPKα1 resulting in increased eNOS phosphorylation and consequent improvement of endothelial function in vivo.

TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice

Nonalcoholic fatty liver is characterized by the fatty deformation and lipid deposition of hepatic parenchymal cells that are associated with cardiometabolic diseases. In this study, we report the effect of capsaicin on its receptor, transient receptor potential vanilloid 1 (TRPV1) cation channel, in preventing fatty liver formation. Functional TRPV1 has been detected in hepatocytes and liver tissues. TRPV1 activation by capsaicin reduced lipid accumulation and triglyceride level in the liver from wild-type (WT) mice. However, these effects were absent in the liver from TRPV1(-/-) mice. Chronic dietary capsaicin increased the hepatic uncoupling protein 2 (UCP2) expression in WT but not in TRPV1(-/-) mice (P < 0.01). We conclude that TRPV1 long-time activation might prevent high-fat diet-induced fatty liver in mice through upregulation of hepatic UCP2. Dietary capsaicin may represent a promising intervention in populations at high risk for fatty liver.

Upregulation of UCP2 by Adiponectin: The Involvement of Mitochondrial Superoxide and hnRNP K

BackgroundThe adipocyte-derived hormone adiponectin elicits protective functions against fatty liver diseases and hepatic injuries at least in part by stimulating the expression of a mitochondrial inner membrane transporter, uncoupling protein 2 (UCP2). The present study was designed to investigate the cellular and molecular mechanisms underlying adiponectin-induced UCP2 expression.Methodology/Principal FindnigsMice were treated with adiponectin and/or different drug inhibitors. Parenchymal (PCs) and nonparenchymal (NPCs) cells were fractionated from the liver tissues for mitochondria isolation, Western blotting and quantitative PCR analysis. Mitochondrial superoxide production was monitored by MitoSOX staining and flow cytometry analysis. Compared to control mice, the expression of UCP2 was significantly lower in NPCs, but not PCs of adiponectin knockout mice (AKO). Both chronic and acute treatment with adiponectin selectively increased the mRNA and protein abundance of UCP2 in NPCs, especially in the enriched endothelial cell fractions. The transcription inhibitor actinomycin D could not block adiponectin-induced UCP2 expression, whereas the protein synthesis inhibitor cycloheximide inhibited the elevation of UCP2 protein but not its mRNA levels. Mitochondrial content of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a nucleic acid binding protein involved in regulating mRNA transportation and stabilization, was significantly enhanced by adiponectin, which also evoked a transient elevation of mitochondrial superoxide. Rotenone, an inhibitor of mitochondrial respiratory complex I, abolished adiponectin-induced superoxide production, hnRNP K recruitment and UCP2 expression.Conclusions/SignificanceMitochondrial superoxide production stimulated by adiponectin serves as a trigger to initiate the translocation of hnRNP K, which in turn promotes UCP2 expressions in liver.

UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets

Uncoupling Protein 2 (UCP2) is expressed in the pancreatic β-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/− islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2−/− and GK+/− islets compared with GK+/− islets and UCP2 deficiency improved glucose tolerance of GK+/− mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/− mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

Mesenchymal Stromal Cells Protect Cancer Cells From ROS-induced Apoptosis and Enhance the Warburg Effect by Secreting STC1

Previous studies have demonstrated that mesenchymal stromal cells (MSCs) enhance cell survival through upregulation and secretion of stanniocalcin-1 (STC1). This study shows that MSC-derived STC1 promotes survival of lung cancer cells by uncoupling oxidative phosphorylation, reducing intracellular reactive oxygen species (ROS), and shifting metabolism towards a more glycolytic metabolic profile. MSC-derived STC1 upregulated uncoupling protein 2 (UCP2) in injured A549 cells in an STC1-dependent manner. Knockdown of UCP2 reduced the ability of MSCs and recombinant STC1 (rSTC1) to reduce cell death in the A549 population. rSTC1-treated A549 cells displayed decreased levels of ROS, mitochondrial membrane potential (MMP), and increased lactate production, all of which were dependent on the upregulation of UCP2. Our data suggest that MSCs can promote cell survival by regulating mitochondrial respiration via STC1.

Activation of AMP-Activated Protein Kinase Is Required for Berberine-Induced Reduction of Atherosclerosis in Mice: The Role of Uncoupling Protein 2

AimsBerberine, a botanical alkaloid purified from Coptidis rhizoma, is reported to activate the AMP-activated protein kinase (AMPK). Whether AMPK is required for the protective effects of berberine in cardiovascular diseases remains unknown. This study was designed to determine whether AMPK is required for berberine-induced reduction of oxidative stress and atherosclerosis in vivo.MethodsApoE (ApoE-/-) mice and ApoE-/-/AMPK alpha 2-/- mice that were fed Western diets were treated with berberine for 8 weeks. Atherosclerotic aortic lesions, expression of uncoupling protein 2 (UCP2), and markers of oxidative stress were evaluated in isolated aortas.ResultsIn ApoE-/- mice, chronic administration of berberine significantly reduced aortic lesions, markedly reduced oxidative stress and expression of adhesion molecules in aorta, and significantly increased UCP2 levels. In contrast, in ApoE-/-/AMPK alpha 2-/- mice, berberine had little effect on those endpoints. In cultured human umbilical vein endothelial cells (HUVECs), berberine significantly increased UCP2 mRNA and protein expression in an AMPK-dependent manner. Transfection of HUVECs with nuclear respiratory factor 1 (NRF1)-specific siRNA attenuated berberine-induced expression of UCP2, whereas transfection with control siRNA did not. Finally, berberine promoted mitochondrial biogenesis that contributed to up-regulation of UCP2 expression.ConclusionWe conclude that berberine reduces oxidative stress and vascular inflammation, and suppresses atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression.

Electrical stimulation of cerebellar fastigial nucleus up-regulates uncoupling protein 4 and stabilizes mitochondrial membrane potential in the cortex

Electrical stimulation of cerebellar fastigial nucleus up-regulates uncoupling protein 4 and stabilizes mitochondrial membrane potential in the cortex

Muramyl‐dipeptide‐induced mitochondrial proton leak in macrophages is associated with upregulation of uncoupling protein 2 and the production of reactive oxygen and reactive nitrogen species

The synthetic immunomodulator muramyl dipeptide (MDP) has been shown to induce, in vivo, mitochondrial proton leak. In the present work, we extended these findings to the cellular level and confirmed the effects of MDP in vitro on murine macrophages. The macrophage system was then used to analyse the mechanism of the MDP-induced mitochondrial proton leak. Our results demonstrate that the cellular levels of superoxide anion and nitric oxide were significantly elevated in response to MDP. Moreover, isolated mitochondria from cells treated with MDP presented a significant decrease in respiratory control ratio, an effect that was absent following treatment with a non-toxic analogue such as murabutide. Stimulation of cells with MDP, but not with murabutide, rapidly upregulates the expression of the mitochondrial protein uncoupling protein 2 (UCP2), and pretreatment with vitamin E attenuates upregulation of UCP2. These findings suggest that the MDP-induced reactive species upregulate UCP2 expression in order to counteract the effects of MDP on mitochondrial respiratory efficiency.

Feed restriction up-regulates uncoupling protein 3 (UCP3) gene expression in heart and red muscle tissues of gilthead sea bream ( Sparus aurata L.) : New insights in substrate oxidation and energy expenditure

The physiological regulation of the mitochondrial uncoupling protein 3 (UCP3) remains practically unexplored in fish and the aim of this study was to examine the effects of ration size on the regulation of UCP3 in heart, red skeletal muscle and white skeletal muscle of gilthead sea bream ( Sparus aurata L.). Juvenile fish were fed at three different levels for 11 weeks: i) full ration until visual satiety (R 100 group), ii) 70% of satiation (R 70 group) and iii) 70% of satiation with two finishing weeks at the maintenance ration (20% of the satiation level) (R 70–20 group). The thirty percent feed restriction improved fish performance, increasing feed conversion efficiency and circulating levels of insulin-like growth factor-I (IGF-I). Fish of the R 70–20 group showed reduced growth and low circulating levels of IGF-I in combination with increased circulating concentrations of growth hormone and free fatty acids. Feed restriction did not alter UCP3 transcript levels in white skeletal muscle, but improved this tissue's oxidative capacity as assessed by changes in glycolytic and oxidative mitochondrial enzyme activities. In contrast, in cardiac and red skeletal muscle tissues, this dietary treatment primarily increased UCP3 mRNA expression. The respiratory control ratio of freshly isolated heart mitochondria was slightly lower in R 70–20 fish than in R 100 fish, which suggests that there was an increase in mitochondrial uncoupling concomitant with the enhanced UCP3 mRNA expression. Altogether, these findings highlight the different adaptive mechanism of glycolytic and highly oxidative muscle tissues for their rapid adjustment to varying feed intake.

Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain

Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention.

Verification of the Antidiabetic Effects of Cinnamon (Cinnamomum zeylanicum) Using Insulin-Uncontrolled Type 1 Diabetic Rats and Cultured Adipocytes

It has long been believed that an intake of cinnamon (Cinnamomum zeylanicum) alleviates diabetic pathological conditions. However, it is still controversial whether the beneficial effect is insulin-dependent or insulin-mimetic. This study was aimed at determining the insulin-independent effect of cinnamon. Streptozotocin-induced diabetic rats were divided into four groups and orally administered with an aqueous cinnamon extract (CE) for 22 d. The diabetic rats that had taken CE at a dose of more than 30 mg/kg/d were rescued from their hyperglycemia and nephropathy, and these rats were found to have upregulation of uncoupling protein-1 (UCP-1) and glucose transporter 4 (GLUT4) in their brown adipose tissues as well as in their muscles. This was verified by using 3T3-L1 adipocytes in which CE upregulates GLUT4 translocation and increases the glucose uptake. CE exhibited its anti-diabetic effect independently from insulin by at least two mechanisms: i) upregulation of mitochondrial UCP-1, and ii) enhanced translocation of GLUT4 in the muscle and adipose tissues.

Maternal consumption of high-prebiotic fibre or -protein diets during pregnancy and lactation differentially influences satiety hormones and expression of genes involved in glucose and lipid metabolism in offspring in rats

Risk of developing the metabolic syndrome may be influenced by nutritional environment early in life. We examined the effects of high-fibre (HF) and high-protein (HP) diets consumed during pregnancy and lactation on satiety hormones and expression of genes involved in glucose and lipid metabolism in offspring. Wistar dams were fed a control (C), HF or HP diets during pregnancy and lactation. At parturition, litters were culled to ten pups. At 21 d, all pups were weaned onto C diet. At 7, 14, 21, 28 and 35 d after birth, blood was analysed for satiety hormones and tissues for mRNA expression in offspring. No differences were observed in litter size or birth weight. At 21 d, offspring of HF dams had greater adjusted intestinal mass and lower liver weight than those of C but not of HP dams. Plasma glucose at 28 d and amylin at 7, 14 and 28 d were lower in HF v. C and HP offspring. Glucagon-like peptide-1 was higher in HP offspring than in HF offspring at 7 d but was higher in HF v. C offspring at 21 d. Offspring of HF dams had higher glucose transporter (GLUT2 and Na+-dependent glucose/galactose transporter) mRNA expression at 21 d v. C and HP offspring. In brown adipose tissue, HF and HP up-regulated uncoupling protein-1 and PPAR-γ coactivator. HP was associated with increased resistin and IL-6 mRNA expression. The present study demonstrates that maternal diet composition differentially regulates circulating satiety hormones and genes involved in glucose transport and energy metabolism in offspring. These early changes could have long-term consequences for obesity risk.

Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice without adiponectin

The beneficial effects of rosiglitazone on non-alcoholic fatty liver disease (NAFLD) have been reported. Rosiglitazone treatment stimulates the production of adiponectin, an insulin-sensitizing adipokine with hepatoprotective functions. The present study aims to investigate the hepatic actions of rosiglitazone in mice without adiponectin. NAFLD was induced in wild type and adiponectin knockout (AKO) mice by high-fat diet feeding. After rosiglitazone treatment, mice were subjected to evaluations on systemic insulin sensitivity, lipid profiles, hepatic steatosis, and inflammation, as well as the expression and activity of key molecules involved in energy metabolism and mitochondrial functions. Rosiglitazone treatment prevented hepatic inflammation and reduced the expression of pro-inflammatory cytokines in livers of wild type mice. In contrast, in livers of AKO mice, the same treatment induced severe hepatomegaly and microvesicular hepatosteatosis, and caused abnormal accumulation of fatty acyl CoA, glycogen, and their intermediate metabolites. Compared to wild type littermates, the anti-inflammatory and the mitochondria-stimulatory activity of rosiglitazone were largely attenuated in AKO mice. Replenishment with either adiponectin or uncoupling protein 2 (UCP2) significantly reduced fatty acyl CoA accumulation and increased mitochondrial activities in livers of rosiglitazone-treated AKO mice. In addition, adiponectin, but not UCP2, promoted the activation of glycogen synthase kinase 3beta (GSK3beta), a key molecule involved in regulating glycogen homeostasis. Rosiglitazone elicits its protective functions against NAFLD largely through the induction of adiponectin, which prevents mitochondria stresses by promoting GSK3beta activation and UCP2 upregulation, two pathways coordinating the glucose and lipid metabolism in liver.

Oral Intake of Rosiglitazone Promotes a Central Antihypertensive Effect Via Upregulation of Peroxisome Proliferator-Activated Receptor-γ and Alleviation of Oxidative Stress in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Rosiglitazone, a synthetic ligand of transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), possesses a blood pressure-lowering effect beyond insulin sensitizing and glucose lowering. Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of neurogenic vasomotor tone are located, contributes to neural mechanisms of hypertension. Activation of PPAR-gamma protects against oxidative stress in RVLM by upregulation of mitochondrial uncoupling protein 2 (UCP2). We tested the hypothesis that oral intake of rosiglitazone exerts a central antihypertensive effect by ameliorating oxidative stress in RVLM via transcriptional upregulation of UCP2 after PPAR-gamma activation. In adult spontaneously hypertensive rats but not normotensive Wistar-Kyoto rats, oral intake of rosiglitazone for 1 week resulted in vasodepression and a reduction in the vasomotor components of the systemic arterial pressure spectrum, our experimental index for sympathetic vasomotor tone. These antihypertensive effects of rosiglitazone in spontaneously hypertensive rats were abrogated by microinjection bilaterally into RVLM of PPAR-gamma small interfering RNA. Oral intake of rosiglitazone also upregulated UCP2 and ameliorated the heightened superoxide anion level in RVLM of spontaneously hypertensive rats. Protection against oxidative stress in RVLM by rosiglitazone was abrogated by PPAR-gamma small interfering RNA or by antisense oligonucleotide against ucp2 mRNA. Gene knockdown of ucp2 in RVLM also reversed the antihypertensive effect of rosiglitazone. These results suggest that oral intake of rosiglitazone promotes a central antihypertensive effect by decreasing sympathetic vasomotor activity through a PPAR-gamma-dependent protection against oxidative stress in RVLM via transcriptional upregulation of the mitochondrial UCP2.

Oral intake of rosiglitazone promotes central antihypertensive effect via upregulation of mitochondrial uncoupling protein and alleviation of oxidative stress in rostral ventrolateral medulla of spontaneously hypertensive rats

Rosiglitazone, a synthetic ligand of transcription factor peroxisome proliferator‐activated receptor‐γ (PPARγ), possess blood pressure‐lowering effect beyond insulin sensitizing. We test the hypothesis that oral intake of rosiglitazone exerts central antihypertensive effect by amelioration of oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, via transcriptional upregulation of mitochondrial uncoupling protein 2 (UCP2). Oral intake of rosiglitazone resulted in vasodepression in adult spontaneously hypertensive rats (SHR) but not normotensive WKY rats. This antihypertensive effect of rosiglitazone was abrogated by microinjection bilaterally into RVLM of PPARγ small interfering RNA (siRNA). Oral intake of rosiglitazone also upregulated the UCP2 and ameliorated the heightened superoxide level in RVLM of SHR. Protection against oxidative stress in RVLM by rosiglitazone was abrogated by PPARγ siRNA or by knocking down ucp2 mRNA. The same treatments also reversed the antihypertensive effect of rosiglitazone. These results suggest that oral intake of rosiglitazone promotes central antihypertensive effect through a PPARγ‐dependent protection against oxidative stress in RVLM via transcriptional upregulation of UCP2. Supported by research grants NSC98‐2321‐B‐182A‐004 and NSC 97‐2321‐B075B‐001 from National Science Council, Taiwan.

Leucine Deprivation Decreases Fat Mass by Stimulation of Lipolysis in White Adipose Tissue and Upregulation of Uncoupling Protein 1 (UCP1) in Brown Adipose Tissue

OBJECTIVEWhite adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduction in abdominal fat mass. The cellular mechanisms responsible for this loss, however, are unclear. The goal of current study is to investigate possible mechanisms.RESEARCH DESIGN AND METHODSMale C57BL/6J mice were fed either control, leucine-deficient, or pair-fed diets for 7 days. Changes in metabolic parameters and expression of genes and proteins related to lipid metabolism were analyzed in WAT and BAT.RESULTSWe found that leucine deprivation for 7 days increases oxygen consumption, suggesting increased energy expenditure. We also observed increases in lipolysis and expression of β-oxidation genes and decreases in expression of lipogenic genes and activity of fatty acid synthase in WAT, consistent with increased use and decreased synthesis of fatty acids, respectively. Furthermore, we observed that leucine deprivation increases expression of uncoupling protein (UCP)-1 in BAT, suggesting increased thermogenesis.CONCLUSIONSWe show for the first time that elimination of dietary leucine produces significant metabolic changes in WAT and BAT. The effect of leucine deprivation on UCP1 expression is a novel and unexpected observation and suggests that the observed increase in energy expenditure may reflect an increase in thermogenesis in BAT. Further investigation will be required to determine the relative contribution of UCP1 upregulation and thermogenesis in BAT to leucine deprivation-stimulated fat loss.

Protective effects of peroxisome proliferator‐activated receptors γ coactivator‐1α against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia

Peroxisome proliferator-activated receptors gamma coactivator-1alpha (PGC-1alpha) may regulate the mitochondrial antioxidant defense system under many neuropathological settings. However, the exact role of PGC-1alpha in ischemic brain damage is still under debate. Based on an experimental model of transient global ischemia (TGI), this study evaluated the hypothesis that the activation of PGC-1alpha signaling pathway protects hippocampal CA1 neurons against delayed neuronal death after TGI. In Sprague-Dawley rats, significantly increased content of oxidized proteins in the hippocampal CA1 tissue was observed as early as 30 min after TGI, followed by augmentation of PGC-1alpha expression at 1 hr. Expression of uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2) in the hippocampal CA1 neurons was upregulated 4-48 hr after TGI. In addition, knock-down of PGC-1alpha expression by pretreatment with a specific antisense oligodeoxynucleotide in the hippocampal CA1 subfield downregulated the expression of UCP2 and SOD2 with resultant exacerbation of oxidative stress and augmentation of delayed neuronal cell death in the hippocampus after TGI. Overall, our results indicate that PGC-1alpha is induced by cerebral ischemia leading to upregulation of UCP2 and SOD2, thereby providing a neuroprotective effect against ischemic brain injury in the hippocampus by ameliorating oxidative stress.