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1.
PLoS One ; 9(12): e114790, 2014.
Article in English | MEDLINE | ID: mdl-25501421

ABSTRACT

BACKGROUND: Low-grade metabolic inflammation and hypertension are primary mechanisms involved in obesity-associated adverse health effects. Berries, especially Nordic wild blueberries (hereafter referred to as bilberries), represent an important source of dietary anthocyanins, a group of polyphenols with potential beneficial effects to combat obesity-associated metabolic disturbances. METHODS: The effects of 5% or 10% (w/w) of whole bilberries (BB) were studied on the development of obesity and its metabolic disturbances in C57BL mice fed with a high-fat diet (HFD) for three months. Cytokines, inflammatory cells, systolic blood pressure, glucose tolerance, insulin sensitivity, weight gain, body fat, food consumption and energy metabolism were assessed. RESULTS: Bilberries ameliorated type 1 pro-inflammatory responsiveness induced by HFD. This was indicated by the altered cytokine profile and the reduced prevalence of interferon gamma -producing T-cells, in particular T helper type 1 cells. Bilberries also prevented the progression of obesity associated long term increase in systolic blood pressure in mice. CONCLUSIONS: Bilberries reduce the development of systemic inflammation and prevent the progression of chronic hypertension, thus supporting their potential role in alleviating the adverse health effects associated with developing obesity.


Subject(s)
Diet, High-Fat/adverse effects , Hypertension/complications , Hypertension/drug therapy , Obesity/complications , Vaccinium myrtillus/chemistry , Adipokines/blood , Adipose Tissue/drug effects , Animals , Anthocyanins/pharmacology , Anthocyanins/therapeutic use , Biomarkers/blood , Blood Pressure/drug effects , Body Weight/drug effects , Cytokines/blood , Eating/drug effects , Energy Metabolism/drug effects , Glucose/metabolism , Immunomodulation/drug effects , Inflammation/complications , Inflammation/drug therapy , Insulin Resistance , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Obesity/immunology , Obesity/metabolism , Plant Extracts
2.
Int J Pharm ; 454(1): 67-73, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23834832

ABSTRACT

Recently, mesoporous silicon (PSi) microparticles have been shown to extend the duration of action of peptides, reducing the need for frequent injections. Glucagon-like peptide 1 (GLP-1) is a potential novel treatment for type 2 diabetes. The aim of this study was to evaluate whether GLP-1 loading into PSi microparticles reduce blood glucose levels over an extended period. GLP-1 (pI 5.4) was loaded and released from the negatively charged thermally oxidized (TOPSi, pI 1.8) and thermally carbonized (TCPSi, pI 2.6) PSi microparticles and from the novel positively charged amine modified microparticles, designated as TOPSi-NH2-D (pI 8.8) and TCPSi-NH2-D (pI 8.8), respectively. The adsorption of GLP-1 onto the PSi microparticles could be increased 3-4-fold by changing the PSi surface charge from negative to positive, indicating that the positive surface charge of PSi promoted an electrostatic interaction between the negatively charged peptide. All the GLP-1 loaded PSi microparticles lowered the blood glucose levels after a single s.c. injection but surprisingly, TOPSi-NH2-D and TCPSi-NH2-D were not able to prolong the effect when compared to TOPSi, TCPSi or GLP-1 solution. However, TOPSi-NH2-D and TCPSi-NH2-D microparticles were able to carry improved payloads of active GLP-1 encouraging continuing further attempts to achieve sustained release.


Subject(s)
Blood Glucose/drug effects , Drug Carriers , Glucagon-Like Peptide 1/pharmacology , Hypoglycemic Agents/pharmacology , Silicon/chemistry , Adsorption , Animals , Blood Glucose/metabolism , Chemistry, Pharmaceutical , Delayed-Action Preparations , Glucagon-Like Peptide 1/administration & dosage , Glucagon-Like Peptide 1/chemistry , Glucagon-Like Peptide 1/metabolism , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/metabolism , Injections, Subcutaneous , Male , Mice , Mice, Inbred C57BL , Particle Size , Porosity , Solubility , Surface Properties , Technology, Pharmaceutical/methods , Time Factors
3.
Mol Nutr Food Res ; 57(11): 1959-68, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23868375

ABSTRACT

SCOPE: Betaine (BET) reduces diet-induced liver lipid accumulation, and may relieve obesity-related metabolic disturbances. The aim of our study was to analyze metabolite alterations after supplementation of BET, polydextrose (PDX, a soluble dietary fiber), or their combination (BET PDX) via drinking water to C57BL/6J mice fed a high-fat (HF) diet. METHODS AND RESULTS: BET supplementation increased BET levels in plasma, muscle, and liver (p < 0.05), and the nontargeted LC-MS metabolite profiling revealed an increase in several metabolites in the carnitine biosynthesis pathway after BET supplementation both in liver and muscle. These included carnitine and acetylcarnitine (1.4-fold, p < 0.05), propionylcarnitine and γ-butyrobetaine (1.5-fold, p < 0.05), and several other short-chain acylcarnitines (p < 0.05) in muscle. These changes were slightly higher in the BET PDX group. Furthermore, BET reduced the HF diet induced accumulation of triglycerides in liver (p < 0.05). The supplementations did not attenuate the HF diet induced increase in body weight gain or the increase in adipose tissue mass. Instead, the combination of BET and PDX tended to increase adiposity. CONCLUSION: Our results suggest that increased availability of BET in different tissues, especially in muscle, after BET supplementation has an impact on carnitine metabolism, and this could further explain the link between BET and lipid metabolism.


Subject(s)
Betaine/administration & dosage , Carnitine/metabolism , Diet, High-Fat , Dietary Supplements , Liver/drug effects , Muscle, Skeletal/drug effects , Acetylcarnitine/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Adiposity/drug effects , Animals , Betaine/analogs & derivatives , Betaine/blood , Betaine/metabolism , Blood Glucose/metabolism , Carnitine/analogs & derivatives , Chromatography, Liquid , Fasting , Glucans/administration & dosage , Insulin/blood , Leptin/blood , Lipid Metabolism/drug effects , Liver/metabolism , Male , Mass Spectrometry , Metabolomics/methods , Mice , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , Obesity/metabolism , Triglycerides/blood , Weight Gain/drug effects
4.
Prog Neuropsychopharmacol Biol Psychiatry ; 37(2): 217-21, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22336057

ABSTRACT

Individuals with a history of childhood maltreatment present increased rates of metabolic disturbances, but the underlying mechanisms for such phenomena are poorly understood. This study examined whether the secretion of adipokines, adipocyte-derived inflammation markers closely associated with metabolic disorders, is altered in individuals with a history of childhood maltreatment. The serum levels of inflammatory markers adiponectin and resistin were measured from 147 general population participants who had a history of adverse mental symptoms, and who also reported their experiences of childhood maltreatment. Participants with experiences of childhood maltreatment (n=30) had lowered levels of serum adiponectin (p=0.007) and resistin (p=0.028). The differences in adiponectin levels persisted in multivariate modeling with adjustments for age, gender, and body mass index (OR for each 1 standard deviation decrease in the serum adiponectin level 2.65, 95% CI 1.31-5.35, p=0.007). Additional adjustments for marital status or a diagnosis of major depressive disorder, or the exclusion of individuals using NSAIDs, oral corticosteroids, or antidepressants did not alter the results. The association between resistin levels and childhood maltreatment did not remain independent in the same models. Our findings suggest that in individuals with previously reported adverse mental symptoms, a history of childhood maltreatment is independently associated with lowered levels of the anti-inflammatory marker adiponectin. This may lead to a lowered anti-inflammatory buffer capacity, which can, in turn, increase the susceptibility to physical and psychological states characterized by pronounced pro-inflammation.


Subject(s)
Adiponectin/blood , Adult Survivors of Child Abuse , Resistin/blood , Adult , Age Factors , Biomarkers/blood , Depressive Disorder, Major/blood , Female , Humans , Inflammation/blood , Male , Mental Health , Middle Aged , Sex Factors , Surveys and Questionnaires
5.
J Nutr Metab ; 2011: 525094, 2011.
Article in English | MEDLINE | ID: mdl-21977315

ABSTRACT

The potential of resveratrol to mimic beneficial effects of calorie restriction (CR) was investigated. We compared the effects of both CR (70% of ad libitum energy intake) or resveratrol (2 g/kg or 4 g/kg food) on high-fat diet-induced obesity and fatty liver formation in C57Bl/6J mice, and we examined their effects on calorimetry, metabolic performance, and the expressions of inflammatory genes and SIRT proteins. We found that resveratrol with 4 g/kg dose partially prevented hepatic steatosis and hepatocyte ballooning and induced skeletal muscle SIRT1 and SIRT4 expression while other examined parameter were unaffected by resveratrol. In contrast, CR provided superior protection against diet-induced obesity and fatty liver formation as compared to resveratrol, and the effects were associated with increased physical activity and ameliorated adipose tissue inflammation. CR increased expressions of SIRT3 in metabolically important tissues, suggesting that the beneficial effects of CR are mediated, at least in part, via SIRT3-dependent pathways.

6.
Prog Neuropsychopharmacol Biol Psychiatry ; 34(6): 846-51, 2010 Aug 16.
Article in English | MEDLINE | ID: mdl-20382196

ABSTRACT

Major depressive disorder (MDD) has been associated with dysregulated immune systems and impaired T cell function, but data on depression-related alterations in the levels of immunomodulatory growth factors are scarce. In order to further clarify the mechanisms underlying immune system dysregulation in depressed subjects, we examined the associations between MDD and serum levels of two immunomodulatory growth factors, interleukin (IL)-7 and granulocyte-colony stimulating factor (G-CSF), in 122 subjects (MDD with long-term symptomatology, n=61; controls, n=61). The MDD subjects had lowered levels of IL-7. In a model adjusted for age, gender and body mass index, subjects in the lowest tertile of IL-7 had a 3.4-fold increased likelihood for MDD (p=0.010). Further adjustments for sleep disturbances, alcohol use, smoking, and metabolic syndrome did not alter these findings. Moreover, the exclusion of subjects with rheumatoid arthritis, coronary heart disease, or the use of non-steroidal anti-inflammatory medications or oral corticosteroids only slightly attenuated the findings. The G-CSF levels did not differ between the two groups. The lowering of the serum levels of IL-7, a regulator of T cell homeostasis, in MDD subjects may underlie the depression-related impaired T cell function.


Subject(s)
Depressive Disorder, Major/blood , Granulocyte Colony-Stimulating Factor/blood , Interleukin-7/blood , Adult , Female , Humans , Male , Middle Aged , Odds Ratio , Psychiatric Status Rating Scales , Severity of Illness Index , Statistics, Nonparametric
7.
Cardiovasc Psychiatry Neurol ; 2010: 501349, 2010.
Article in English | MEDLINE | ID: mdl-20300596

ABSTRACT

Depression is an independent risk factor for cardiovascular diseases and is associated with metabolic syndrome (MetS). Levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue-type and urokinase-type plasminogen activators, are associated with MetS. To clarify the role of PAI-1 in subjects with long-term adverse mental symptomatology (LMS; including depression) and MetS, we measured circulating PAI-1 levels in controls (n = 111), in subjects with MetS and free of mental symptoms (n = 42), and in subjects with both MetS and long-term mental symptoms (n = 70). PAI-1 increased linearly across the three groups in men. In logistic regression analysis, men with PAI-1 levels above the median had a 3.4-fold increased likelihood of suffering from the comorbidity of long-term adverse mental symptoms and MetS, while no such associations were detected in women. In conclusion, our results suggest that in men high PAI-1 levels are independently associated with long-term mental symptomatology.

8.
Atherosclerosis ; 210(2): 479-85, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20056223

ABSTRACT

OBJECTIVE: Plasma adiponectin and high-density lipoprotein cholesterol (HDL-C) exhibit a well-known positive metabolic correlation. Neither heritability nor genome-wide linkage analysis for the high-molecular weight (HMW) adiponectin is available. This work estimates the genetic and environmental determinants and the heritabilities of the adiponectins and lipid traits in Finnish families with early onset coronary heart disease (CHD) and low HDL-C. METHODS: Heritability and genome-wide univariate linkage analysis was performed for total and HMW adiponectin in extended families from Northern Finland with early onset CHD and low HDL-C using a variance components approach. The genetic and environmental correlations between the plasma adiponectins and various lipid traits were also studied and a bivariate analysis for HDL-C and the adiponectins carried out. RESULTS: In the partial correlation analysis (adjusted for sex, age, BMI and statin use) the adiponectins showed a stronger correlation with HDL-C (total 0.57, p=0.001, HMW 0.51, p<0.005) than with any other lipid trait in unrelated subjects. Our estimates detected strong heritability for total (0.53+/-0.10), HMW (0.51+/-0.10) and the HMW/total adiponectin ratio (0.68+/-0.11). Univariate linkage analysis showed suggestive evidence of linkage on chromosome 11p15 for total adiponectin and on 3q13.2-q24 and 6p21 for the HMW adiponectin. The strongest environmental cross-correlation between the adiponectins and lipids was seen between HDL-C and total adiponectin (rhoe=0.64, p<0.05), whereas the strongest genetic correlation was detected between low-density lipoprotein cholesterol and the HMW adiponectin (rhog=-0.48, p<0.05). CONCLUSION: No significant genetic correlations between HDL-C and the adiponectins were observed. Therefore, the metabolic association between HDL-C and adiponectin is most likely regulated by complex genetic pathways and environmental factors.


Subject(s)
Adiponectin/genetics , Adiponectin/metabolism , Cholesterol, HDL/metabolism , Coronary Disease/genetics , Adult , Age of Onset , Chromosome Mapping , Coronary Disease/metabolism , Environment , Family Health , Female , Finland , Genome-Wide Association Study , Humans , Male , Middle Aged , Models, Genetic , Molecular Weight
9.
Psychoneuroendocrinology ; 35(2): 226-32, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19592174

ABSTRACT

OBJECTIVE: To examine the role of chemokines of two major chemokine families, CC and CXC, in major depressive disorder (MDD) in a population-based sample. METHOD: The serum levels of CC chemokines MCP-1 and MIP-1beta, and CXC chemokine IL-8 were measured from 122 participants (MDD group, n=61; controls, n=61). Depression severity was assessed with the 29-item Hamilton Depression Rating Scale. RESULTS: The MDD group had lower levels of MCP-1, MIP-1beta and IL-8 than the healthy controls. The likelihood of major depressive disorder for participants with chemokine levels below the median (MCP-1: < 26.26 pg/mL; MIP-1beta: < 42.57 pg/mL; IL-8: < 2.86 pg/mL) was 3.6 (p=0.002) for MIP-1beta and 2.4 (p=0.037) for IL-8 in regression models adjusted for age, gender, body mass index, smoking, and alcohol consumption. MCP-1 did not associate with the presence of MDD after adjustments for potential confounders. Further adjustments for somatic illnesses or medications did not affect these findings. CONCLUSION: Our findings suggest that depression-related alterations of inflammatory markers may be more complex than previously assumed, and that at least some of the chemokines may be down-regulated.


Subject(s)
Chemokines/blood , Depressive Disorder, Major/blood , Adult , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Case-Control Studies , Chemokine CCL2/analysis , Chemokine CCL2/blood , Chemokine CCL4/analysis , Chemokine CCL4/blood , Chemokines/analysis , Depressive Disorder, Major/drug therapy , Female , Humans , Interleukin-8/analysis , Interleukin-8/blood , Male , Middle Aged , Models, Statistical , Multivariate Analysis
10.
BMC Public Health ; 9: 410, 2009 Nov 12.
Article in English | MEDLINE | ID: mdl-19909544

ABSTRACT

BACKGROUND: Unemployment is a source of acute and long-term psychosocial stress. Acute and chronic psychosocial stress can induce pronounced changes in human immune responses. In this study we tested our hypothesis that stress-induced low-grade tissue inflammation is more prevalent among the unemployed. METHODS: We determined the inflammatory status of 225 general population subjects below the general retirement age (65 years in Finland). Those who had levels of both interleukin-6 (>or= 0.97 pg/mL) and high-sensitivity C-reactive protein (>or= 1.49 mg/L) above the median were assessed to have an elevated inflammatory status (n = 72). RESULTS: An elevated inflammatory status was more common among the unemployed than among other study participants (59% versus 30%, p = 0.011). In the final multivariate model, those who were unemployed had over five-fold greater odds for having an elevated inflammatory status (OR 5.20, 95% CI 1.55-17.43, p = 0.008). CONCLUSION: This preliminary finding suggests that stress-induced low-grade inflammation might be a link between unemployment and ill health.


Subject(s)
Inflammation/etiology , Stress, Psychological/complications , Unemployment/psychology , Adult , C-Reactive Protein/analysis , Economic Recession , Female , Finland , Humans , Interleukin-6/blood , Linear Models , Male , Middle Aged
11.
PLoS Genet ; 5(7): e1000543, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19578400

ABSTRACT

The mitochondrial beta-oxidation system is one of the central metabolic pathways of energy metabolism in mammals. Enzyme defects in this pathway cause fatty acid oxidation disorders. To elucidate the role of 2,4-dienoyl-CoA reductase (DECR) as an auxiliary enzyme in the mitochondrial beta-oxidation of unsaturated fatty acids, we created a DECR-deficient mouse line. In Decr(-/-) mice, the mitochondrial beta-oxidation of unsaturated fatty acids with double bonds is expected to halt at the level of trans-2, cis/trans-4-dienoyl-CoA intermediates. In line with this expectation, fasted Decr(-/-) mice displayed increased serum acylcarnitines, especially decadienoylcarnitine, a product of the incomplete oxidation of linoleic acid (C(18:2)), urinary excretion of unsaturated dicarboxylic acids, and hepatic steatosis, wherein unsaturated fatty acids accumulate in liver triacylglycerols. Metabolically challenged Decr(-/-) mice turned on ketogenesis, but unexpectedly developed hypoglycemia. Induced expression of peroxisomal beta-oxidation and microsomal omega-oxidation enzymes reflect the increased lipid load, whereas reduced mRNA levels of PGC-1alpha and CREB, as well as enzymes in the gluconeogenetic pathway, can contribute to stress-induced hypoglycemia. Furthermore, the thermogenic response was perturbed, as demonstrated by intolerance to acute cold exposure. This study highlights the necessity of DECR and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.


Subject(s)
Hypoglycemia/physiopathology , Ketone Bodies/biosynthesis , Mitochondria/enzymology , Oxidoreductases Acting on CH-CH Group Donors/deficiency , Stress, Physiological , Animals , Fatty Acids, Unsaturated/metabolism , Female , Glucose/metabolism , Hypoglycemia/enzymology , Hypoglycemia/genetics , Hypoglycemia/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/genetics , Mitochondria/metabolism , Oxidation-Reduction , Oxidoreductases Acting on CH-CH Group Donors/genetics , Triglycerides/metabolism
12.
Int J Circumpolar Health ; 67(2-3): 164-78, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18767337

ABSTRACT

OBJECTIVES: To review the current literature on the health effects of vitamin D, especially the effects on inhabitants living in the northern latitudes. STUDY DESIGN: Literature review. METHODS: The scientific literature concerning health effects of vitamin D was reviewed and the current dietary recommendations for inhabitants living in northern latitudes were discussed. RESULTS: Vitamin D is a steroid-structured hormone produced in the skin upon exposure to UVB-radiation or obtained from certain food products (for example, liver). Its production is mediated by the vitamin D receptor, which belongs to the nuclear receptor family, and exerts its function as a transcription factor regulating several target genes. Active metabolites of vitamin D play an important role in calcium and phosphate homeostasis. Deficiency of vitamin D results in diminished bone mineralization and an increased risk of fractures. In addition, vitamin D is connected to a variety of other diseases that include different cancer types, muscular weakness, hypertension, autoimmune diseases, multiple sclerosis, type 1 diabetes, schizophrenia and depression. CONCLUSIONS: Vitamin D plays a fundamental role in calcium and phosphate homeostasis. A deficiency of vitamin D has been attributed to several diseases. Since its production in the skin depends on exposure to UVB-radiation via the sunlight, the level of vitamin D is of crucial importance for the health of inhabitants who live in the Nordic latitudes where there is diminished exposure to sunlight during the winter season. Therefore, fortification or supplementation of vitamin D is necessary for most of the people living in the northern latitudes during the winter season to maintain adequate levels of circulating 25(OH)D3 to maintain optimal body function and prevent diseases.


Subject(s)
Vitamin D Deficiency/epidemiology , Vitamin D/metabolism , Arctic Regions , Calcification, Physiologic , Diet , Humans , Neoplasms/etiology , Nutrition Policy , Receptors, Calcitriol/metabolism , Vitamin D/biosynthesis , Vitamin D/toxicity , Vitamin D Deficiency/complications
13.
World J Gastroenterol ; 14(28): 4462-72, 2008 Jul 28.
Article in English | MEDLINE | ID: mdl-18680224

ABSTRACT

AIM: To characterise the effect of energy restriction (ER) on liver lipid and primary metabolite profile by using metabolomic approach. We also investigated whether the effect of energy restriction can be further enhanced by modification of dietary protein source and calcium. METHODS: Liver metabolomic profile of lean and obese C57Bl/6J mice (n = 10/group) were compared with two groups of weight-reduced mice. ER was performed on control diet and whey protein-based high-calcium diet (whey + Ca). The metabolomic analyses were performed using the UPLC/MS based lipidomic platform and the HPLC/MS/MS based primary metabolite platform. RESULTS: ER on both diets significantly reduced hepatic lipid accumulation and lipid droplet size, while only whey + Ca diet significantly decreased blood glucose (P < 0.001) and serum insulin (P < 0.01). In hepatic lipid species the biggest reduction was in the level of triacylglycerols and ceramides while the level of cholesterol esters was significantly increased during ER. Interestingly, diacylglycerol to phospholipid ratio, an indicator of relative amount of diabetogenic diglyceride species, was increased in the control ER group, but decreased in the whey + Ca ER group (P < 0.001, vs obese). ER on whey + Ca diet also totally reversed the obesity induced increase in the relative level of lipotoxic ceramides (P < 0.001, vs obese; P > 0.05, vs lean). These changes were accompanied with up-regulated TCA cycle and pentose phosphate pathway metabolites. CONCLUSION: ER-induced changes on hepatic metabolomic profile can be significantly affected by dietary protein source. The therapeutic potential of whey protein and calcium should be further studied.


Subject(s)
Calcium, Dietary/pharmacology , Dietary Proteins/pharmacology , Energy Metabolism/physiology , Fatty Liver/metabolism , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Body Weight/physiology , Disease Models, Animal , Fatty Liver/physiopathology , Insulin/blood , Lipid Metabolism/drug effects , Lipid Metabolism/physiology , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL
14.
J Mol Biol ; 372(2): 341-55, 2007 Sep 14.
Article in English | MEDLINE | ID: mdl-17669420

ABSTRACT

The nuclear receptors peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the metabolic syndrome. Here, we show that they are direct regulators of the family of pyruvate dehydrogenase kinase (PDK) genes, whose products act as metabolic homeostats in sensing hunger and satiety levels in key metabolic tissues by modulating the activity of the pyruvate dehydrogenase complex. Mis-regulation of this tightly controlled network may lead to hyperglycemia. In human embryonal kidney cells we found the mRNA expression of PDK2, PDK3 and PDK4 to be under direct primary control of PPAR ligands, and in normal mouse kidney tissue Pdk2 and Pdk4 are PPAR targets. Both, treatment of HEK cells with PPARbeta/delta-specific siRNA and the genetic disruption of the Pparbeta/delta gene in mouse fibroblasts resulted in reduced expression of Pdk genes and abolition of induction by PPARbeta/delta ligands. These findings suggest that PPARbeta/delta is a key regulator of PDK genes, in particular the PDK4/Pdk4 gene. In silico analysis of the human PDK genes revealed two candidate PPAR response elements in the PDK2 gene, five in the PDK3 gene and two in the PDK4 gene, but none in the PDK1 gene. For seven of these sites we could demonstrate both PPARbeta/delta ligand responsiveness in context of their chromatin region and simultaneous association of PPARbeta/delta with its functional partner proteins, such as retinoidXreceptor, co-activator and mediator proteins and phosphorylated RNA polymerase II. In conclusion, PDK2, PDK3 and PDK4 are primary PPARbeta/delta target genes in humans underlining the importance of the receptor in the control of metabolism.


Subject(s)
Gene Expression Regulation, Enzymologic , Multigene Family/genetics , PPAR delta/metabolism , PPAR-beta/metabolism , Protein Serine-Threonine Kinases/genetics , Animals , Cell Line , Humans , Mice , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Response Elements/genetics
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