Dietary Lipids and Dyslipidemia in Chronic Kidney Disease.

The progression of chronic kidney disease (CKD) leads to altered lipid metabolism. CKD patients exhibit high blood triglyceride (TG) levels, reduced concentrations and functionality of high-density lipoproteins (HDL), and elevated levels of atherogenic small, dense, low-density lipoproteins (sdLDL). Disorders of lipid metabolism and other metabolic disturbances place CKD patients at high risk for cardiovascular disease (CVD). Extensive evidence supports the cardioprotective effects of unsaturated fatty acids, including their beneficial effect on serum cholesterol and TG levels. Dietary lipids might therefore be especially important in the nutritional management of CKD. We review current dietary recommendations for fat intake by CKD patients and suggest potential nutritional interventions by emphasizing dietary lipids that might improve the blood lipid profile and reduce cardiovascular risk in CKD.

Polymorphism in exon 6 of the human NT5E gene is associated with aortic valve calcification.

NT5E encodes ecto-5'-nucleotidase (e5NT, CD73) which hydrolyses extracellular AMP to adenosine. Adenosine has been shown to play a protective role against aortic valve calcification (AVC). We identified two nonsynonymous missense single nucleotide polymorphisms (c.1126A > G, p.T376A and c.1136T > C, p.M379T) in exon 6 of the human NT5E gene. Since both substitutions might affect e5NT activity and consequently alter extracellular adenosine levels, we evaluated the association between NT5E alleles and calcific aortic valve disease in 119 patients (95 patients with AVC and 24 controls). In AVC patients, the frequency of the G allele at c.1126 and the frequency of the GG genotype as well as the frequency of the C allele at c.1136, and the frequencies of CC and TC genotypes tended to be higher as compared to controls. The allele and genotype frequencies in AVC patients and controls were also compared to those calculated from the 1000 Genomes Project data for control individuals of European ancestry (n = 503). We found that the frequency of the C allele at c.1136 is significantly higher in patients with AVC than in the European controls (0.111 vs. 0.054, P = 0.0052). Moreover, e5NT activity in aortic valves showed a trend toward lower levels in AVC patients with CC and TC genotypes than in those with the TT genotype. Our findings indicate that the genetic polymorphism of NT5E may contribute to the pathogenesis of calcific aortic valve disease and that the C allele of SNP c.1136 is associated with an increased risk of AVC.

Circulating leptin levels do not reflect the amount of body fat in the dunlin Calidris alpina during migration.

Leptin is a peptide hormone that plays an important role in the regulation of energy homeostasis. Studies in mammals have shown that circulating leptin levels reflect adiposity and that this adipocyte-derived cytokine acts as an afferent satiety signal to the brain, decreasing food intake and increasing energy expenditure. Since leptin has been found in the liver and adipose tissue of migratory birds that are able to accumulate fat reserves as endogenous fuel for flight, we hypothesized that individuals with higher fat score would have higher plasma leptin levels, as it had been found previously in mammals. The aim of this study was to determine if circulating leptin levels correlate with the amount of body fat in a migratory bird, the dunlin Calidris alpina. Adult dunlins were caught during autumn migration on the Baltic coast, and their fat score was determined. Blood samples from 150 birds were used to assess the levels of circulating leptin. We did not find any statistical differences between dunlins with various fat scores. In fact, plasma leptin levels tended to be lower in fat birds than in lean individuals. Our data indicate that in wild birds in migration mode leptin does not reflect the amount of accumulated fat. It suggests that leptin in birds during migration is neither involved in the regulation of energy homeostasis nor acts as a signal to control the amount of body fat.

Effects of DHEA on metabolic and endocrine functions of adipose tissue.

Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the major circulating adrenal steroids and serve as substrates for sex hormone biosynthesis. DHEA is effectively taken up by adipose tissue, where the concentrations of free DHEA are four to ten times higher than those found in the circulation. DHEA reduces adipose tissue mass and inhibits the proliferation and differentiation of adipocytes; it may also protect against obesity by lowering the activity of stearoyl-CoA desaturase 1 in fat cells. Recent studies demonstrate that DHEA stimulates triacylglycerol hydrolysis in adipose tissue by increasing the expression and activity of adipose triglyceride lipase and hormone-sensitive lipase, the key enzymes of lipolysis. DHEA has been shown to modulate insulin signaling pathways, enhance glucose uptake in adipocytes, and increase insulin sensitivity in patients with DHEA deficiency or abnormal glucose tolerance. Additionally, by suppressing the activity of 11ß-hydroxysteroid dehydrogenase 1 in adipocytes, DHEA may promote intra-adipose inactivation of cortisol to cortisone. Several studies have demonstrated that DHEA may also regulate the expression and secretion of adipokines such as leptin, adiponectin, and resistin. The effects of DHEA on adipokine expression in adipose tissue are depot-specific, with visceral fat being the most responsive. The mechanisms underlying DHEA actions in adipose tissue are still unclear; however, they involve nuclear receptors such as androgen receptor and peroxisome proliferator-activated receptors γ and α. Because clinical trials investigating the effects of DHEA failed to yield consistent results, further studies are needed to clarify the role of DHEA in the regulation of human adipose tissue physiology.

Fat-reducing effects of dehydroepiandrosterone involve upregulation of ATGL and HSL expression, and stimulation of lipolysis in adipose tissue.

Dehydroepiandrosterone (DHEA) reduces body fat in rodents and humans, and increases glycerol release from isolated rat epididymal adipocytes and human visceral adipose tissue explants. It suggests that DHEA stimulates triglyceride hydrolysis in adipose tissue; however, the mechanisms underlying this action are still unclear. We examined the effects of DHEA on the expression of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), the key enzymes of lipolysis, in rat epididymal white adipose tissue (eWAT). Male Wistar rats were fed a diet containing 0.6% DHEA for 2 weeks and eWAT was analyzed for mRNA and protein expression of ATGL and HSL, as well as mRNA expression of peroxisome proliferator-activated receptor γ 2 (PPARγ2) and its downstream target fatty acid translocase (FAT). Glycerol release from eWAT explants and serum free fatty acids (FFA) were also measured. Rats that received DHEA gained less weight, had 23% lower eWAT mass and 31% higher serum FFA levels than controls. Cultured explants of eWAT from DHEA-treated rats released 81% more glycerol than those from control rats. DHEA administration upregulated ATGL mRNA (1.62-fold, P<0.05) and protein (1.78-fold, P<0.05) expression as well as augmented HSL mRNA levels (1.36-fold, P<0.05) and Ser660 phosphorylation of HSL (2.49-fold, P<0.05). PPARγ2 and FAT mRNA levels were also increased in DHEA-treated rats (1.61-fold, P<0.05 and 2.16-fold, P<0.05; respectively). Moreover, ATGL, HSL, and FAT mRNA levels were positively correlated with PPARγ2 expression. This study demonstrates that DHEA promotes lipid mobilization in adipose tissue by increasing the expression and activity of ATGL and HSL. The effects of DHEA appear to be mediated, at least in part, via PPARγ2 activation, which in turn upregulates ATGL and HSL gene expression.

[Leptin as a mediator between obesity and cardiac dysfunction]. / Leptyna jako hormon laczacy otylosc z dysfunkcja miesnia sercowego.

Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and involved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue. These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients.

Intermittent fasting up-regulates Fsp27/Cidec gene expression in white adipose tissue.

OBJECTIVE: Fat-specific protein of 27 kDa (FSP27) is a novel lipid droplet protein that promotes triacylglycerol storage in white adipose tissue (WAT). The regulation of the Fsp27 gene expression in WAT is largely unknown. We investigated the nutritional regulation of FSP27 in WAT. METHODS: The effects of intermittent fasting (48 d, eight cycles of 3-d fasting and 3-d refeeding), caloric restriction (48 d), fasting-refeeding (3-d fasting and 3-d refeeding), and fasting (3 d) on mRNA expression of FSP27, peroxisome proliferator-activated receptor γ (PPARγ2), CCAAT/enhancer binding protein α (C/EBPα), and M isoform of carnitine palmitoyltransferase 1 (a positive control for PPARγ activation) in epididymal WAT and on serum triacylglycerol, insulin, and leptin levels were determined in Wistar rats. We also determined the effects of PPARγ activation by rosiglitazone or pioglitazone on FSP27 mRNA levels in primary rat adipocytes. RESULTS: Long-term intermittent fasting, in contrast to other dietary manipulations, significantly up-regulated Fsp27 gene expression in WAT. Moreover, in rats subjected to intermittent fasting, serum insulin levels were elevated; PPARγ2 and C/EBPα mRNA expression in WAT was increased, and there was a positive correlation of Fsp27 gene expression with PPARγ2 and C/EBPα mRNA levels. FSP27 mRNA expression was also increased in adipocytes treated with PPARγ agonists. CONCLUSION: Our study demonstrates that the transcription of the Fsp27 gene in adipose tissue may be induced in response to nutritional stimuli. Furthermore, PPARγ2, C/EBPα, and insulin may be involved in the nutritional regulation of FSP27. Thus intermittent fasting, despite lower caloric intake, may promote triacylglycerol deposition in WAT by increasing the expression of genes involved in lipid storage, such as Fsp27.

[Trans-fatty acids--effects on coronary heart disease]. / Trans-kwasy tluszczowe a ryzyko choroby wiencowej.

Trans-fatty acids (TFA) are formed during the industrial process of hydrogenation of vegetable oils. The consumption of hydrogenated fats has increased significantly over the last few decades. In Poland, the average daily intake of TFA for adults was estimated to be 2.8 to 6.9 g; which greatly exceeds the recommended daily maximum of 2 g/day (less than 1% of total energy intake). Increasing trans-fatty acid intake has detrimental effects on the lipid profile: TFA raise total cholesterol, LDL-cholesterol and triglyceride concentrations, and decrease HDL-cholesterol levels. Moreover, dietary trans-fatty acids may increase plasma levels of lipoprotein (a) and biomarkers of inflammation and endothelial dysfunction. Several studies have demonstrated that a high intake of TFA is associated with an increased risk of coronary heart disease. In addition, TFA consumption has been implicated as an independent risk factor for sudden cardiac arrest. It is therefore necessary to reduce the intake of hydrogenated fats rich in trans-fatty acids in order to minimize the adverse effects of TFA on health.

[Role of leptin in the regulation of lipid and carbohydrate metabolism]. / Rola leptyny w regulacji metabolizmu lipidów i weglowodanów.

Leptin is a hormone secreted primarily by adipose tissue and its blood levels depend on the amount of fat stored in adipocytes. Leptin has a wide range of physiological effects. Acting directly or through the sympathetic nervous system it participates in the regulation of energy metabolism. Leptin inhibits synthesis of triacylglycerols in the liver, adipose tissue and skeletal muscles, thus reducing the intracellular lipid content in these tissues. In adipocytes, leptin down-regulates the expression of genes encoding fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), the major enzymes of fatty acid synthesis, while it up-regulates the expression of the hormone-sensitive lipase (HSL) encoding gene, thus stimulating hydrolysis of triacylglycerols in adipose tissue. Moreover, leptin enhances fatty acid oxidation in adipocytes, and skeletal and cardiac muscle by increasing the expression of genes encoding key enzymes involved in this process, carnitine palmitoyltransferase 1 (CPT1) and medium chain acyl-CoA dehydrogenase (MCAD). It has also been demonstrated that this hormone improves insulin sensitivity and glucose tolerance by stimulating glucose transport and metabolism in many tissues. It is known that leptin is involved in the long-term regulation of food intake. However, increasing evidence suggests that it may also influence energy substrate utilization in peripheral tissues. Therefore, leptin can effectively control whole-body energy homeostasis by altering lipid and carbohydrate metabolism, especially in adipose tissue and muscles.

[Dietary trans-fatty acids and metabolic syndrome]. / Trans-kwasy tluszczowe w diecie--rola w rozwoju zespolu metabolicznego.

Trans-fatty acids (TFAs), products of partial hydrogenation of vegetable oils, have become more prevalent in our diet since the 1960s, when they replaced animal fats. TFAs also occur naturally in meat and dairy products from ruminants. There is growing evidence that dietary trans-fatty acids may increase the risk of metabolic syndrome. Several studies have demonstrated adverse effects of TFAs on plasma lipids and lipoproteins. In dietary trials, trans-fatty acids have been shown to raise the total cholesterol/HDL cholesterol ratio and Lp(a) levels in blood. Moreover, a high intake of TFAs has been associated with an increased risk of coronary heart disease. Prospective cohort studies have shown that dietary trans-fatty acids promote abdominal obesity and weight gain. In addition, it appears that TFA consumption may be associated with the development of insulin resistance and type 2 diabetes. The documented adverse health effects of TFAs emphasise the importance of efforts to reduce the content of partially hydrogenated vegetable oils in foods.

Up-regulation of NPY gene expression in hypothalamus of rats with experimental chronic renal failure.

Anorexia is possibly one of the most important causes of malnutrition in uremic patients. The cause of this abnormality is still unknown. Considering that: (a) NPY is one of the most important stimulants of food intake; (b) eating is a central nervous system regulated process and (c) NPY is expressed in hypothalamus, we hypothesized that the decrease of NPY gene expression in the hypothalamus could be an important factor contributing to anorexia associated with uremic state. In contrast to the prediction, the results presented in this paper indicate that the NPY gene expression in the hypothalamus of chronic renal failure (CRF) rats was significantly higher than in the hypothalamus of control (pair-fed) rats. Moreover, we found that serum NPY concentration in CRF rats was higher than in control (pair-fed) animals. The increase of plasma NPY concentration in CRF rats may be due to the greater synthesis of the neuropeptide in liver, since higher level of NPY mRNA was found in liver of CRF rats. The results obtained revealed that experimental chronic renal failure is associated with the increase of NPY gene expression in hypothalamus and liver of rats.

Leptin is synthesized in the liver and adipose tissue of the dunlin (Calidris alpina).

Fat is the main source of energy for birds during a long-distance flight. Migration routes are usually divided into several steps. In stopover sites migratory birds restore energy reserves needed for continuation of migration. During a long-distance flight and when foraging at a stopover site birds should be able to assess their actual reserves accumulated in the form of fat stores. The information about energy being stored in body reserves may be provided by circulating factors involved in body mass regulation, such as adipose-derived hormone leptin. To date, little is known about the expression and potential role of leptin in birds. The aim of the present study was to determine whether leptin is synthesized in the liver and adipose tissue of the dunlin (Calidris alpina), a long-distance migrant. Western blot analysis with leptin-specific antibody detected a protein with a molecular mass of approximately 15-16 kDa in dunlin liver and adipose tissue. To our knowledge, this is the first report demonstrating leptin expression in the liver and adipose tissue of a migratory bird. This finding raises the possibility that in birds leptin may signal the status of energy reserves during migratory flight.

Loss of ecto-5'nucleotidase from porcine endothelial cells after exposure to human blood: Implications for xenotransplantation.

The endothelial cell surface expression of ecto-5'-nucleotidase (E5'N, CD73) is thought to be essential for the extracellular formation of cytoprotective, anti-thrombotic and immunosuppressive adenosine. Decreased E5'N activity may play a role in xenograft acute vascular rejection, preventing accommodation and tolerance mechanisms. We investigated the extent of changes in E5'N activity and other enzymes of purine metabolism in porcine hearts or endothelial cells when exposed to human blood or plasma and studied the role of humoral immunity in this context. Pig hearts, wild type (WT, n = 6) and transgenic (T, n = 5) for human decay accelerating factor (hDAF), were perfused ex vivo with fresh human blood for 4 h. Pig aortic endothelial cells (PAEC) were exposed for 3 h to autologous porcine plasma (PP), normal (NHP) or heat inactivated human plasma (HHP), with and without C1-inhibitor. Enzyme activities were measured in heart or endothelial cell homogenates with an HPLC based procedure. The baseline activity of E5'N in WT and T porcine hearts were 6.60 +/- 0.33 nmol/min/mg protein and 8.54 +/- 2.10 nmol/min/mg protein respectively (P < 0.01). Ex vivo perfusion of pig hearts with fresh human blood for 4 h resulted in a decrease in E5'N activity to 4.01 +/- 0.32 and 4.52 +/- 0.52 nmol/min/mg protein (P < 0.001) in WT and T hearts respectively, despite attenuation of hyperacute rejection in transgenic pigs. The initial PAEC activity of E5'N was 9.10 +/- 1.40 nmol/min/mg protein. Activity decreased to 6.76 +/- 0.57 and 4.58 +/- 0.47 nmol/min/mg protein (P < 0.01) after 3 h exposure of HHP and NHP respectively (P < 0.05), whereas it remained unchanged at 9.62 +/- 0.88 nmol/min/mg protein when incubated with PP controls. C1-inhibitor partially preserved E5'N activity, similar to the effect of HHP. Adenosine deaminase, adenosine kinase and AMP deaminase (other enzymes of purine metabolism) showed a downward trend in activity, but none were statistically significant. We demonstrate a specific decrease in E5'N activity in pig hearts following exposure to human blood which impairs adenosine production resulting in a loss of a cytoprotective phenotype, contributing to xenograft rejection. This effect is triggered by human humoral immune responses, and complement contributes but does not fully mediate E5'N depletion.

Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma.

Dehydroepiandrosterone (DHEA), an adrenal steroid, is known to decrease body fat. Thus, it may also alter the endocrine functions of adipose tissue. The aim of this study was to determine if administration of DHEA might influence adiponectin gene expression and secretion from adipose tissue. We demonstrate here the inducing effect of exogenously administered DHEA on adiponectin gene expression in epididymal WAT and adiponectin levels in serum of rats fed a DHEA-containing diet (0.6%, w/w) for 2 weeks, accompanied by a reduction in epididymal adipose tissue mass. A corresponding increase in peroxisome proliferator-activated receptor gamma (PPAR(gamma)) mRNA expression suggests that PPAR(gamma) may be involved in the up-regulation of adiponectin gene expression after DHEA treatment. The presented observations indicate that the positive effects of DHEA, which seems to play a protective role against insulin resistance and atherosclerosis, may be in fact indirect and due to up-regulation of adiponectin gene expression and stimulation of adiponectin secretion from adipose tissue.

Effects of chronic administration of clenbuterol on function and metabolism of adult rat cardiac muscle.

Clenbuterol (Clen), a beta(2)-agonist, is known to produce skeletal and myocardial hypertrophy. This compound has recently been used in combination with left ventricular assist devices for the treatment of end-stage heart failure to reverse or prevent the adverse effects of unloading-induced myocardial atrophy. However, the mechanisms of action of Clen on myocardial cells have not been fully elucidated. In an attempt to clarify this issue, we examined the effects of chronic administration of Clen on Ca(2+) handling and substrate preference in cardiac muscle. Rats were treated with either 2 mg x kg(-1) x day(-1) Clen or saline (Sal) for 4 wk with the use of osmotic minipumps. Ventricular myocytes were enzymatically dissociated. Cells were field stimulated at 0.5, 1, and 2 Hz, and cytoplasmic Ca(2+) transients were monitored with the use of the fluorescent indicator indo-1 acetoxymethyl ester. Two-dimensional surface area and action potentials in current clamp were also measured. We found that in the Clen group there was significant hypertrophy at the organ and cellular levels compared with Sal. In Clen myocytes, the amplitude of the indo-1 ratio transients was significantly increased. Sarcoplasmic reticulum Ca(2+) content, estimated by rapid application of 20 mM caffeine, was significantly increased in the Clen group. The action potential was prolonged in the Clen group compared with Sal. Carbohydrate contribution to the tricarboxylic cycle (Krebs cycle) flux was increased several times in the Clen group. This increase was associated with decreased expression of peroxisome proliferator-activated receptor-alpha. This study shows that chronic administration of Clen induces cellular hypertrophy and increases oxidative carbohydrate utilization together with an increase in sarcoplasmic reticulum Ca(2+) content, which results in increased amplitude of the Ca(2+) transients. These effects could be important when Clen is used in conjunction with left ventricular assist devices treatment.

[Adiponectin gene polymorphism and protein dysfunction in the development of insulin resistance]. / Polimorfizm genu i zaburzenia funkcjonalne adiponektyny jako jedna z przyczyn rozwoju opornosci na insuline.

Adiponectin, an adipocyte-secreted protein encoded by the ACDC gene (also known as APM1), has been shown to play an important role in the regulation of fatty acid and glucose metabolism in liver and muscle, where it modulates insulin sensitivity. Adiponectin enhances fatty acid oxidation in liver and muscle, thus reducing triglyceride content in these tissues. Moreover, it stimulates glucose utilization in muscle and inhibits glucose production by the liver, consequently decreasing blood glucose levels. Plasma adiponectin levels are positively correlated with insulin sensitivity in humans. Circulating adiponectin forms a wide range of multimers. Mutations in the ACDC gene result in an impaired multimerization and/or impaired secretion of adiponectin from adipocytes, both linked to the development of insulin resistance and type II diabetes. This review focuses on the molecular mechanisms underlying hypoadiponectinemia associated with the diabetic phenotype. We further discuss the more recent findings that implicate adiponectin multimer formation as an important feature of the biological function of this adipocyte-derived hormone.

Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue.

Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in human blood, is considered to be one of fat-reducing hormones. However, the molecular mechanisms underlying DHEA mode of action in obesity has not been fully clarified. The pivotal role in the maintenance of cellular lipid and energy balance is played by peroxisome proliferator-activated receptor alpha (PPARalpha) which acts as transcriptional activator of numerous genes encoding enzymes involved in fatty acid catabolism. Lately published papers suggest that resistin, a low molecular-weight protein produced by adipose tissue, may act as an inhibitor of adipocyte differentiation and could regulate adipose tissue mass. Recent studies have established that the promoter region of the resistin gene contains several putative PPAR response elements. Since DHEA has been characterized as a peroxisome proliferator able to induce hepatic genes through PPARalpha, we hypothesised that DHEA might affect PPARalpha and, subsequently, resistin gene expression in adipose tissue. In order to test this hypothesis, an experiment was performed comparing PPARalpha and resistin gene expression in white adipose tissue (WAT) of male Wistar rats fed standard or DHEA-supplemented (0.6% (w/w)) diet for 2 weeks. DHEA administration to the rats induced PPARalpha and resistin gene expression in WAT (3- and 2.25-fold, respectively; as determined by real-time reverse transcription-polymerase chain reaction (RT-PCR)); reduced body weight, epididymal adipose tissue mass and decreased serum leptin levels. We propose that DHEA may impact on the transcription of resistin gene through a mechanism involving PPARalpha and that an elevated resistin level may lead to an inhibition of adipogenesis and a decrease in adipose tissue mass.

[Resistine--a new hormone secreted by adipose tissue (adipose tissue in insulin resistance)]. / Rezystyna--nowy hormon wydzielany przez tkanke tluszczowa (rola tkanki tluszczowej w rozwoju opornosci na insuline).

Obesity is an important risk factor for the development of insulin resistance and type 2 diabetes. The molecular mechanism linking obesity to insulin resistance is, however, unclear. Recently, a new circulating hormone resistine, which is expressed in adipose tissue, has been identified. Resistine has been shown to antagonize insulin action. Resistine levels are increased in diet-induced obesity as well as in genetic models of obesity and insulin resistance. Furthermore, resistine gene expression is markedly downregulated by treatment with anti-diabetic drugs called thiazolidinediones, that improve target-tissue sensitivity to insulin. It has been found that in human abdominal adipose tissue, which is thought to be a main risk factor for insulin resistance, amount of resistine mRNA is higher than in other fat depots. Resistine, therefore, may play a role in the pathogenesis of obesity-related insulin resistance.

Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart.

Cardiac hypertrophy in humans is associated with a decrease in myocardial fatty acid beta-oxidation (FAO) and accompanying alterations in metabolic gene expression. Flux through the cardiac FAO pathway, which is the principal source of energy production in the adult mammalian heart, is tightly controlled in accordance with energy demands. In rodents, the FAO pathway is under control of a nuclear peroxisome proliferator-activated receptor alpha (PPARalpha?. We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth in humans. We analysed the amount of PPARalpha protein in human cardiac tissue. PPARalpha protein level was measured in homogenates prepared from left ventricular biopsies taken from five control donor hearts and compared to the amount of this transcription factor in biopsies from five patients with compensated end-stage heart failure (HF) at the time of transplantation. Using Western blot analysis with a monoclonal antibody against human PPARalpha, we observed a significant decrease (54%) in the mean amount of PPARalpha in the group of HF patients compared to that in the donor tissue. This study indicates that the decrease in cardiac PPARalpha transcription factor gene expression observed in the failing human heart could play an important role in a reduction in fatty acid utilisation by the adult heart during cardiac hypertrophy.