Home About us Contact
|
Home About us Contact | ||
|
|
||
Metabolic Role (metabolic + role)
Selected AbstractsLactate kinetics in human tissues at rest and during exerciseACTA PHYSIOLOGICA, Issue 4 2010Gerrit Van Hall Abstract Lactate production in skeletal muscle has now been studied for nearly two centuries and still its production and functional role at rest and during exercise is much debated. In the early days skeletal muscle was mainly seen as the site of lactate production during contraction and lactate production associated with a lack of muscle oxygenation and fatigue. Later it was recognized that skeletal muscle not only played an important role in lactate production but also in lactate clearance and this led to a renewed interest, not the least from the Copenhagen School in the 1930s, in the metabolic role of lactate in skeletal muscle. With the introduction of lactate isotopes muscle lactate kinetics and oxidation could be studied and a simultaneous lactate uptake and release was observed, not only in muscle but also in other tissues. Therefore, this review will discuss in vivo human: (1) skeletal muscle lactate metabolism at rest and during exercise and suggestions are put forward to explain the simultaneous lactate uptake and release; and (2) lactate metabolism in the heart, liver, kidneys, brain, adipose tissue and lungs will be discussed and its potential importance in these tissues. [source] Fat as a fuel: emerging understanding of the adipose tissue,skeletal muscle axisACTA PHYSIOLOGICA, Issue 4 2010K. N. Frayn Abstract The early pioneers in the field of metabolism during exercise such as Lindhard and Krogh understood the importance of fat as a fuel for muscle contraction. But they could not have understood the details of the pathways involved, as neither the metabolic role of adipose tissue nor the transport role of non-esterified fatty acids (NEFA) in the plasma was clearly understood at the time. We now recognize that the onset of muscular contraction coincides with an increase in the delivery of NEFA from adipose tissue, probably coordinated by the sympatho-adrenal system. During light exercise, adipose tissue-derived NEFA make up the majority of the oxidative fuel used by muscle. As exercise is prolonged, the importance of NEFA increases. The onset of exercise is marked by an increased proportion of NEFAs entering ,-oxidation rather than re-esterification and recycling. At moderate intensities of exercise, other sources of fat, potentially plasma- and intramyocellular-triacylglycerol, supplement the supply of plasma NEFA. The delivery of NEFA is augmented by increased adipose tissue blood flow and by other stimuli such as atrial natriuretic peptide. Only during high-intensity exercise is there a failure of adipose tissue to deliver sufficient fatty acids for muscle (which is coupled with an inability of muscle to use them, even when fatty acids are supplied artificially). This limitation of adipose tissue NEFA delivery may reflect some feedback inhibition of lipolysis, perhaps via lactate, or possibly ,-adrenergic inhibition of lipolysis at very high catecholamine concentrations. [source] Glutamate spillover augments GABA synthesis and release from axodendritic synapses in rat hippocampusHIPPOCAMPUS, Issue 1 2010Misty M. Stafford Abstract Tight coupling between gamma-aminobutyric acid (GABA) synthesis and vesicle filling suggests that the presynaptic supply of precursor glutamate could dynamically regulate inhibitory synapses. Although the neuronal glutamate transporter excitatory amino acid transporter 3 (EAAT3) has been proposed to mediate such a metabolic role, highly efficient astrocytic uptake of synaptically released glutamate normally maintains low-extracellular glutamate levels. We examined whether axodendritic inhibitory synapses in stratum radiatum of hippocampal area CA1, which are closely positioned among excitatory glutamatergic synapses, are regulated by synaptic glutamate release via presynaptic uptake. Under conditions of spatially and temporally coordinated release of glutamate and GABA within pyramidal cell dendrites, blocking glial glutamate uptake enhanced quantal release of GABA in a transporter-dependent manner. These physiological findings correlated with immunohistochemical studies revealing expression of EAAT3 by interneurons and uptake of D-asparate into putative axodendritic inhibitory terminals only when glial uptake was blocked. These results indicate that spillover of glutamate between adjacent excitatory and inhibitory synapses can occur under conditions when glial uptake incompletely clears synaptically released glutamate. Our anatomical studies also suggest that perisomatic inhibitory synapses, unlike synapses within dendritic layers of hippocampus, are not capable of glutamate uptake and therefore transporter-mediated dynamic regulation of inhibition is a unique feature of axodendritic synapses that may play a role in maintaining a homeostatic balance of inhibition and excitation. © 2009 Wiley-Liss, Inc. [source] Fat tissue, aging, and cellular senescenceAGING CELL, Issue 5 2010Tamara Tchkonia Summary Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro-inflammatory, tissue-remodeling, senescent-like state. Other mesenchymal progenitors also can acquire a pro-inflammatory, adipocyte-like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro-inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress-responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent-like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro-inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role. [source] Transport characteristics of N -acetyl- l -aspartate in rat astrocytes: involvement of sodium-coupled high-affinity carboxylate transporter NaC3/NaDC3-mediated transport systemJOURNAL OF NEUROCHEMISTRY, Issue 3 2005Takuya Fujita Abstract We investigated in the present study the transport characteristics of N -acetyl- l -aspartate in primary cultures of astrocytes from rat cerebral cortex and the involvement of NA+ -coupled high-affinity carboxylate transporter NaC3 (formerly known as NaDC3) responsible for N -acetyl- l -aspartate transport. N -acetyl- l -aspartate transport was NA+ -dependent and saturable with a Michaelis,Menten constant (Km) of ,110 µm. NA+ -activation kinetics revealed that the NA+ to- N -acetyl- l -aspartate stoichiometry was 3 : 1 and concentration of Na+ necessary for half-maximal transport (KNAm) was 70 mm. NA+ -dependent N -acetyl- l -aspartate transport was competitively inhibited by succinate with an inhibitory constant (Ki) of 14.7 µm, which was comparable to the Km value of NA+ -dependent succinate transport (29.4 µm). l -Aspartate also inhibited NA+ -dependent [14C]N -acetyl- l -aspartate transport with relatively low affinity (Ki = 2.2 mm), whereas N -acetyl- l -aspartate was not able to inhibit NA+ -dependent aspartate transport in astrocytes. In addition, Li+ was found to have a significant inhibitory effect on the NA+ -dependent N -acetyl- l -aspartate transport in a concentration-dependent manner. Furthermore, RT,PCR and western blot analyses revealed that NaC3 is expressed in primary cultures of astrocytes. Taken collectively, these results indicate that NaC3 expressed in rat cerebrocortical astrocytes is responsible for NA+ -dependent N -acetyl- l -aspartate transport. This transporter is likely to be an essential prerequisite for the metabolic role of N -acetyl- l -aspartate in the process of myelination. [source] Pioglitazone in the treatment of NASH: the role of adiponectinALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2010A. Gastaldelli Summary Background, Plasma adiponectin is decreased in NASH patients and the mechanism(s) for histological improvement during thiazolidinedione treatment remain(s) poorly understood. Aim, To evaluate the relationship between changes in plasma adiponectin following pioglitazone treatment and metabolic/histological improvement. Methods, We measured in 47 NASH patients and 20 controls: (i) fasting glucose, insulin, FFA and adiponectin concentrations; (ii) hepatic fat content by magnetic resonance spectroscopy; and (iii) peripheral/hepatic insulin sensitivity (by double-tracer oral glucose tolerance test). Patients were then treated with pioglitazone (45 mg/day) or placebo and all measurements were repeated after 6 months. Results, Patients with NASH had decreased plasma adiponectin levels independent of the presence of obesity. Pioglitazone increased 2.3-fold plasma adiponectin and improved insulin resistance, glucose tolerance and glucose clearance, steatosis and necroinflammation (all P < 0.01,0.001 vs. placebo). In the pioglitazone group, plasma adiponectin was significantly associated (r = 0.52, P = 0.0001) with hepatic insulin sensitivity and with the change in both variables (r = 0.44, P = 0.03). Increase in adiponectin concentration was related also to histological improvement, in particular, to hepatic steatosis (r = ,0.46, P = 0006) and necroinflammation (r = ,0.56, P < 0.0001) but importantly also to fibrosis (r = ,0.29, P = 0.03). Conclusions, Adiponectin exerts an important metabolic role at the level of the liver, and its increase during pioglitazone treatment is critical to reverse insulin resistance and improve liver histology in NASH patients. [source] Therapeutic aspects of growth hormone and insulin-like growth factor-I treatment on visceral fat and insulin sensitivity in adultsDIABETES OBESITY & METABOLISM, Issue 1 2007K. C. J. Yuen Growth hormone (GH) is generally considered to exert anti-insulin actions, whereas insulin-like growth factor I (IGF-I) has insulin-like properties. Paradoxically, GH deficient adults and those with acromegaly are both predisposed to insulin resistance, but one cannot extrapolate from these pathological conditions to determine the normal metabolic roles of GH and IGF-I on glucose homeostasis. High doses of GH treatment have major effects on lipolysis, which plays a crucial role in promoting its anti-insulin effects, whereas IGF-I acts as an insulin sensitizer that does not exert any direct effect on lipolysis or lipogenesis. Under physiological conditions, the insulin-sensitizing effect of IGF-I is only evident after feeding when the bioavailability of circulating IGF-I is increased. In contrast, many studies in GH deficient adults have consistently shown that GH replacement improves the body composition profile although these studies differ considerably in terms of age, the presence or absence of multiple pituitary hormone deficiency, and whether GH deficiency was childhood or adult-onset. However, the improvement in body composition does not necessarily translate into improvements in insulin sensitivity presumably due to the anti-insulin effects of high doses of GH therapy. More recently, we have found that a very low dose GH therapy (0.1 mg/day) improved insulin sensitivity without affecting body composition in GH-deficient adults and in subjects with metabolic syndrome, and we postulate that these effects are mediated by its ability to increase free ,bioavailable' IGF-I without the induction of lipolysis. These results raise the possibility that this low GH dose may play a role in preventing the decline of ,-cell function and the development of type 2 diabetes in these "high risk" subjects. [source] Nucleotide variability and linkage disequilibrium patterns at the porcine FABP5 geneANIMAL GENETICS, Issue 5 2008A. Ojeda Summary Fatty acid binding protein 5 (FABP5) is a major positional and physiological candidate gene for the porcine FAT1 QTL on SSC4. Here we characterize the nucleotide polymorphism and haplotype variability of FABP5 and we compare it with that of FABP4, given their close physical location and similar metabolic roles. DNA resequencing of the FABP5 gene region in 29 pigs from 14 breeds and in European and Japanese wild boars revealed 36 polymorphisms in 5.2 kb, and a nucleotide diversity of 0.19%, comparable to values reported in other domestic species but sixfold lower than that previously found for FABP4. Remarkably, both the nucleotide variability and the haplotype structure of FABP5 and FABP4 were dramatically different, and the Hudson,Kreitman,Aguadé test was highly significant. Nevertheless, both genes also had similarities. The neighbour-joining trees of their haplotypes did not show a geographical arrangement for any of the genes. Besides, both genes presented a similar extent and pattern of linkage disequilibrium. Haplotype blocks did not extend for large stretches (,1 kb in both genes), and the number of tag SNPs required to capture all variability was higher than previously expected. Our findings indicate that FABP4 and FABP5 have undergone different selective or evolutive processes. The fact that haplotype blocks were so small may require us to increase the number of SNPs in prospective whole-genome association studies in the pig. [source] | |||||||||||||