Metabolic Overload Research Articles

Chronic High Glucose and Pyruvate Levels Differentially Affect Mitochondrial Bioenergetics and Fuel-stimulated Insulin Secretion from Clonal INS-1 832/13 Cells

Glucotoxicity in pancreatic β-cells is a well established pathogenetic process in type 2 diabetes. It has been suggested that metabolism-derived reactive oxygen species perturb the β-cell transcriptional machinery. Less is known about altered mitochondrial function in this condition. We used INS-1 832/13 cells cultured for 48 h in 2.8 mm glucose (low-G), 16.7 mm glucose (high-G), or 2.8 mm glucose plus 13.9 mm pyruvate (high-P) to identify metabolic perturbations. High-G cells showed decreased responsiveness, relative to low-G cells, with respect to mitochondrial membrane hyperpolarization, plasma membrane depolarization, and insulin secretion, when stimulated acutely with 16.7 mm glucose or 10 mm pyruvate. In contrast, high-P cells were functionally unimpaired, eliminating chronic provision of saturating mitochondrial substrate as a cause of glucotoxicity. Although cellular insulin content was depleted in high-G cells, relative to low-G and high-P cells, cellular functions were largely recovered following a further 24-h culture in low-G medium. After 2 h at 2.8 mm glucose, high-G cells did not retain increased levels of glycolytic or TCA cycle intermediates but nevertheless displayed increased glycolysis, increased respiration, and an increased mitochondrial proton leak relative to low-G and high-P cells. This notwithstanding, titration of low-G cells with low protonophore concentrations, monitoring respiration and insulin secretion in parallel, showed that the perturbed insulin secretion of high-G cells could not be accounted for by increased proton leak. The present study supports the idea that glucose-induced disturbances of stimulus-secretion coupling by extramitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.

Effect of Icodextrin on Heart Rate Variability in Diabetic Patients on Peritoneal Dialysis

Spectral analysis of heart rate variability is a noninvasive method for evaluating autonomic cardiovascular dysfunction under various clinical conditions, such as in dialysis patients, in whom an imbalance between the sympathetic and parasympathetic nervous system appears to be an important risk factor for sudden cardiovascular death and arrhythmia. ♢ We compared the effect of icodextrin-based dialysis solution, an option that allows for better metabolic and fluid overload control, with that of glucose-based dialysis fluid on sympathetic and parasympathetic activity in the heart, as assessed by heart rate variability, in diabetic patients on peritoneal dialysis (PD). ♢ This secondary analysis uses data from a randomized controlled trial in diabetic PD patients with high or high-average peritoneal transport using icodextrin-based (ICO group, n = 30) or glucose-based (GLU group, n = 29) solutions for the long dwell. All patients underwent 24-hour electrocardiographic Holter monitoring at baseline, and at 6 and 12 months of follow-up. ♢ We observed no significant differences between the groups in most of the variables analyzed, although values were, in general, below reference values. In the ICO group, total power and both low- and high-frequency power in normalized units increased, but the percentage of RR intervals with variation of more than 50 ms declined over time; in the GLU group, all those values declined. Plasma catecholamine levels were higher at baseline and declined over time. ♢ These results indicate a partial recovery of sympathetic activity in the ICO group, probably because of better extracellular fluid control and lower exposure to glucose with the use of icodextrin-based dialysis solutions.

Coordinated and Interactive Expression of Genes of Lipid Metabolism and Inflammation in Adipose Tissue and Liver during Metabolic Overload

BackgroundChronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT), often accompanied by non-alcoholic fatty liver disease (NAFLD). In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated.Methodology/Principal FindingsApoE*3Leiden mice were fed HFD or chow for different periods up to 12 weeks. Gene expression in WAT and liver over time was evaluated by micro-array analysis. WAT hypertrophy and inflammation were analyzed histologically. Bayesian hierarchical cluster analysis of dynamic WAT gene expression identified groups of genes (‘clusters’) with comparable expression patterns over time. HFD evoked an immediate response of five clusters of ‘lipid metabolism’ genes in WAT, which did not further change thereafter. At a later time point (>6 weeks), inflammatory clusters were induced. Promoter analysis of clustered genes resulted in specific key regulators which may orchestrate the metabolic and inflammatory responses in WAT. Some master regulators played a dual role in control of metabolism and inflammation. When WAT inflammation developed (>6 weeks), genes of lipid metabolism and inflammation were also affected in corresponding livers. These hepatic gene expression changes and the underlying transcriptional responses in particular, were remarkably similar to those detected in WAT.ConclusionIn WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time. Both processes may be controlled and interlinked by specific transcriptional regulators. When WAT inflammation began, the hepatic response to HFD resembled that in WAT. In all, WAT and liver respond to metabolic overload by adaptations in expression of gene clusters that control lipid metabolism and inflammatory processes in an orchestrated and interrelated manner.

Sarcolipin is a novel regulator of muscle based thermogenesis and metabolism in mammals

Sarcolipin (SLN) is a novel regulator of Sarco/Endoplasmic Reticulum Ca2+‐ATPase (SERCA) pump and it is expressed exclusively in striated muscle. Recent in‐vitro studies suggested that SLN can increase heat production by uncoupling SERCA‐mediated ATP hydrolysis from Ca2+ transport but its role in muscle physiology has not been established. To demonstrate that SLN is the basis for muscle thermogenesis in vivo, we challenged SLN−/− mice to acute cold (4°C). Here we show that SLN−/− mice without interscapular Brown Adipose Tissue (iBAT) failed to maintain core body temperature (Tc, 37°C) and died when exposed to acute cold (4°C), whereas wildtype (WT) mice without iBAT were able to maintain Tc. Overexpression of SLN in the null background fully restored muscle‐based thermogenesis, suggesting that SLN is the basis for SERCA‐mediated heat production. We found that curare mediated blockade of shivering in WT mice without iBAT did not significantly compromise thermogenesis indicating existence of non‐shivering thermogenesis (NST) in muscle. We show that Ryanodine receptor (RyR1)‐mediated Ca2+ leak is an important mechanism for SERCA‐activated heat generation. We also provide experimental data to suggest that SLN can interact with SERCA in the presence of Ca2+ and is thereby capable of promoting uncoupling of the SERCA pump and increasing heat production. We further demonstrate that loss of SLN predisposes mice to diet induced obesity, which suggests that SLN mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and this mechanism could be recruited in energy metabolism.

From laboratory to pilot plant E. coli fed-batch cultures: optimizing the cellular environment for protein maximization

For recombinant protein production in E. coli fed-batch cultures, post-induction conditions have great influence in the quantity and quality of the product. The present paper covers the effect of different factors affecting the cellular environment in recombinant aldolase (rhamnulose-1-phosphate aldolase, RhuA) production. An operational mode employing an exponential addition profile for constant specific growth rate has been analyzed, in order to understand and define possible modifications with influence on post-induction cellular behavior. A constant addition profile has been demonstrated to render higher specific aldolase production than the exponential addition profile, probably due to a more constant environment for the cells. On the other hand, amino acid (leucine) supplementation has proven to increase protein quality in terms of activity units (U) per unit mass of RhuA (Umg(-1)RhuA), alleviating metabolic overload. Based on the above, a production process was set up and scaled up to pilot plant. Resulting production was double that of a standard laboratory operation, 45,000UL(-1), and almost all the protein retained the 6xHis-tag with the highest quality, 11.3Umg(-1) RhuA.

Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice.

Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM). Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of T2DM and complications, and that removal of the metabolic overload with dietary interventions may be more efficacious. We explored the efficacy and systems effects of pharmaceutical interventions versus dietary lifestyle intervention (DLI) in developing T2DM and complications. To mimic the situation in humans, high fat diet (HFD)-fed LDLr−/− mice with already established disease phenotype were treated with ten different drugs mixed into HFD or subjected to DLI (switch to low-fat chow), for 7 weeks. Interventions were compared to untreated reference mice kept on HFD or chow only. Although most of the drugs improved HFD-induced hyperglycemia, drugs only partially affected other risk factors and also had limited effect on disease progression towards microalbuminuria, hepatosteatosis and atherosclerosis. By contrast, DLI normalized T2DM risk factors, fully reversed hepatosteatosis and microalbuminuria, and tended to attenuate atherogenesis. The comprehensive beneficial effect of DLI was reflected by normalized metabolite profiles in plasma and liver. Analysis of disease pathways in liver confirmed reversion of the metabolic distortions with DLI. This study demonstrates that the pathogenesis of T2DM towards complications is reversible with DLI and highlights the differential effects of current pharmacotherapies and their limitation to resolve the disease.

Nrf2 regulates antioxidative and liver regeneration promoting genes

The liver is frequently challenged by insults such as toxins and alcohol, viral infection or metabolic overload. In contrast to other organs, the liver has a unique capability to regenerate after injury. However, sustained presence of the damaging insult prolongs the regeneration response, resulting in liver fibrosis and cirrhosis or acute liver failure. Liver regeneration can be impaired by permanent oxidative stress mediated by the formation of reactive oxygen species (ROS). ROS are produced by metabolic intermediates of xenobiotics, mitochondrial leakage, induction of CYP2 family and activation of inflammatory cells. A crucial player in the defense against oxidative stress is the transcription factor NF-E2-related factor 2 (Nrf2). It has been shown that Nrf2 binds to the cis-acting enhancer element, antioxidant response element (ARE), controlling expression of many antioxidant proteins such as glutathione S-transferase and NADH quinone oxidoreductase 1. Furthermore it was demonstrated that Nrf2 plays a crucial liver regeneration after partial hepatectomy, ethanol or bile acid toxicity.

Effect of Iron-Mediated Oxidative Stress on Insulin Resistance Through the Forkhead Box-Containing Protein O Subfamily-1 (FOXO-1) Pathway in Chronic Hepatitis C

Aims: Chronic hepatitis C virus (HCV) infection is often associated with glucose metabolic disorders and iron overload. It has recently been shown that reactive oxygen species (ROS) increase gluconeogenesis in hepatocytes through the forkhead box-containing protein O subfamily-1 (FOXO1)-dependent pathway. The aim of this study is proving a cause-and-effect relationship between iron-mediated ROS production and insulin resistance (IR) in chronic hepatitis C (CH-C) patients. Methods: The study included 42 patients with CH-C (22 males and 20 females, median age 53 years). Homeostasis model assessment of insulin resistance (HOMA-IR) value was assessed for each patient at entry. Gene expression levels in the biopsied liver tissues were determined by quantitative reverse transcription-polymerase chain reaction (RT- PCR). In addition, the effect of ROS on gluconeogenesis was assessed using HepG2 cells treated with a well-known ROS generator, diethylmaleate (DEM). Results: The serum ferritin levels were significantly correlated with the serum aspartate aminotransferase level, alanine aminotransferase level, HOMA-IR value, grade of fatty accumulation, total hepatic iron score, and 8-OH-deoxy-2’-guanosine (8-OHdG)-positive cell count. FOXO1 expression was correlated with 8-OHdG-positive cell count, phosphoenolpyruvate carboxykinase (PEPCK) expression, and HOMA-IR. In HepG2 cells, the gene transcription of FOXO1 and PEPCK was increased by DEM treatment, which was associated with an increase in non-phosphorylated FOXO1 protein in the nuclear fraction. Conclusions: Iron-mediated ROS production enhances gluconeogenesis through the FOXO1-mediated pathway and is an affecting factor to IR in patients with CH-C.

Tracing Fatty Acid Metabolism by Click Chemistry

Fatty acids are abundant constituents of all biological systems, and their metabolism is important for normal function at all levels of an organism. Aberrations in fatty acid metabolism are associated with pathological states and have become a focus of current research, particularly due to the interest in metabolic overload diseases. Here we present a click-chemistry-based method that allows tracing of fatty acid metabolism in virtually any biological system. It combines high sensitivity with excellent linearity and fast sample turnover. Since it is free of radioactivity, it can be combined with any other modern analysis technology and can be used in high-throughput applications. Using the new method, we provide for the first time an analysis of cellular fatty metabolism with high time resolution and a comprehensive comparison of utilization of a broad spectrum of fatty acids in hepatoma and adipose cell lines.

Relationships between physiological indicators in blood, and their yield, as well as chemical composition of milk obtained from organic dairy cows

The occurrence of metabolic overload in cows maintained in organic herds is very likely, because organic production promotes feeding with high roughage diets and discourages supplementation with concentrates supplementation. It has the potential to negatively affect milk quality. The aim of this study was to determine the influence of physiological indicators in blood, reflecting the energy metabolism and liver status of dairy cows kept in organic herds, on the content of bioactive components in milk and the influence of lactation stage and feeding season on changes in milk components. A significant positive correlation was found between β-hydroxybutyric acid and the daily milk yield of lactating cows. β-Hydroxybutyric acid was negatively correlated with lactation phase and polyunsaturated fatty acids as well as saturated fatty acids content in milk. A significant negative correlation was observed between average daily milk yield and alanine aminotransferase concentration in blood. A low level of production in organic farms had a positive impact on the content of conjugated linoleic acid (20% increase), vitamin A (21% increase) and vitamin E (11% increase). The study has shown significant correlations between metabolic profiles and milk yields, as well as milk composition. In addition, there is evidence that the intensity of the production system significantly influences the metabolic profile and chemical composition of cow's milk. It could even be concluded that the ecological system affects not only the quality of milk, but also the health of cows.

Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals

The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca(2+), which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.

Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance

Activating transcription factor 6α (ATF6α) is essential for the endoplasmic reticulum (ER) stress response. Since recent studies suggested that ER stress is involved in the pathogenesis of type 2 diabetes mellitus, we have analyzed Atf6α-null (Atf6α−/−) mice challenged with metabolic overload or genetic manipulations. Atf6α−/− mice were fed a high-fat diet to create diet-induced obese (DO) mice, and were subjected to examination of glucose homeostasis with biochemical and morphological analysis of the pancreatic β-cell and liver tissues. Atf6α-null mice were also crossed with genetic models of diabetes caused either by insulin resistance (Agouti obese mice) or by impaired insulin secretion (Ins2WT/C96Y mice). Atf6α−/− DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6α−/− DO mice with the swollen β-cell ER, a typical feature of cells with ER stress. In the liver of Atf6α−/− DO mice, XBP-1 splicing was increased, suggesting that higher ER stress was present. ATF6-deficient mice showed increased mRNA expressions of glucose-6-phosphatase and SREBP1c associated with a tendency for a higher degree of steatosis in the liver. However, Atf6α−/− DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6α-deficient Agouti mice. In addition, ATF6α-deficiency accelerated reduction in pancreatic insulin content in Ins2WT/C96Y mice. These data suggested that ATF6α contributes to both prevention and promotion of diabetes; it protects β-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance.

Hepatocytes polyploidization and cell cycle control in liver physiopathology.

Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of “diploid-polyploid conversion” during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels), oxidative stress, toxic insult, and chronic hepatitis etc.). Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.

Effect of laser on the remnant liver after the first 24 hours following 70% hepatectomy in rats

To evaluate the mitochondrial function of the remnant liver (RL) in the early phase of liver regeneration in rats after 70% partial hepatectomy (PH). Sixty male Wistar rats (200-250g) submitted to 70% PH were divided into five groups according to the time of euthanasia and application or not of laser light: C = Control, time zero; 2 minutes, 4, 6 and 24 hours after PH. The dose of laser radiation was 22.5 J/cm(2), wavelength of 660 nm (visible/red), in the remnant liver. We studied the respiration activated by ADP (state 3), basal mitochondrial respiration (state 4), respiratory control ratio (RCR) and mitochondrial membrane potential (MMP). The mitochondrial function of RL changed at 4 and 6 hours after PH, with a significant increase in state 3 and a concomitant increase in state 4 and with maintenance of RCR. MMP differed significantly between the groups biostimulated with laser radiation and the control group 4 hours after HP, with a substantial reduction in the non-laser groups. The laser light at the dose used in this study did not induce additional damage to the RL and seems to have delayed the hepatocellular metabolic overload of the remnant liver.

Disruption of HIF-1α in hepatocytes impairs glucose metabolism in diet-induced obesity mice

The liver plays a central role in glucose homeostasis in the whole-body by responding to environmental factors including nutrients, hormones, and oxygen. In conditions of metabolic overload such as diabetes mellitus and obesity, coordinated regulation between oxygen supply and consumption has been reported to be disrupted and subsequently cause tissue hypoxia, although pathological significance of the disease-related hypoxia remains elusive. To investigate the role of tissue hypoxia in the liver on systemic glucose homeostasis, mice lacking HIF-1α gene, a critical component of a master regulator of hypoxic response, in hepatocytes were exposed to high fat/sucrose diet (HFSD). Exposure to HFSD for 5 weeks elicited liver hypoxia with a transient increase in HIF-1α protein expression in the liver of control mice. Glucose disposal was marginally impaired in control mice when challenged oral glucose tolerance test, but such impairment was enhanced in the mutant mice. This alteration was accompanied by a complete inhibition of glucokinase induction with a significant reduction of hepatic glucose uptake. Mice fed HFSD for 20 weeks exhibited fasting hyperglycemia and glucose intolerance, whereas these metabolic phenotypes deteriorated considerably with severe insulin resistance in skeletal muscles and adipose tissues in the mutant mice. These findings suggest that HIF-1 in hepatocytes plays protective roles against the progression of diabetes mellitus.

Inflammation and the metabolic syndrome.

Inflammation and the metabolic syndrome.

Culinary plants and their potential impact on metabolic overload

Contemporary human behavior has led a large proportion of the population to metabolic overload and obesity. Postprandial hyperlipidemia and hyperglycemia evoke redox imbalance in the short term and lead to complex chronic disease in the long term with repeated occurrence. Complex diseases are best prevented with complex components of plants; thus, current nutrition research has begun to focus on the development of plant-based functional foods and dietary supplements for health and well-being. Furthermore, given the wide range of species, parts, and secondary metabolites, culinary plants can contribute significant variety and complexity to the human diet. Although understanding the health benefits of culinary plants has been one of the great challenges in nutritional science due to their inherent complexity, it is an advantageous pursuit. This review will address the challenges and opportunities relating to studies of the health benefits of culinary plants, with an emphasis on obesity attributed to metabolic overload.

Nrf2, a transcription factor mainly involved in antioxidant defense, regulates the expression of ALR, Augmenter of Liver Regeneration

The liver is frequently challenged by so called metabolic overload, lipid accumulation, viruses or toxins, which induce the formation of reactive oxygen species (ROS). ROS can damage lipids, protein and DNA by peroxidation leading to complete degradation. A crucial player in the defense against oxidative stress is NF-E2-related factor 2 (Nrf2). The transcription factor Nrf2 is important for protecting cells against oxidative damage. It has been shown that Nrf2 binds to the antioxidant response element (ARE) controlling the expression of antioxidant proteins involved in the detoxification of harmful compounds. Additionally, Augmenter of Liver Regeneration (ALR) was reported to be upregulated in models of liver damage caused by oxidative stress. Recent micro array analysis demonstrated that Nrf2 regulates several cytoprotective proteins including ALR. Furthermore, promoter analysis of ALR predicts the presence of ARE, the potential binding site for Nrf2. Therefore, we aimed to verify whether Nrf2 is involved in the regulation of ALR expression. Treatment of primary human hepatocytes and HepG2 cells with tBHQ, a well known ARE-activator, induced mRNA and protein expression of ALR. Furthermore, the promoter activity of ALR was significantly induced after co-transfection of Nrf2 over control and dominant negative mutant of Nrf2 (dnNrf2). The functional impact of increased promoter activity after Nrf2-transfection was underlined by elevated mRNA and protein levels of ALR. In addition, we could show that ALR expression in livers from Nrf2-/- KO mice compared to Nrf2+/+ mice was attenuated during hepatic regeneration after a two-third hepatectomy. In conclusion, we demonstrated that the anti-oxidant transcription factor Nrf2 regulates the expression of ALR, and this regulation is mediated by activation of ARE. Thus, we speculate that ALR might play an important role as hepatotrophic factor against oxidative stress caused by different insults in the liver.

Urinary Excretion of Vitamin K Metabolites in Term and Preterm Infants: Relationship to Vitamin K Status and Prophylaxis

Little is known about the metabolic turnover and excretion of vitamin K in healthy newborn infants and the metabolic consequences of prophylactic regimens designed to protect against vitamin K deficiency bleeding (VKDB). We measured the excretion of two urinary metabolites (≤ 24 h) of vitamin K (5C- and 7C-aglycones) in term infants before (n = 11) and after (n = 5) a 1000 μg i.m. dose of vitamin K1 (K1) and in preterm infants after 200 μg i.m. (n = 4), 500 μg i.m. (n = 4), or 200 μg i.v. (n = 5). In preterm infants, we also measured serum K1, vitamin K1 2,3-epoxide, and PIVKA-II at 5 d postpartum. Before prophylaxis, the rate of 5C- and 7C-aglycone excretion was 25 times lower than adults, reflecting low vitamin K stores at birth. After prophylaxis, the excretion rate correlated to K1 dose (r = 0.6) but was two orders of magnitude lower than that in adults, probably reflecting the immaturity of neonatal catabolism. All term and 10 of 13 preterm infants mainly excreted 5C-aglycone. We present evidence that increased excretion of the 7C-aglycone was associated with metabolic overload because of the exposure to high-tissue K1 concentrations. Measurement of the 5C- and 7C-aglycones may facilitate longitudinal studies of vitamin K status in neonates and aid the development of improved prophylactic regimens.

Chronic Inflammation in Obesity and the Metabolic Syndrome

The increasing incidence of obesity and the metabolic syndrome is disturbing. The activation of inflammatory pathways, used normally as host defence, reminds the seriousness of this condition. There is probably more than one cause for activation of inflammation. Apparently, metabolic overload evokes stress reactions, such as oxidative, inflammatory, organelle and cell hypertrophy, generating vicious cycles. Adipocyte hypertrophy, through physical reasons, facilitates cell rupture, what will evoke an inflammatory reaction. Inability of adipose tissue development to engulf incoming fat leads to deposition in other organs, mainly in the liver, with consequences on insulin resistance. The oxidative stress which accompanies feeding, particularly when there is excessive ingestion of fat and/or other macronutrients without concomitant ingestion of antioxidant-rich foods/beverages, may contribute to inflammation attributed to obesity. Moreover, data on the interaction of microbiota with food and obesity brought new hypothesis for the obesity/fat diet relationship with inflammation. Beyond these, other phenomena, for instance psychological and/or circadian rhythm disturbances, may likewise contribute to oxidative/inflammatory status. The difficulty in the management of obesity/metabolic syndrome is linked to their multifactorial nature where environmental, genetic and psychosocial factors interact through complex networks.