Essential metabolism required for T and B lymphocyte functions: an update.

Lymphocytes act as regulatory and effector cells in inflammation and infection situations. A metabolic switch towards glycolytic metabolism predominance occurs during T lymphocyte differentiation to inflammatory phenotypes (Th1 and Th17 cells). Maturation of T regulatory cells, however, may require activation of oxidative pathways. Metabolic transitions also occur in different maturation stages and activation of B lymphocytes. Under activation, B lymphocytes undergo cell growth and proliferation, associated with increased macromolecule synthesis. The B lymphocyte response to an antigen challenge requires an increased adenosine triphosphate (ATP) supply derived mainly through glycolytic metabolism. After stimulation, B lymphocytes increase glucose uptake, but they do not accumulate glycolytic intermediates, probably due to an increase in various metabolic pathway 'end product' formation. Activated B lymphocytes are associated with increased utilization of pyrimidines and purines for RNA synthesis and fatty acid oxidation. The generation of plasmablasts and plasma cells from B lymphocytes is crucial for antibody production. Antibody production and secretion require increased glucose consumption since 90% of consumed glucose is needed for antibody glycosylation. This review describes critical aspects of lymphocyte metabolism and functional interplay during activation. We discuss the primary fuels for the metabolism of lymphocytes and the particularities of T and B cell metabolism, including the differentiation of lymphocytes, stages of development of B cells, and the production of antibodies.

Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1ß in type 2 diabetes.

Interleukin 1ß (IL-1ß) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1ß. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1ß production in vitro. Processing of IL-1ß initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1ß in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.

Butyrate Lowers Cellular Cholesterol through HDAC Inhibition and Impaired SREBP-2 Signalling.

In animal studies, HDAC inhibitors such as butyrate have been reported to reduce plasma cholesterol, while conferring protection from diabetes, but studies on the underlying mechanisms are lacking. This study compares the influence of butyrate and other HDAC inhibitors to that of statins on cholesterol metabolism in multiple cell lines, but primarily in HepG2 hepatic cells due to the importance of the liver in cholesterol metabolism. Sodium butyrate reduced HepG2 cholesterol content, as did sodium valproate and the potent HDAC inhibitor trichostatin A, suggesting HDAC inhibition as the exacting mechanism. In contrast to statins, which increase SREBP-2 regulated processes, HDAC inhibition downregulated SREBP-2 targets such as HMGCR and the LDL receptor. Moreover, in contrast to statin treatment, butyrate did not increase cholesterol uptake by HepG2 cells, consistent with its failure to increase LDL receptor expression. Sodium butyrate also reduced ABCA1 and SRB1 protein expression in HepG2 cells, but these effects were not consistent across all cell types. Overall, the underlying mechanism of cell cholesterol lowering by sodium butyrate and HDAC inhibition is consistent with impaired SREBP-2 signalling, and calls into question the possible use of butyrate for lowering of serum LDL cholesterol in humans.

Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer's Disease.

Alzheimer's disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.

Host cell glutamine metabolism as a potential antiviral target.

A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.

The HDAC Inhibitor Butyrate Impairs ß Cell Function and Activates the Disallowed Gene Hexokinase I.

Histone deacetylase (HDAC) inhibitors such as butyrate have been reported to reduce diabetes risk and protect insulin-secreting pancreatic ß cells in animal models. However, studies on insulin-secreting cells in vitro have found that butyrate treatment resulted in impaired or inappropriate insulin secretion. Our study explores the effects of butyrate on insulin secretion by BRIN BD-11 rat pancreatic ß cells and examined effects on the expression of genes implicated in ß cell function. Robust HDAC inhibition with 5 mM butyrate or trichostatin A for 24 h in ß cells decreased basal insulin secretion and content, as well as insulin secretion in response to acute stimulation. Treatment with butyrate also increased expression of the disallowed gene hexokinase I, possibly explaining the impairment to insulin secretion, and of TXNIP, which may increase oxidative stress and ß cell apoptosis. In contrast to robust HDAC inhibition (>70% after 24 h), low-dose and acute high-dose treatment with butyrate enhanced nutrient-stimulated insulin secretion. In conclusion, although protective effects of HDAC inhibition have been observed in vivo, potent HDAC inhibition impairs ß cell function in vitro. The chronic low dose and acute high dose butyrate treatments may be more reflective of in vivo effects.

The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes.

Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent partly on their state of activation and partly on the availability of various energy yielding and biosynthetic substrates (fatty acids, glucose, and amino acids). These substrates are essential to fuel-based metabolic reprogramming that supports optimal immune function, including the inflammatory response. In this review, we will focus on metabolism in macrophages and lymphocytes and discuss the role of fatty acids in governing the phenotype, activation, and functional status of these important cells. We summarize the current understanding of the pathways of fatty acid metabolism and related mechanisms of action and also explore possible new perspectives in this exciting area of research.

The Critical Role of Cell Metabolism for Essential Neutrophil Functions.

Neutrophils were traditionally considered as short-lived cells with abundant secretory and protein synthetic activity. Recent studies, however, indicate neutrophils are in reality a heterogeneous population of cells. Neutrophils differentiate from pluripotent stem cells in the bone marrow, and can further mature in the blood stream and can have different phenotypes in health and disease conditions. Neutrophils undergo primary functions such as phagocytosis, production of reactive oxygen species (ROS), release of lipid mediators and inflammatory proteins (mainly cytokines), and apoptosis. Neutrophils stimulate other neutrophils and trigger a cascade of immune and inflammatory responses. The underpinning intracellular metabolisms that support these neutrophil functions are herein reported. It has been known for many decades that neutrophils utilize glucose as a primary fuel and produce lactate as an end product of glycolysis. Neutrophils metabolize glucose through glycolysis and the pentose- phosphate pathway (PPP). Mitochondrial glucose oxidation is very low. The PPP provides the reduced nicotinamide adenine dinucleotide phosphate (NADPH) for the NADPH-oxidase (NOX) complex activity to produce superoxide from oxygen. These cells also utilize glutamine and fatty acids to produce the required adenosine triphosphate (ATP) and precursors for the synthesis of molecules that trigger functional outcomes. Neutrophils obtained from rat intraperitoneal cavity and incubate for 1 hour at 37°C metabolize glutamine at higher rate than that of glucose. Glutamine delays neutrophil apoptosis and maintains optimal NOX activity for superoxide production. Under limited glucose provision, neutrophils move to fatty acid oxidation (FAO) to obtain the required energy for the cell function. FAO is mainly associated with neutrophil differentiation and maturation. Hypoxia, hormonal dysfunction, and physical exercise markedly change neutrophil metabolism. It is now become clear that neutrophil metabolism underlies the heterogeneity of neutrophil phenotypes and should be intense focus of investigation.

Serum Vitamin D status is associated with increased blastocyst development rate in women undergoing IVF.

RESEARCH QUESTION: To determine the relationship between vitamin D (VitD) status and embryological, clinical pregnancy and live birth outcomes in women undergoing IVF. DESIGN: Cross-sectional, observational study conducted at a university-affiliated private IVF clinic. A total of 287 women underwent 287 IVF cycles and received a fresh embryo transfer. Patients had their serum 25-hydroxyvitamin D2/D3 (VitD) determined on the day of oocyte retrieval, which was analysed in relation to blastocyst development rate, clinical pregnancy and live birth outcomes. RESULTS: In stepwise, multivariable logistic regression models, increases in blastocyst development rate, number and quality, along with embryo cryopreservation and utilization rates were associated with women with a sufficient VitD status (≥20 ng/ml). For a single increase in the number of blastocysts generated per cycle or embryos cryopreserved per cycle, the likelihood for the patient to be VitD sufficient was increased by 32% (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.10-1.58, P = 0.002 and OR 1.33, 95% CI 1.10-1.60, P = 0.004, respectively). Clinical pregnancy (40.7% versus 30.8%, P = 0.086) and live birth rates (32.9% versus 25.8%, P = 0.195) in the sufficient VitD group versus the insufficient group were not significantly different and VitD sufficiency was not significantly associated with these outcomes. CONCLUSION: A strong relationship was observed between blastocyst development and VitD sufficiency. However, there was no association between VitD and clinical pregnancy or live birth outcomes. Further larger studies are needed to investigate whether the observed effect on blastocyst development may have downstream implications on subsequent clinical pregnancy or live birth rates, and on a potential mechanism where sufficient VitD concentrations are linked to improved IVF outcomes.

Butyrate generated by gut microbiota and its therapeutic role in metabolic syndrome.

Metabolic syndrome (MetS) and the associated incidence of cardiovascular disease and type 2 diabetes represents a significant contributor to morbidity and mortality worldwide. Butyrate, a short-chain fatty acid produced by the gut microbiome, has long been known to promote growth in farmed animals and more recently has been reported to improve body weight and composition, lipid profile, insulin sensitivity and glycaemia in animal models of MetS. In vitro studies have examined the influence of butyrate on intestinal cells, adipose tissue, skeletal muscle, hepatocytes, pancreatic islets and blood vessels, highlighting genes and pathways that may contribute to its beneficial effects. Butyrate's influences in these cells have been attributed primarily to its epigenetic effects as a histone deacetylase inhibitor, as well as its role as an agonist of free fatty acid receptors, but clear mechanistic evidence is lacking. There is also uncertainty whether results from animal studies can translate to human trials due to butyrate's poor systemic availability and rapid clearance. Hitherto, several small-scale human clinical trials have failed to show significant benefits in MetS patients. Further trials are clearly needed, including with formulations designed to improve butyrate's availability. Regardless, dietary intervention to increase the rate of butyrate production may be a beneficial addition to current treatment. This review outlines the current body of evidence on the suitability of butyrate supplementation for MetS, looking at mechanistic effects on the various components of MetS and highlighting gaps in the knowledge and roadblocks to its use in humans.

Reticulon-1 and Reduced Migration toward Chemoattractants by Macrophages Differentiated from the Bone Marrow of Ultraviolet-Irradiated and Ultraviolet-Chimeric Mice.

The ability of macrophages to respond to chemoattractants and inflammatory signals is important for their migration to sites of inflammation and immune activity and for host responses to infection. Macrophages differentiated from the bone marrow (BM) of UV-irradiated mice, even after activation with LPS, migrated inefficiently toward CSF-1 and CCL2. When BM cells were harvested from UV-irradiated mice and transplanted into naive mice, the recipient mice (UV-chimeric) had reduced accumulation of elicited monocytes/macrophages in the peritoneal cavity in response to inflammatory thioglycollate or alum. Macrophages differentiating from the BM of UV-chimeric mice also had an inherent reduced ability to migrate toward chemoattractants in vitro, even after LPS activation. Microarray analysis identified reduced reticulon-1 mRNA expressed in macrophages differentiated from the BM of UV-chimeric mice. By using an anti-reticulon-1 Ab, a role for reticulon-1 in macrophage migration toward both CSF-1 and CCL2 was confirmed. Reticulon-1 subcellular localization to the periphery after exposure to CSF-1 for 2.5 min was shown by immunofluorescence microscopy. The proposal that reduced reticulon-1 is responsible for the poor inherent ability of macrophages to respond to chemokine gradients was supported by Western blotting. In summary, skin exposure to erythemal UV radiation can modulate macrophage progenitors in the BM such that their differentiated progeny respond inefficiently to signals to accumulate at sites of inflammation and immunity.

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (ß-Amyloid; Aß). Both IAPP and Aß can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD. Here, we review the role of HSP in moderating T2D and AD, as well as propose that these chaperone proteins are an important link in the relationship between T2D and AD.

Oxidative stress pathways in pancreatic ß-cells and insulin-sensitive cells and tissues: importance to cell metabolism, function, and dysfunction.

It is now accepted that nutrient abundance in the blood, especially glucose, leads to the generation of reactive oxygen species (ROS), ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from antioxidant mechanisms, the cell, or indeed the tissue, becomes overwhelmed by oxidative stress, leading to the activation of intracellular stress-associated pathways. Activation of the same or similar pathways also appears to play a role in mediating insulin resistance, impaired insulin secretion, and late diabetic complications. The ability of antioxidants to protect against the oxidative stress induced by hyperglycemia and elevated free fatty acid (FFA) levels in vitro suggests a causative role of oxidative stress in mediating the latter clinical conditions. In this review, we describe common biochemical processes associated with oxidative stress driven by hyperglycemia and/or elevated FFA and the resulting clinical outcomes: ß-cell dysfunction and peripheral tissue insulin resistance.

Mechanisms of vitamin D action in skeletal muscle.

Vitamin D receptor expression and associated function have been reported in various muscle models, including C2C12, L6 cell lines and primary human skeletal muscle cells. It is believed that 1,25-hydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, has a direct regulatory role in skeletal muscle function, where it participates in myogenesis, cell proliferation, differentiation, regulation of protein synthesis and mitochondrial metabolism through activation of various cellular signalling cascades, including the mitogen-activated protein kinase pathway(s). It has also been suggested that 1,25(OH)2D3 and its associated receptor have genomic targets, resulting in regulation of gene expression, as well as non-genomic functions that can alter cellular behaviour through binding and modification of targets not directly associated with transcriptional regulation. The molecular mechanisms of vitamin D signalling, however, have not been fully clarified. Vitamin D inadequacy or deficiency is associated with muscle fibre atrophy, increased risk of chronic musculoskeletal pain, sarcopenia and associated falls, and may also decrease RMR. The main purpose of the present review is to describe the molecular role of vitamin D in skeletal muscle tissue function and metabolism, specifically in relation to proliferation, differentiation and protein synthesis processes. In addition, the present review also includes discussion of possible genomic and non-genomic pathways of vitamin D action.

Oleoyl-lysophosphatidylinositol enhances glucagon-like peptide-1 secretion from enteroendocrine L-cells through GPR119.

The gastrointestinal tract is increasingly viewed as critical in controlling glucose metabolism, because of its role in secreting multiple glucoregulatory hormones, such as glucagon like peptide-1 (GLP-1). Here we investigate the molecular pathways behind the GLP-1- and insulin-secreting capabilities of a novel GPR119 agonist, Oleoyl-lysophosphatidylinositol (Oleoyl-LPI). Oleoyl-LPI is the only LPI species able to potently stimulate the release of GLP-1 in vitro, from murine and human L-cells, and ex-vivo from murine colonic primary cell preparations. Here we show that Oleoyl-LPI mediates GLP-1 secretion through GPR119 as this activity is ablated in cells lacking GPR119 and in colonic primary cell preparation from GPR119-/- mice. Similarly, Oleoyl-LPI-mediated insulin secretion is impaired in islets isolated from GPR119-/- mice. On the other hand, GLP-1 secretion is not impaired in cells lacking GPR55 in vitro or in colonic primary cell preparation from GPR55-/- mice. We therefore conclude that GPR119 is the Oleoyl-LPI receptor, upstream of ERK1/2 and cAMP/PKA/CREB pathways, where primarily ERK1/2 is required for GLP-1 secretion, while CREB activation appears dispensable.

UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow-Differentiated Dendritic Cells.

A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow (BM) of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with BM from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the BM of nonirradiated mice, those from UV-irradiated mice produced more lactate, consumed more glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4-dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from BM of UV-irradiated mice. UV-induced prostaglandin E2 has been implicated as an intermediary in the effects of UV radiation on BM cells. DCs differentiating from BM cells pulsed in vitro for 2 hours with dimethyl prostaglandin E2 were functionally similar to those from the BM of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice.

Epigenetic effects of metformin: From molecular mechanisms to clinical implications.

There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.

Inducible nitric oxide synthase inhibitor 1400W increases Na+ ,K+ -ATPase levels and activity and ameliorates mitochondrial dysfunction in Ctns null kidney proximal tubular epithelial cells.

Nitric oxide (NO) has been shown to play an important role in renal physiology and pathophysiology partly through its influence on various transport systems in the kidney proximal tubule. The role of NO in kidney dysfunction associated with lysosomal storage disorder, cystinosis, is largely unknown. In the present study, the effects of inducible nitric oxide synthase (iNOS)-specific inhibitor, 1400W, on Na+ ,K+ -ATPase activity and expression, mitochondrial integrity and function, nutrient metabolism, and apoptosis were investigated in Ctns null proximal tubular epithelial cells (PTECs). Ctns null PTECs exhibited an increase in iNOS expression, augmented NO and nitrite/nitrate production, and reduced Na+ ,K+ -ATPase expression and activity. In addition, these cells displayed depolarized mitochondria, reduced adenosine triphosphate content, altered nutrient metabolism, and elevated apoptosis. Treatment of Ctns null PTECs with 1400W abolished these effects which culminated in the mitigation of apoptosis in these cells. These findings indicate that uncontrolled NO production may constitute the upstream event that leads to the molecular and biochemical alterations observed in Ctns null PTECs and may explain, at least in part, the generalized proximal tubular dysfunction associated with cystinosis. Further studies are needed to realize the potential benefits of anti-nitrosative therapies in improving renal function and/or attenuating renal injury in cystinosis.

Molecular actions of vitamin D in reproductive cell biology

Vitamin D (VitD) is an important secosteroid and has attracted attention in several areas of research due to common VitD deficiency in the population, and its potential to regulate molecular pathways related to chronic and inflammatory diseases. VitD metabolites and the VitD receptor (VDR) influence many tissues including those of the reproductive system. VDR expression has been demonstrated in various cell types of the male reproductive tract, including spermatozoa and germ cells, and in female reproductive tissues including the ovaries, placenta and endometrium. However, the molecular role of VitD signalling and metabolism in reproductive function have not been fully established. Consequently, the aim of this work is to review current metabolic and molecular aspects of the VitD­VDR axis in reproductive medicine and to propose the direction of future research. Specifically, the influence of VitD on sperm motility, calcium handling, capacitation, acrosin reaction and lipid metabolism is examined. In addition, we will also discuss the effect of VitD on sex hormone secretion and receptor expression in primary granulosa cells, along with the impact on cytokine production in trophoblast cells. The review concludes with a discussion of the recent developments in VitD­VDR signalling specifically related to altered cellular bioenergetics, which is an emerging concept in the field of reproductive medicine.

A past and present overview of macrophage metabolism and functional outcomes.

In 1986 and 1987, Philip Newsholme et al. reported macrophages utilize glutamine, as well as glucose, at high rates. These authors measured key enzyme activities and consumption and production levels of metabolites in incubated or cultured macrophages isolated from the mouse or rat intraperitoneal cavity. Metabolic pathways essential for macrophage function were then determined. Macrophages utilize glucose to generate (i) ATP in the pathways of glycolysis and mitochondrial oxidative phosphorylation, (ii) glycerol 3-phosphate for the synthesis of phospholipids and triacylglycerols, (iii) NADPH for the production of reactive oxygen species (ROS) and (iv) ribose for the synthesis of RNA and subsequently production and secretion of protein mediators (e.g. cytokines). Glutamine plays an essential role in macrophage metabolism and function, as it is required for energy production but also provides nitrogen for synthesis of purines, pyrimidines and thus RNA. Macrophages also utilize fatty acids for both energy production in the mitochondria and lipid synthesis essential to plasma membrane turnover and lipid meditator production. Recent studies utilizing metabolomic approaches, transcriptional and metabolite tracking technologies have detailed mitochondrial release of tricarboxylic acid (TCA) intermediates (e.g. citrate and succinate) to the cytosol, which then regulate pro-inflammatory responses. Macrophages can reprogramme their metabolism and function according to environmental conditions and stimuli in order to polarize phenotype so generating pro- or anti-inflammatory cells. Changes in macrophage metabolism result in modified function/phenotype and vice versa. The plasticity of macrophage metabolism allows the cell to quickly respond to changes in environmental conditions such as those induced by hormones and/or inflammation. A past and present overview of macrophage metabolism and impact of endocrine regulation and the relevance to human disease are described in this review.