Impaired Energy Homeostasis Research Articles

Isolation of Flavonoids from Deguelia duckeana and Their Effect on Cellular Viability, AMPK, eEF2, eIF2 and eIF4E.

Preparations of Deguelia duckeana, known in Brazil as timbó, are used by indigenous people to kill fish. Reinvestigation of its extracts resulted in the isolation and identification of 11 known flavonoids identified as 3,5,4’-trimethoxy-4-prenylstilbene (1), 4-methoxyderricidine (2), lonchocarpine (3), 4-hydroxylonchocarpine (4), 4-methoxylonchocarpine (5), 5-hydroxy-4’,7-dimethoxy-6-prenylflavanone (6), 4’-hydroxyisolonchocarpine (7), 4’-methoxyisolonchocarpine (8), 3’,4’,7-trimethoxyflavone (9), 3’,4’-methylenedioxy-7-methoxyflavone (10), and 2,2-dimethyl-chromone-5,4’-hydroxy-5’-methoxyflavone (11). Except for 1, 3, and 4 all of these flavonoids have been described for the first time in D. duckeana and the flavanone 6 for the first time in nature. Compounds 2, 3, 4, 7, 9, and 10 were studied for their potential to induce cell death in neuronal SK-N-SH cells. Only the chalcone 4 and the flavanone 7 significantly induced lactate dehydrogenase (LDH) release, which was accompanied by activation of caspase-3 and impairment of energy homeostasis in the MTT assay and may explain the killing effect on fish. Interestingly, the flavone 10 reduced cell metabolism in the MTT assay without inducing cytotoxicity in the LDH assay. Furthermore, the flavonoids 2, 3, 4, 7, and 10 induced phosphorylation of the AMP-activated protein kinase (AMPK) and the eukaryotic elongation factor 2 (eEF2). The initiation factor eIF4E was dephosphorylated in the presence of these compounds. The initiation factor eIF2alpha was not affected. Further studies are needed to elucidate the importance of the observed effects on protein synthesis and potential therapeutic perspectives.

Gut microbiota in health and disease: an overview focused on metabolic inflammation.

In concern to the continuously rising global prevalence of obesity, diabetes and associated diseases, novel preventive and therapeutic approaches are urgently required. However, to explore and develop such innovative strategies, a meticulous comprehension of the biological basis of these diseases is extremely important. Past decade has witnessed an enormous amount of research investigation and advancement in the field of obesity, diabetes and metabolic syndrome, with the gut microbiota receiving a special focus in the triangle of nutrition, health and diseases. In particular, the role of gut microbiota in health and diseases has been one of the most vigorous and intriguing field of recent research; however, much still remains to be elucidated about its precise role in host metabolism and immune functions and its implication in the onset, progression as well as in the amelioration of metabolic ailments. Recent investigations have suggested a significant contribution of the gut microbiota in the regulation and impairment of energy homeostasis, thereby causing metabolic disorders, such as metabolic endotoxemia, insulin resistance and type 2 diabetes. Numerous inflammatory biomarkers have been found to be associated with obesity, diabetes and risk of other associated adverse outcomes, thereby suggesting that a persistent low-grade inflammatory response is a potential risk factor. In this milieu, this review intends to discuss potential evidences supporting the disturbance of the gut microbiota balance and the intestinal barrier permeability as a potential triggering factor for systemic inflammation in the onset and progression of obesity, type 2 diabetes and metabolic syndrome.

Some Operational Characteristics of Glycine Release in Rat Retina: The Role of Reverse Mode Operation of Glycine Transporter Type-1 (GlyT-1) in Ischemic Conditions.

Rat posterior eyecups containing the retina were prepared, loaded with [(3)H]glycine and superfused in order to determine its release originated from glycinergic amacrine cells and/or glial cells. Deprivation of oxygen and glucose from the Krebs-bicarbonate buffer used for superfusion evoked a marked increase of [(3)H]glycine release, an effect that was found to be external Ca(2+)-independent. Whereas oxygen and glucose deprivation increased [(3)H]glycine release, its uptake was reduced suggesting that energy deficiency shifts glycine transporter type-1 operation from normal to reverse mode. The increased release of [(3)H]glycine evoked by oxygen and glucose deprivation was suspended by addition of the non-competitive glycine transporter type-1 inhibitor NFPS and the competitive inhibitor ACPPB further suggesting the involvement of this transporter in the mediation of [(3)H]glycine release. Oxygen and glucose deprivation also evoked [(3)H]glutamate release from rat retina and the concomitantly occurring release of the NMDA receptor agonist glutamate and the coagonist glycine makes NMDA receptor pathological overstimulation possible in hypoxic conditions. [(3)H]Glutamate release was suspended by addition of the excitatory amino acid transporter inhibitor TBOA. Sarcosine, a substrate inhibitor of glycine transporter type-1, also increased [(3)H]glycine release probably by heteroexchange shifting transporter operation into reverse mode. This effect of sarcosine was also external Ca(2+)-independent and could be suspended by NFPS. Energy deficiency in retina induced by ouabain, an inhibitor of the Na(+)-K(+)-dependent ATPase, and by rotenone, a mitochondrial complex I inhibitor added with the glycolytic inhibitor 2-deoxy-D-glucose, led to increase of retinal [(3)H]glycine efflux. These effects of ouabain and rotenone/2-deoxy-D-glucose could also be blocked by NFPS pointed to the preferential reverse mode operation of glycine transporter type-1 as a consequence of impaired cellular energy homeostasis. Immunohistochemical studies revealed that glycine transporter type-1, of which reverse mode operation assures [(3)H]glycine release, is expressed in amacrine cells in the inner nuclear and plexiform layers of the retina and also in Müller macroglia cells. We conclude that disruption of the balanced normal/reverse mode operation of glycine transporter type-1 is likely a significant factor contributing to neurotoxic processes of the retina. The possibility to inhibit glycine transporter type-1 mediated glycine efflux by drugs more potently than glycine uptake might offer some therapeutic potential for the treatment of various neurodegenerative disorders of the retina.

Irisin plasma concentration in PCOS and healthy subjects is related to body fat content and android fat distribution

Irisin (Ir), a recently identified adipo-myokine, cleaved and secreted from the protein FNDC5 in response to physical activity, has been postulated to induce the differentiation of a subset of white adipocytes into brown fat and to mediate the beneficial effects on metabolic homeostasis. Metabolic syndrome (MS), a cluster of factors leading to impaired energy homeostasis, affects a significant proportion of subjects suffering from polycystic ovary syndrome (PCOS). The aim of our study was to investigate the relationship between Ir plasma concentrations and metabolic disturbances. The study group consisted of 179 PCOS patients and a population of 122 healthy controls (both groups aged 25–35 years). A subset of 90 subjects with MS was isolated. A positive association between Ir plasma level and MS in the whole group and in controls was found. In subjects with high adipose body content (>40%), Ir was higher than in lean persons (<30%). Our results showed a significant positive association between Ir concentration and android type of adipose tissue in the whole study group and in the control group. Understanding the role of Ir in increased energy expenditure may lead to the development of new therapeutics for obesity and obesity-related diseases.

Sirtuins Function as the Modulators in Aging-related Diseases in Common or Respectively.

Sirtuins Function as the Modulators in Aging-related Diseases in Common or Respectively.

Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice.

DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.

Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress.

Idiosyncratic drug-induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient-specific and drug-specific mechanisms) leading to DILI are poorly understood. Among the patient-specific determinants of susceptibility to INH-associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug-metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial. However, these polymorphisms are merely correlative, and other molecular determinants of susceptibility have remained largely unknown. Regarding the drug-specific mechanisms underlying INH-induced liver injury, novel concepts have been emerging. Among these are covalent protein adduct formation via novel reactive intermediates, leading to hapten formation and a potential immune response, and interference with endogenous metabolism. Furthermore, INH and/or INH metabolites (e.g. hydrazine) can cause mitochondrial injury, which can lead to mitochondrial oxidant stress and impairment of energy homeostasis. Recent studies have revealed that underlying impairment of complex I function can trigger massive hepatocellular injury induced by otherwise nontoxic concentrations of INH superimposed on these mitochondrial deficiencies. This review discusses these emerging new paradigms of INH-induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis.

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels well characterized in neuronal signal transmission. Moreover, recent studies have revealed nAChR expression in nonneuronal cell types throughout the body, including tissues involved in metabolism. In the present study, we screen gene expression of nAChR subunits in pancreatic islets and adipose tissues. Mice pancreatic islets present predominant expression of α7 and β2 nAChR subunits but at a lower level than in central structures. Characterization of glucose and energy homeostasis in α7β2nAChR−/− mice revealed no major defect in insulin secretion and sensitivity but decreased glycemia apparently unrelated to gluconeogenesis or glycogenolysis. α7β2nAChR−/− mice presented an increase in lean and bone body mass and a decrease in fat storage with normal body weight. These observations were associated with elevated spontaneous physical activity in α7β2nAChR−/− mice, mainly due to elevation in fine vertical (rearing) activity while their horizontal (ambulatory) activity remained unchanged. In contrast to α7nAChR−/− mice presenting glucose intolerance and insulin resistance associated to excessive inflammation of adipose tissue, the present metabolic phenotyping of α7β2nAChR−/− mice revealed a metabolic improvement possibly linked to the increase in spontaneous physical activity related to central β2nAChR deficiency.

Mom’s Milk Molds Neural Wiring for Metabolism

Vogt et al. demonstrate that, in mice, maternal high-fat feeding during lactation is sufficient to program the offspring for impaired energy and glucose homeostasis throughout their lifetime. They reveal that the resulting abnormal insulin signaling in the offspring interferes with the formation of hypothalamic neural circuits that contribute to metabolic status.

Discovery of Nesfatin-1 and Overview of Biological Actions and New Developments

Obesity arises from an impairment of energy homeostasis, which essentially involves the balance of food intake and energy dissipation. Some secreted molecules in the hypothalamus have become the focus of recent attention for their important roles in the regulation of food intake. One such molecule, nesfatin-1, is a novel molecule originally expressed in the hypothalamic nuclei of the brain, which exerts its satiety function in conjunction with other molecules, including oxytocin and pro-opiomelanocortin (POMC). Nesfatin-1 is processed from its precursor, DNA binding/EF-hand/acidic protein (NEFA)/nucleobindin 2 (NUCB2), and its mRNA is unexpectedly stabilized by troglitazone, a ligand for peroxisome proliferator-activated receptor γ (PPARγ). Subsequent analyses and observations have demonstrated that nesfatin-1 is also located in brain nuclei outside the hypothalamus and in peripheral tissues, and that nesfatin-1 neurons in the brain receive several signals. These findings imply that nesfatin-1 is an endogenous molecule important for the regulation of not only food intake but also other physiological functions. We discuss what is currently known about nesfatin-1, including new developments in our understanding of its distribution, regulation, and biological function.

Yuzu Extract Prevents Cognitive Decline and Impaired Glucose Homeostasis in β-Amyloid–Infused Rats1–3

Our preliminary study revealed that dementia induced by β-amyloid accumulation impairs peripheral glucose homeostasis (unpublished). We therefore evaluated whether long-term oral consumption of yuzu (Citrus junos Tanaka) extract improves cognitive dysfunction and glucose homeostasis in β-amyloid–induced rats. Male rats received hippocampal CA1 infusions of β-amyloid (25-35) [plaque forming β-amyloid; Alzheimer disease (AD)] or β-amyloid (35–25) [non–plaque forming β-amyloid; C (non-Alzheimer disease control)] at a rate of 3.6 nmol/d for 14 d. AD rats were divided into 2 dietary groups that received either 3% lyophilized 70% ethanol extracts of yuzu (AD-Y) or 3% dextrin (AD-C) in high-fat diets (43% energy as fat). The AD-C group exhibited greater hippocampal β-amyloid deposition, which was not detected in the C group, and attenuated hippocampal insulin signaling. Yuzu treatment prevented β-amyloid accumulation, increased tau phosphorylation, and attenuated hippocampal insulin signaling observed in AD-C rats. Consistent with β-amyloid accumulation, the AD-C rats experienced cognitive dysfunction, which was prevented by yuzu. AD-C rats gained less weight than did C rats due to decreased feed consumption, and yuzu treatment prevented the decrease in feed consumption. Serum glucose concentrations were higher in AD-C than in C rats at 40–120 min after glucose loading during an oral-glucose-tolerance test, but not at 0–40 min. Serum insulin concentrations were highly elevated in AD-C rats but not enough to lower serum glucose to normal concentrations, indicating that rats in the AD-C group had insulin resistance and a borderline diabetic state. Although AD-C rats were profoundly insulin resistant, AD-Y rats exhibited normal first and second phases of glucose tolerance and insulin sensitivity and secretion. In conclusion, yuzu treatment prevented the cognitive dysfunction and impaired energy and glucose homeostasis induced by β-amyloid infusion.

AB0026 Pathophysiological hypoxia affects both redox state and il-2 signaling of human cd4+ t cells and concomitantly impairs survival and proliferation

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease of diarthrodial joints, characterized by the infiltration of immune cells, alterations of cellular redox state and pathophysiological local tissue hypoxia (<1% O2).ObjectivesWe...

Pathophysiological hypoxia affects the redox state and IL‐2 signalling of human CD4+ T cells and concomitantly impairs survival and proliferation

Inflamed areas are characterized by infiltration of immune cells, local hypoxia and alterations of cellular redox states. We investigated the impact of hypoxia on survival, proliferation, cytokine secretion, intracellular energy and redox state of human CD4(+) T cells. We found that pathophysiological hypoxia (<2% O2 ) significantly decreased CD4(+) T-cell survival after mitogenic stimulation. This effect was not due to an increased caspase-3/7-mediated apoptosis or adenosine-5'-triphosphate (ATP) consumption/depletion. However, the ability of stimulated T cells to proliferate was reduced under hypoxic conditions, despite increased expression of CD25. Pathophysiological hypoxia was also found to modify intracellular ROS (iROS) levels in stimulated T cells over time as compared with levels found in normoxia. Physiological hypoxia (5% O2 ) did not decrease CD4(+) T-cell survival and proliferation or modify iROS levels as compared with normoxia. We conclude that pathophysiological hypoxia affects T-cell proliferation and viability via disturbed IL-2R signalling downstream of STAT5a phosphorylation, but not as a result of impaired cellular energy homeostasis. We suggest iROS links early events in T-cell stimulation to the inhibition of the lymphoproliferative response under pathophysiological hypoxic conditions. The level of iROS may therefore act as a mediator of immune functions leading to down-regulation of long-term T-cell activity in inflamed tissues.

Yuzu (Citrus junos Tanaka) improves cognitive function and glucose homeostasis in β‐amyloid infused rats

Our preliminary study revealed that dementia induced by β‐amyloid accumulation itself exacerbates peripheral glucose homeostasis in rats. We were interested to study that long‐term oral consumption of Yuzu extract improves cognitive dysfunction and glucose homeostasis in the β‐‐amyloid‐induced rats. Male rats received intracerebralventricular infusions of β‐amyloid (25–35) (AMY) or β‐amyloid (35–25) (RAMY), at a rate of 3.6 nmol/day for 14 days. AMY‐infused rats were divided into two groups: one group received 3% lyophilized 70% ethanol extracts of Yuzu in a high fat diet and the other group received 3% dextrin. After 6 weeks of treatment, AMY increased β‐amyloid deposition in the hippocampus and the accumulation was not detected in RAMY. AMY attenuated hippocampal insulin signaling to induce hyperphosphorylation of tau. Yuzu treatment prevented the attenuation of the hippocampal insulin signaling in AMY‐infused rats and reduced tau phosphorylation. As a result, AMY induced cognitive dysfunction in comparison to RAMY while yuzu reversed cognitive impairment. AMY decreased body weight without lowering visceral fat accumulation by decreasing food intake and yuzu treatment blocked the decrease. However, yuzu treated rats had less visceral fat. AMY did not disrupt glucose tolerance due to increased insulin secretion although AMY exacerbated insulin resistance as indicated by HOMA‐IR and insulin tolerance tests. Yuzu treatment tended to improve the first phase of glucose tolerance and it was related to improved insulin sensitivity since it decreased insulin secretion. In conclusion, yuzu treatment alleviated cognitive dysfunction and impaired energy and glucose homeostasis by improving insulin sensitivity in rats with AMY‐induced cognitive dysfunction.

Effect of histidine administration to female rats during pregnancy and lactation on enzymes activity of phosphoryltransfer network in cerebral cortex and hippocampus of the offspring

Histidinemia is an inborn error of metabolism of amino acids caused by deficiency of histidase activity in liver and skin with consequent accumulation of histidine in plasma and tissues. Histidinemia is an autosomal recessive trait usually considered harmless to patients and their offspring, but some patients and children born from histidinemic mothers have mild neurologic alterations. Considering that histidinemia is one of the most frequently identified metabolic conditions, in the present study we investigated the effect of L-histidine load to female rats during pregnancy and lactation on some parameters of phosphoryltransfer network in cerebral cortex and hippocampus of the offspring. Pyruvate kinase, cytosolic and mitochondrial creatine kinase activities decreased in cerebral cortex and in hippocampus of rats at 21days of age and this pattern remained in the cerebral cortex and in hippocampus at 60days of age. Moreover, adenylate kinase activity was reduced in the cerebral cortex and in hippocampus of the offspring at 21days of age, whereas the activity was increased in the two tissues at 60days of age. These results suggest that administration of L-histidine to female rats in the course of pregnancy and lactation could impair energy homeostasis in the cerebral cortex and hippocampus of the offspring. Considering that histidinemia is usually a benign condition and little attention has been given to maternal histidinemia, it seems important to perform more studies in the children born from histidinemic mothers.

Glucose-6-phosphatase-β, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality

AbstractGlucose-6-phosphatase-β (G6Pase-β or G6PC3) deficiency, also known as severe congenital neutropenia syndrome 4, is characterized not only by neutropenia but also by impaired neutrophil energy homeostasis and functionality. We now show the syndrome is also associated with macrophage dysfunction, with murine G6pc3−/− macrophages having impairments in their respiratory burst, chemotaxis, calcium flux, and phagocytic activities. Consistent with a glucose-6-phosphate (G6P) metabolism deficiency, G6pc3−/− macrophages also have a lower glucose uptake and lower levels of G6P, lactate, and ATP than wild-type macrophages. Furthermore, the expression of NADPH oxidase subunits and membrane translocation of p47phox are down-regulated, and G6pc3−/− macrophages exhibit repressed trafficking in vivo both during an inflammatory response and in pregnancy. During pregnancy, the absence of G6Pase-β activity also leads to impaired energy homeostasis in the uterus and reduced fertility of G6pc3−/− mothers. Together these results show that immune deficiencies in this congenital neutropenia syndrome extend beyond neutrophil dysfunction.

Reduced density of hypothalamic VGF-immunoreactive neurons in schizophrenia: a potential link to impaired growth factor signaling and energy homeostasis

Protein expression of VGF (nonacronymic) is induced by nerve/brain-derived growth factor, neurotrophin 3, and insulin. VGF is synthesized by neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. After enzymatic processing, smaller VGF-derived peptides are secreted into the cerebrospinal fluid (CSF) or blood. These peptides play important roles by improving synaptic plasticity, neurogenesis, and energy homeostasis, which are impaired in schizophrenia. Based on previous observations of neuroendocrine and hypothalamic deficits in schizophrenia and to determine whether increased levels of the VGF fragment 23-62 in CSF, which have been described in a recent study, were related to changes in hypothalamic VGF expression, an immunohistochemical study was performed in 20 patients with schizophrenia and 19 matched control subjects. N- (D-20) and C-terminal (R-15) VGF antibodies yielded similar results and immunolabeled a vast majority of PVN and SON neurons. Additionally, D20-VGF immunohistochemistry revealed immunostained fibers in the pituitary stalk and neurohypophysis that ended at vessel walls, suggesting axonal transport and VGF secretion. The cell density of D20-VGF-immunoreactive neurons was reduced in the left PVN (P = 0.002) and SON (P = 0.008) of patients with schizophrenia. This study provides the first evidence for diminished hypothalamic VGF levels in schizophrenia, which might suggest increased protein secretion. Our finding was particularly significant in subjects without metabolic syndrome (patients with a body mass index ≤28.7 kg/m(2)). In conclusion, apart from beneficial effects on synaptic plasticity and neurogenesis, VGF may be linked to schizophrenia-related alterations in energy homeostasis.

Mechanisms of disease: hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most-common monogenically inherited form of heart disease, characterized by thickening of the left ventricular wall, contractile dysfunction, and potentially fatal arrhythmias. HCM is also the most-common cause of sudden cardiac death in individuals younger than 35 years of age. Much progress has been made in the elucidation of the genetic basis of HCM, resulting in the identification of more than 900 individual mutations in over 20 genes. Interestingly, most of these genes encode sarcomeric proteins, such as myosin-7 (also known as cardiac muscle β-myosin heavy chain; MYH7), cardiac myosin-binding protein C (MYBPC3), and cardiac muscle troponin T (TNNT2). However, the molecular events that ultimately lead to the clinical phenotype of HCM are still unclear. We discuss several potential pathways, which include altered calcium cycling and sarcomeric calcium sensitivity, increased fibrosis, disturbed biomechanical stress sensing, and impaired cardiac energy homeostasis. An improved understanding of the pathological mechanisms involved will result in greater specificity and success of therapies for patients with HCM.

Association Between Polymorphisms in MTHFR and APOA5 and Metabolic Syndrome in the Greek Population

Impaired energy homeostasis and low-grade inflammation have been related to components of the metabolic syndrome (MetS) such as dyslipidemia, obesity, and insulin resistance. Single-nucleotide polymorphisms in the genes encoding for IL-6 (g.-634G>C; c.174G>C), TNFα (g.-308G>A), methylenetetrahydrofolate reductase (MTHFR) (c.677C>T), APOC3 (c.3175C>G), and APOA5 (g.-1131T>C) have been implicated in the processes of inflammation and energy intake that take place in the development of MetS manifestations. The aim of this study was to investigate the association between these polymorphisms and MetS, as defined by the National Cholesterol Education Program-Adult treatment Panel III criteria, in the Greek population. Overall, 30 unrelated subjects who met the criteria of MetS and 60 matched control subjects from central Greece were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. There was a significant association between both MTHFR c.677C>T (odds ratio: 4.02; confidence interval: 1.496-10.777; p=0.003) and APOA5 g.-1131T>C (odds ratio: 3.514; confidence interval: 1.065-11.585; p=0.035) and MetS. Analysis of constructed haplotypes showed a highly significant association between 677C-1131T-3175C haplotype and MetS (p<0.0001). Carriers of both MTHFR c.677T and APOA5 g.-1131C were associated with increased triglyceride levels (p=0.001 and p=0.003, respectively), compared with noncarriers. These results support a role for MTHFR and APOA5 as risk factors for MetS and suggest their further validation in larger independent populations.

G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis

AbstractG6PC3 (or glucose-6-phosphatase-β) deficiency underlies a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. Here we show that murine G6pc3−/− neutrophils undergoing ER stress activate protein kinase-like ER kinase and phosphatidylinositol 3,4,5-trisphosphate/Akt signaling pathways, and that neutrophil apoptosis is mediated in part by the intrinsic mitochondrial pathway. In G6PC3-deficient patients, granulocyte colony-stimulating factor (G-CSF) improves neutropenia, but its impact on neutrophil apoptosis and dysfunction is unknown. We now show that G-CSF delays neutrophil apoptosis in vitro by modulating apoptotic mediators. However, G6pc3−/− neutrophils in culture exhibit accelerated apoptosis compared with wild-type neutrophils both in the presence or absence of G-CSF. Limiting glucose (0.6mM) accelerates apoptosis but is more pronounced for wild-type neutrophils, leading to similar survival profiles for both neutrophil populations. In vivo G-CSF therapy completely corrects neutropenia and normalizes levels of p-Akt, phosphatidylinositol 3,4,5-trisphosphate, and active caspase-3. Neutrophils from in vivo G-CSF–treated G6pc3−/− mice exhibit increased glucose uptake and elevated intracellular levels of G6P, lactate, and adenosine-5′-triphosphate, leading to improved functionality. Together, the results strongly suggest that G-CSF improves G6pc3−/− neutrophil survival by modulating apoptotic mediators and rectifies function by enhancing energy homeostasis.