Lactate Release Research Articles

Effect of acute exercise intensity on cognitive inhibition and well-being: Role of lactate and BDNF polymorphism in the dose-response relationship.

There is evidence in the literature that acute exercise can modify cognitive function after the effort. However, there is still some controversy concerning the most effective exercise modality to improve cognitive function in acute interventions. Regarding these different exercise modalities, the dose-response relationship between exercise intensity and cognitive response is one of the most challenging questions in exercise and cognition research. In this study, we tested the impact of moderate-intensity (MICT), high-intensity (HIIT) exercise sessions, or control situation (CTRL) on cognitive inhibition (measured with the Stroop Test). Thirty-six young college students participated in this study, where a within-subject repeated measure design was used. ANOVA 2×3 demonstrated that HIIT improved the acute cognitive response to a higher degree when compared to MICT or CTRL (p < 0.05). The cognitive improvements correlated with lactate release, providing a plausible molecular explanation for the cognitive enhancement (r < -0.2 and p < 0.05 for all the Stroop conditions). Moreover, a positive trend in wellbeing was observed after both exercise protocols (HIIT and MICT) but not in the CTRL situation. Genetic BDNF single nucleotide polymorphism did not influence any interactions (p < 0.05). In this sense, our results suggest that exercise intensity could be a key factor in improved cognitive function following exercise in young college students, with no additional impact of BDNF polymorphism. Moreover, our results also provide evidence that exercise could be a useful tool in improving psychological wellbeing.

Guanosine Prevents Spatial Memory Impairment and Hippocampal Damage Following Amyloid-β1-42 Administration in Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative illness responsible for cognitive impairment and dementia. Accumulation of amyloid-beta (Aβ) peptides in neurons and synapses causes cell metabolism to unbalance, and the production of reactive oxygen species (ROS), leading to neuronal death and cognitive damage. Guanosine is an endogenous nucleoside recognized as a neuroprotective agent since it prevents glutamate-induced neurotoxicity by a mechanism not yet completely elucidated. In this study, we evaluated behavioral and biochemical effects in the hippocampus caused by the intracerebroventricular (i.c.v.) infusion of Aβ1-42 peptide (400 pmol/site) in mice, and the neuroprotective effect of guanosine (8 mg/kg, i.p.). An initial evaluation on the eighth day after Aβ1-42 infusion showed no changes in the tail suspension test, although ex vivo analyses in hippocampal slices showed increased ROS production. In the second protocol, on the tenth day following Aβ1-42 infusion, no effect was observed in the sucrose splash test, but a reduction in the recognition index in the object location test showed impaired spatial memory. Analysis of hippocampal slices showed no ROS production and mitochondrial membrane potential alteration, but a tendency to increase glutamate release and a significant lactate release, pointing to a metabolic alteration. Those effects were accompanied by decreased cell viability and increased membrane damage. Guanosine treatment prevented behavioral and biochemical alterations evoked by Aβ1-42, suggesting a potential role against behavioral and biochemical damage evoked by Aβ in the hippocampus.

Colonocyte-derived lactate promotes E. coli fitness in the context of inflammation-associated gut microbiota dysbiosis

BackgroundIntestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.ResultsWe investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.ConclusionsThe release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition.4h64TYW6e28QusiMD-BunNVideo

SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway.

Nasopharyngeal carcinoma is one of the common malignant tumors that the pathogenesis has not yet been completely defined. SETD1A (histone lysine methyltransferase SET domain-containing 1A) is related to the occurrence of various cancers. However, the role of SETD1A in nasopharyngeal carcinoma remains unclear. The SETD1A overexpression vector, si-NC, si-SETD1A#1, and si-SETD1A#2 were transfected into nasopharyngeal carcinoma cells to overexpress or knockdown SETD1A expression. The assay of biofunction was used to explore the role of SETD1A in nasopharyngeal carcinoma cells. The assay of glucose uptake, lactate release, ATP level, western blot, cell proliferation, and cellular apoptosis analysis were performed to investigate the potential mechanism of SETD1A regulation in nasopharyngeal carcinoma. This study was the first to show that SETD1A was upregulated in nasopharyngeal carcinoma cells and the overexpression of SETD1A significantly promoted the cell proliferation and glycolysis and suppressed the cellular apoptosis. Moreover, SETD1A enhances aerobic glycolysis and cell biological function of nasopharyngeal carcinoma cells via PI3K/AKT signaling pathway. SETD1A induced PI3K/AKT activation and subsequently prevented cellular apoptosis. In conclusion, this study identified overexpressed SETD1A as a positive regulator of proliferation that induced nasopharyngeal carcinoma cells' aerobic glycolysis via PI3K/AKT signaling activation in vitro. This study laid a strong foundation for unveiling the precise anticancer mechanism of SETD1A. The SETD1A may become a novel biomarker for further inhibitor design to obstruct the PI3K/AKT-dependent nasopharyngeal carcinoma progression.

Arginine Deprivation in Microenvironment Makes Multiple Myeloma Resistant to Proteasome Inhibitors Via Increased Lactate Release and Metabolic Rewiring

Arginine Deprivation in Microenvironment Makes Multiple Myeloma Resistant to Proteasome Inhibitors Via Increased Lactate Release and Metabolic Rewiring

Discovery of Mitochondrial Complex I Inhibitors as Anticancer and Radiosensitizer Drugs Based on Compensatory Stimulation of Lactate Release

Cancer cells may stimulate glycolytic flux when O2 becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers of oxidizable substrates or the electron transport chain. Here, we developed a screening procedure based on the capacity of cancer cells to release L-lactate to gain insights on the development of mitochondrial complex I inhibitors. For this purpose, we synthesized derivatives of carboxyamidotriazole, a compound previously described as a potential OXPHOS inhibitor. Two series of derivatives were generated by cycloaddition between benzylazide and either cyanoacetamides or alkynes. A primary assay measuring L-lactate release as a compensatory mechanism upon OXPHOS inhibition led us to identify 15 hits among 28 derivatives. A secondary assay measuring O2 consumption in permeabilized cancer cells confirmed that 12 compounds among the hits exhibited reversible complex I inhibitory activity. Anticancer effects of a short list of 5 compounds identified to induce more L-lactate release than reference compound were then evaluated on cancer cells and tumor-mimicking 3D spheroids. Human and mouse cancer cell monolayers exhibiting high level of respiration in basal conditions were up to 3-fold more sensitive than less oxidative cancer cells. 3D tumor spheroids further revealed potency differences between selected compounds in terms of cytotoxicity but also radiosensitizing activity resulting from local reoxygenation. In conclusion, this study documents the feasibility to efficiently screen in 96-well plate format for mitochondrial complex I inhibitors based on the capacity of drug candidates to induce L-lactate release.

Enzymatic Degradation of Fiber-Reinforced PLA Composite Material

Application of thermoplastic fiber-reinforced lightweight composite materials provides a wide range of advantages that are of particular importance for the mobility sector. UD tapes composed of unidirectionally (UD) oriented inorganic fibers embedded in a thermoplastic matrix represent light-weight materials with high tensile strength. This publication addresses recycling aspects of novel UD tape made of a combination of basalt fibers and different PLA (polylactic acid) formulations. The kinetics of enzyme-based separation of polymer from the fiber were investigated. Different types of UD tapes with a thickness of 270–290 µm reinforced with basalt fiber weight ratios ranging between 51 and 63% were incubated at 37 °C in buffer solution (pH 7.4) containing proteinase K. The influence of enzyme concentration, tape weight per incubation tube, proteinase K activators, and tape types on the rate of enzymatic decomposition was investigated. Enzyme activity was measured by analyzing lactate concentration with lactate dehydrogenase and by measuring weight loss of the composite material. The rate of lactate release increased in the first 30 min of incubation and remained stable for at least 90 min. Weight loss of 4% within 4 h was achieved for a tape with 56% (w/w) fiber content. For a sample with a surface area of 3 cm2 in a buffer volume of 10 mL, the rate of lactate release as a function of enzyme concentration reached saturation at 300 µg enzyme/mL. With this enzyme concentration, the rate of lactate release increased in a linear manner for tape surface areas between 1 and 5 cm2. Four tapes with different PLA types were treated with the enzyme for 17 h. Weight loss ranged between 7 and 24%. Urea at a concentration of 0.5% (w/v) increased lactate release by a factor of 9. Pretreatment of tapes in alkaline medium before enzymatic degradation increased weight loss to 14% compared to 5% without pretreatment. It is concluded that enzymatic PLA hydrolysis from UD tapes is a promising technology for the release of basalt fibers after alkaline pretreatment or for the final cleaning of basalt fibers.

Disruption of mitochondrial function augments the radiosensitivity of prostate cancer cell lines.

Ionizing radiation is one of the most widely used therapeutic methods in the treatment of prostate cancer, but the problem is developing radioresistance of the tumour. There is evidence that metabolic reprogramming in cancer is one of the major contributors to radioresistance and mitochondria play a crucial role in this process. The aim of the study was to assess the influence of oxidative phosphorylation uncoupling to radiosensitivity of prostate cancer cells differing in metabolic phenotype. LNCaP, PC-3 and DU-145 cells were exposed to X-rays and simultaneously treated with 2,4-dinitrophenol (2,4-DNP). The radiosensitive of cell lines was determined by cell clonogenic assay and cell cycle analysis. The cytotoxic effect was evaluated with MTT and CVS (Crystal violet staining) assay, apoptosis detection and cell cycle analysis. The phenotype of the cells was determined by glucose uptake and lactate release, ATP level measurement as well as basal reactive oxygen species level and mRNA expression of genes related to oxidative stress defence. The synergistic effect of 2,4-dinitrophenol and X-ray was observed only in the case of the LNCaP cell line. Phenotypic analysis indicates that this may be due to the highest dependence of these cells on oxidative phosphorylation and sensitivity to disruption of their redox status.

Memory Modulation by Exercise in Young Adults Is Related to Lactate and Not Affected by Sex or BDNF Polymorphism.

Simple SummaryThe health and cognitive benefits associated with physical exercise are widely acknowledged. However, exercise characteristics responsible for the improvement in cognition, along with the underlying mechanisms, remain to be elucidated. In an attempt to resolve these questions, our study compares cognitive outcomes after two distinct exercise modes in young adults. Specifically, we have examined the differences between high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (MIE) on visuospatial and declarative memory, contemplating the influence of exercise-associated parameters such as released lactate and non-modifiable factors, including BDNF polymorphism and biological sex. Our results demonstrate the relevance of exercise intensity and intensity-dependent lactate release in modulating cognitive improvement following exercise with no association with the non-modifiable factors mentioned above. These data suggest that the exercise characteristics and intensity of exercise sessions should be carefully considered to optimize cognitive response in young adults. Conversely, the consideration of genotype and biological sex is inappreciable.Currently, high-intensity interval exercise (HIIE) is on the rise compared to moderate-intensity exercise (MIE) due to its similar benefits for health and performance with low time requirements. Recent studies show how physical exercise can also influence cognitive function, although the optimal dose and underlying mechanisms remain unknown. Therefore, in our study, we have compared the effects on visuospatial and declarative memory of different exercise intensities (HIIE vs. MIE), including possible implicated factors such as lactate released after each session and the Brain-Derived Neurotrophic Factor (BDNF) genotype. Thirty-six undergraduate students participated in this study. The HIIE session consisted of a 3 min warm-up, four 2 min sets at 90–95% of the maximal aerobic speed (MAS) with 2 min of passive recovery between sets, and a 3 min cooldown, and the MIE session implies the same total duration of continuous exercise at 60% of the MAS. Better improvements were found after HIIE than MIE on the backward condition of the visuospatial memory test (p = 0.014, ηp2 = 0.17) and the 48 h retention of the declarative memory test (p = 0.04; d = 0.34). No differences were observed in the forward condition of the visuospatial memory test and the 7-day retention of the declarative memory test (p > 0.05). Moreover, non-modifiable parameters such as biological sex and BDNF polymorphism (Val/Val, Val/Met, or Met/Met) did not modulate the cognitive response to exercise. Curiously, the correlational analysis showed associations (p < 0.05) between changes in memory (visuospatial and declarative) and lactate release. In this sense, our results suggest an important role for intensity in improving cognitive function with exercise, regardless of genetic factors such as biological sex or BDNF Val66Met polymorphism.

Dimethyl Fumarate Inhibits Fibroblast Like Synoviocytes-mediated Inflammation and Joint Destruction in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) as a chronic inflammatory disorder affects around 1% of the world population. Fibroblast-like synoviocyte (FLS), one of the main cells in RA pathogenesis is characterized by hyperproliferation and resistance to apoptosis resulting to synovial hyperplasia. Dimethyl fumarate (DMF) has been licensed for the treatment of multiple sclerosis (MS) and psoriasis; however, its role in RA is unknown. DMF has immunomodulatory properties and may be considered as therapeutic approach in RA treatment. In this study, we aimed to investigate the effect of DMF on controlling FLS-mediated synovial inflammation and joint destruction in RA. FLSs were isolated from synovial tissues of 8 patients with RA and treated with DMF. Apoptosis rate was analyzed by Annexin V-FITC. Cell proliferation was measured by carboxyfluorescein succinimidyl ester (CFSE) dye. The matrix metalloproteinase 3 (MMP3) and NF-кB pathway protein (p65) mRNA expression were evaluated by RT-PCR. Also, the IL-6 production and lactate release were measured in FLS supernatant. DMF treatment decreased the cell proliferation and increased apoptosis in a dose dependent manner. DMF-treated FLS showed a reduction in IL-6 and lactate release. Moreover, it was revealed that DMF inhibited the expression of p65 and MMP3. Our data demonstrate that DMF treatment suppresses the aggressive and inflammatory features of RA FLSs. Our Results suggest that DMF might be expected to be evaluated as a therapy for RA.

Tensile strain and altered synovial tissue metabolism in human knee osteoarthritis

Synovium is critical for maintaining joint homeostasis and may contribute to mechanobiological responses during joint movement. We investigated mechanobiological responses of whole synovium from patients with late-stage knee osteoarthritis (OA). Synovium samples were collected during total knee arthroplasty and assigned to histopathology or cyclic 10% tensile strain loading, including (1) static (control); (2) low-frequency (0.3 Hz); and iii) high-frequency (1.0 Hz) for 30-min. After 6-h incubation, tissues were bisected for RNA isolation and immunostaining (3-nitrotyrosine; 3-NT). RNA sequencing was analyzed for differentially expressed genes and pathway enrichment. Cytokines and lactate were measured in conditioned media. Compared to controls, low-frequency strain induced enrichment of pathways related to interferon response, Fc-receptor signaling, and cell metabolism. High-frequency strain induced enrichment of pathways related to NOD-like receptor signaling, high metabolic demand, and redox signaling/stress. Metabolic and redox cell stress was confirmed by increased release of lactate into conditioned media and increased 3-NT formation in the synovial lining. Late-stage OA synovial tissue responses to tensile strain include frequency-dependent increases in inflammatory signaling, metabolism, and redox biology. Based on these findings, we speculate that some synovial mechanobiological responses to strain may be beneficial, but OA likely disturbs synovial homeostasis leading to aberrant responses to mechanical stimuli, which requires further validation.

Early effects of LPS-induced neuroinflammation on the rat hippocampal glycolytic pathway

Neuroinflammation is a common feature during the development of neurological disorders and neurodegenerative diseases, where glial cells, such as microglia and astrocytes, play key roles in the activation and maintenance of inflammatory responses in the central nervous system. Neuroinflammation is now known to involve a neurometabolic shift, in addition to an increase in energy consumption. We used two approaches (in vivo and ex vivo) to evaluate the effects of lipopolysaccharide (LPS)-induced neuroinflammation on neurometabolic reprogramming, and on the modulation of the glycolytic pathway during the neuroinflammatory response. For this, we investigated inflammatory cytokines and receptors in the rat hippocampus, as well as markers of glial reactivity. Mitochondrial respirometry and the glycolytic pathway were evaluated by multiple parameters, including enzymatic activity, gene expression and regulation by protein kinases. Metabolic (e.g., metformin, 3PO, oxamic acid, fluorocitrate) and inflammatory (e.g., minocycline, MCC950, arundic acid) inhibitors were used in ex vivo hippocampal slices. The induction of early inflammatory changes by LPS (both in vivo and ex vivo) enhanced glycolytic parameters, such as glucose uptake, PFK1 activity and lactate release. This increased glucose consumption was independent of the energy expenditure for glutamate uptake, which was in fact diverted for the maintenance of the immune response. Accordingly, inhibitors of the glycolytic pathway and Krebs cycle reverted neuroinflammation (reducing IL-1β and S100B) and the changes in glycolytic parameters induced by LPS in acute hippocampal slices. Moreover, the inhibition of S100B, a protein predominantly synthesized and secreted by astrocytes, inhibition of microglia activation and abrogation of NLRP3 inflammasome assembly confirmed the role of neuroinflammation in the upregulation of glycolysis in the hippocampus. Our data indicate a neurometabolic glycolytic shift, induced by inflammatory activation, as well as a central and integrative role of astrocytes, and suggest that interference in the control of neurometabolism may be a promising strategy for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

In vitro effects of vitamins C and E on adipocyte function and redox status in obesity

BackgroundObesity is associated with a chronic inflammatory state and evident oxidative stress. Antioxidant supplementation may have beneficial effects on adipocyte function and on oxidative stress. Therefore, in this study, we investigated the in vitro effects of vitamins C, E on redox and metabolic parameters in adipocytes of control and obese Wistar rats. MethodsAdipocytes were isolated from abdominal adipose tissue and were cultured in RPMI medium for 24 h, in the presence or the absence of vitamins (C, E at 50 µM). Glucose consumption, lactate and glycerol release, ATP and triglyceride contents, redox balance were investigated with biochemical methods. ResultsThe results showed altered glucose consumption and lactate and glycerol efflux, high triglycerides, low ATP contents (P < 0.01), associated to an intracellular oxidative stress in adipocytes of obese rats. Vitamins C and E restored adipocyte function in obesity. Vitamin E increased lipolysis in adipocytes during obesity (P < 0.01). Redox balance was also modulated by antioxidants, including a reduction in intracellular hydroperoxides and carbonyl proteins levels and an increase in catalase and SOD activities and glutathione contents in adipocytes of obese rats. ConclusionTreatments with vitamins had beneficial effects on adipocyte function, and should be considered in therapeutic approaches for normalizing adipose function in obesity.

Glucocorticoid regulation of lactate release from spinal astrocytes contributes to the induction of spinal LTP of C-fiber-evoked field potentials and the development of mechanical allodynia

High-frequency stimulation (HFS) of the sciatic nerve leads to long-term potentiation (LTP) at C-fiber synapse and long-lasting pain hypersensitivity. The underlying mechanisms, however, are still unclear. In the present study, we investigated the involvement of astrocytes derived l-lactate in the spinal dorsal horn subsequent to glucocorticoid (GC) secretion into the plasma in this process using Sprague-Dawley rats and Aldh1L1-CreERT2 mice of either sex. We found that HFS increased l-lactate and monocarboxylate transporters 1/2 (MCT1/2) in the spinal dorsal horn. Inhibition of glycogenolysis or blocking lactate transport prevented the induction of spinal LTP following HFS. Furthermore, Chemogenetical inhibition of dorsal horn astrocytes, which were activated by HFS, prevented spinal LTP, alleviated the mechanical allodynia and the decreased the level l-lactate and GFAP expression in the dorsal horn following HFS. In contrast, Chemogenetics activation of dorsal horn astrocytes in naïve rats induced spinal LTP as well as mechanical allodynia, and increased GFAP expression and l-lactate. Application of l-lactate directly to the spinal cord of naïve rats induced spinal LTP, mechanical allodynia, and increased spinal expression of p-ERK. Importantly, HFS increased GC in the plasma and glucocorticoid receptor (GR) expression in spinal astrocytes, adrenalectomy or knocking down of GR in astrocytes by using Cre-Loxp system blocked the mechanical allodynia, prevented the spinal LTP and the enhancement of lactate after HFS. These results show that lactate released from spinal astrocytes following glucocorticoid release into the plasma enhance synaptic transmission at the C-fiber synapse and underlie pain chronicity.

The protective effect of the spleen in sickle cell patients. A comparative study between patients with asplenia/hyposplenism and hypersplenism.

Sickle cell disease (SCD) is caused by a point mutation in the beta-globin gene. SCD is characterized by chronic hemolytic anemia, vaso-occlusive events leading to tissue ischemia, and progressive organ failure. Chronic inflammatory state is part of the pathophysiology of SCD. Patients with SCD have extremely variable phenotypes, from mild disease to severe complications including early age death. The spleen is commonly injured in SCD. Early splenic dysfunction and progressive spleen atrophy are common. Splenomegaly and hypersplenism can also occur with the loss of the crucial splenic function. Acute, life-threatening spleen-related complications in SCD are well studied. The association of laboratory parameters with the spleen status including hyposplenism, asplenia, and splenomegaly/hypersplenism, and their implication in vaso-occlusive crisis and long-term complications in SCD remain to be determined. We evaluated the association between the spleen status with clinical and laboratory parameters in 31 SCD patients: Group a) Patients with asplenia/hyposplenism (N = 22) (including auto-splenectomy and splenectomized patients) vs. Group b) patients with splenomegaly and or hypersplenism (N = 9). Laboratory studies included: Complete Blood Count, reticulocyte count, iron metabolism parameters, C Reactive Protein (CRP), Hb variant distribution, and D-dimer. Metabolic and morphological red blood cell (RBC) studies included: density gradient (by Percoll), glucose consumption, lactate release, and K+ leakage, fetal RBC (F-Cells) and F-Reticulocytes, annexinV+, CD71+, oxidative stress measured by GSH presence in RBC and finally Howell Jolly Bodies count were all analyzed by Flow Cytometry. Scanning electron microscopy analysis of RBC was also performed. Patients with asplenia/hyposplenism showed significantly higher WBC, platelet, Hematocrit, hemoglobin S, CRP, D-dimer, Gamma Glutamyl Transferase (GGT), cholesterol, transferrin, annexin V+ RBCs, CD71+ RBCs, together with a markedly lower F Reticulocyte levels in comparison with splenomegaly/hypersplenism patients. In summary, important differences were also found between the groups in the studied RBCs parameters. Further studies are required to elucidate the effect of the spleen including hyper and hypo-splenia on laboratory parameters and in clinical manifestations, vascular pathology, and long-term complications of SCD. The benefits and risks of splenectomy compared to chronic transfusion need to be evaluated in clinical trials and the standard approach managing hypersplenism in SCD patients should be re-evaluated.

Regulatory Effects of Metformin, an Antidiabetic Biguanide Drug, on the Metabolism of Primary Rat Adipocytes.

Metformin is a biguanide compound commonly applied in humans with type 2 diabetes. The drug affects different tissues, including fat tissue. The direct influence of metformin on cells of fat tissue, i.e., adipocytes, is poorly elucidated. In the present study, the short-term (4-h) effects of metformin on lipogenesis, glucose transport, lipolysis, and lactate release in primary rat adipocytes were explored. It was demonstrated that metformin reduced insulin-induced lipogenesis and increased glucose transport into adipocytes. The tested compound also decreased lactate release from fat cells. It was shown that metformin substantially limited lipolysis stimulated by epinephrine (adrenergic receptor agonist) and dibutyryl-cAMP (direct activator of protein kinase A). Moreover, metformin decreased the lipolytic process triggered by DPCPX (adenosine A1 receptor antagonist). In the case of each lipolytic stimulator, the drug evoked a similar inhibitory effect in the presence of 3 and 12 mM glucose. The lipolytic response of adipocytes to epinephrine was also found to be reduced by metformin when glucose was replaced by alanine. It was demonstrated that the tested compound limits the release of both glycerol and fatty acids from fat cells. The results of the present study provided evidence that metformin significantly affects the metabolism of primary rat adipocytes. Its action covers processes related to lipid accumulation and release and occurs after relatively short-term exposure.

L-Arginine increases AMPK phosphorylation and the oxidation of energy substrates in hepatocytes, skeletal muscle cells, and adipocytes.

Previous work has shown that dietary L-arginine (Arg) supplementation reduced white fat mass in obese rats. The present study was conducted with cell models to define direct effects of Arg on energy-substrate oxidation in hepatocytes, skeletal muscle cells, and adipocytes. BNL CL.2 mouse hepatocytes, C2C12 mouse myotubes, and 3T3-L1 mouse adipocytes were treated with different extracellular concentrations of Arg (0, 15, 50, 100 and 400µM) or 400µM Arg + 0.5mM NG-nitro-L-arginine methyl ester (L-NAME; an NOS inhibitor) for 48h. Increasing Arg concentrations in culture medium dose-dependently enhanced (P < 0.05) the oxidation of glucose and oleic acid to CO2 in all three cell types, lactate release from C2C12 cells, and the incorporation of oleic acid into esterified lipids in BNL CL.2 and 3T3-L1 cells. Arg at 400µM also stimulated (P < 0.05) the phosphorylation of AMP-activated protein kinase (AMPK) in all three cell types and increased (P < 0.05) NO production in C2C12 and BNL CL.2 cells. The inhibition of NOS by L-NAME moderately reduced (P < 0.05) glucose and oleic acid oxidation, lactate release, and the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in BNL CL.2 cells, but had no effect (P > 0.05) on these variables inC2C12 or 3T3-L1 cells. Collectively, these results indicate that Arg increased AMPK activity and energy-substrate oxidation in BNL CL.2, C2C12, and 3T3-L1 cells through both NO-dependent and NO-independent mechanisms.

Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes.

Background: In recent decades, obesity has widely emerged as an important risk factor for prostate cancer (PCa). Adipose tissue and PCa cells have been shown to orchestrate a complex interaction network to support tumor growth and evolution; nonetheless, the study of this communication has only been focused on soluble factors, although increasing evidence highlights the key role of extracellular vesicles (EVs) in the modulation of tumor progression. Methods and Results: In the present study, we found that EVs derived from 3T3-L1 adipocytes could affect PC3 and DU145 PCa cell traits, inducing increased proliferation, migration and invasion. Furthermore, conditioning of both PCa cell lines with adipocyte-released EVs resulted in lower sensitivity to docetaxel, with reduced phosphatidylserine externalization and decreased caspase 3 and PARP cleavage. In particular, these alterations were paralleled by an Akt/HIF-1α axis-related Warburg effect, characterized by enhanced glucose consumption, lactate release and ATP production. Conclusions: Collectively, these findings demonstrate that EV-mediated crosstalk exists between adipocytes and PCa, driving tumor aggressiveness.

Rewiring of Glucose and Lipid Metabolism Induced by G Protein-Coupled Receptor 17 Silencing Enables the Transition of Oligodendrocyte Progenitors to Myelinating Cells.

In the mature central nervous system (CNS), oligodendrocytes (OLs) provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, OLs require energy and building blocks for lipids, which implies a great investment of energy fuels and molecular sources of carbon. The oligodendroglial G protein-coupled receptor 17 (GPR17) has emerged as a key player in OL maturation; it reaches maximal expression in pre-OLs, but then it has to be internalized to allow terminal maturation. In this study, we aim at elucidating the role of physiological GPR17 downregulation in OL metabolism by applying transcriptomics, metabolomics and lipidomics on differentiating OLs. After GPR17 silencing, we found a significant increase in mature OL markers and alteration of several genes involved in glucose metabolism and lipid biosynthesis. We also observed an increased release of lactate, which is partially responsible for the maturation boost induced by GPR17 downregulation. Concomitantly, GPR17 depletion also changed the kinetics of specific myelin lipid classes. Globally, this study unveils a functional link between GPR17 expression, lactate release and myelin composition, and suggests that innovative interventions targeting GPR17 may help to foster endogenous myelination in demyelinating diseases.

Overexpressing the hydroxycarboxylic acid receptor 1 in mouse brown adipose tissue restores glucose tolerance and insulin sensitivity in diet-induced obese mice.

Interscapular brown adipose tissue (BAT) plays an important role in controlling glucose homeostasis. Increased glucose entry and glycolysis in BAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1), markedly downregulated in male diet-induced obese (DIO) and ob/ob mice. In this study, we examined the role of HCAR1 in BAT in controlling glucose homeostasis in male DIO mice. We overexpressed HCAR1 in BAT by injecting adeno-associated viruses (AAVs) expressing HCAR1 into the BAT pads of male DIO C57BL/6J mice. Overexpressing HCAR1 in BAT resulted in augmented glucose uptake by BAT in response to treatment with the HCAR1 agonist. HCAR1 overexpression elevated BAT temperature associated with increased thermogenic gene expression in BAT. HCAR1 overexpression prevented body weight gain in male DIO mice. Importantly, mice overexpressing HCAR1 in BAT exhibited improved glucose tolerance and insulin sensitivity. HCAR1 overexpression upregulated the Slc2a4 gene expression and promoted GLUT4 trafficking to the plasma membrane. In addition, mice overexpressing HCAR1 displayed a decrease in hormone-sensitive lipase (HSL) phosphorylation and increased lipogenic enzyme gene expression in BAT. Unlike DIO mice, overexpressing HCAR1 in BAT of mice fed a low-fat diet did not change body weight gain and glucose homeostasis. Taken together, our results support the interpretation that HCAR1 expressed in BAT promotes glucose entry and reduces lipolysis in BAT of male DIO mice. As activation of HCAR1 in BAT restores body weight, glucose tolerance, and insulin sensitivity in male DIO mice, our study suggests that interoceptive lactate detection via HCAR1 in BAT can regulate glucose and lipid substrate utilization and/or availability to promote healthy metabolism.NEW & NOTEWORTHY HCAR1 expressed in BAT can promote glucose entry and reduce lipolysis, resulting in body weight loss and increased insulin sensitivity. Hence, targeting HCAR1 in BAT would provide an alternative way to control body weight and euglycemia in individuals with obesity.