Adaptive Metabolic Changes Research Articles

Functional remodeling of gut microbiota and liver in laying hens as affected by fasting and refeeding after fasting.

Animals will experience energy deprivation processes such as moulting, clutching, migration and long-distance transportation under natural survival conditions and in production practices, and the body will trigger a series of adaptive metabolic changes during these processes. Fasting and refeeding after fasting can induce remodeling of nutrients and energy metabolism. This study aims to investigate the mechanisms by which the gut microbiota and liver of poultry respond to energy deprivation under specific conditions. Ninety 252-day-old laying hens were randomly divided into 3 groups: (1) fed ad libitum (control group); (2) fasted from day 13 to day 17 (fasting group); (3) fasted from day 1 to day 5, then refed on a specific feeding way (refeeding group). After that, the serum, liver, jejunum tissues, and cecum contents were sampled and sent for metabolome, transcriptome, morphology, and 16S rDNA sequencing analyses, respectively. Results showed that food deprivation not only observably decreased the body weight, liver index, and the villus height and villus/crypt ratio of jejunum, but also significantly changed the gut microbiota compositions, serum metabolic profiles, and the hepatic gene expression patterns of laying hens, whereas these changes were effectively reversed by the following refeeding operation. At the same time, metabolome combined transcriptome analysis revealed that both serum differential metabolites and hepatic differential expressed genes (DEGs) were consistently enriched in the lipid and amino metabolism pathways, and strong correlations were synchronously found between the differential metabolites and both of the differential gut microbial genera and DEGs, suggesting the crosstalks among gut, liver and their resulting serum metabolic products. The results suggested that the organism might coordinate to maintain metabolic homeostasis under energy deprivation through a combination of changes in gut microbial composition and hepatic gene expression.

Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.

Single-cell sensor analyses reveal signaling programs enabling Ras-G12C drug resistance.

Clinical resistance to rat sarcoma virus (Ras)-G12C inhibitors is a challenge. A subpopulation of cancer cells has been shown to undergo genomic and transcriptional alterations to facilitate drug resistance but the immediate adaptive effects on Ras signaling in response to these drugs at the single-cell level is not well understood. Here, we used Ras biosensors to profile the activity and signaling environment of endogenous Ras at the single-cell level. We found that a subpopulation of KRas-G12C cells treated with Ras-G12C-guanosine-diphosphate inhibitors underwent adaptive signaling and metabolic changes driven by wild-type Ras at the Golgi and mutant KRas at the mitochondria, respectively. Our Ras biosensors identified major vault protein as a mediator of Ras activation through its scaffolding of Ras signaling pathway components and metabolite channels. Overall, methods including ours that facilitate direct analysis on the single-cell level can report the adaptations that subpopulations of cells adopt in response to cancer therapies, thus providing insight into drug resistance.

Abstract 392: MYB regulates a specific subset of hypoxia-induced genes and exhibits altered genomic occupancy under hypoxia

Abstract Hypoxia, an unavoidable microenvironmental stress, greatly influences the tumor cell behavior and therapeutic outcomes. Under low oxygen condition, tumor cells undergo transcriptional reprogramming, largely mediated through hypoxia-inducible factors (HIFs), triggering adaptive response pathways. We recently demonstrated a significant role of MYB in hypoxic survival of pancreatic cancer cells by facilitating adaptive changes in cellular metabolism in collaboration with HIF1α. Here, we employed genome-wide deep sequencing approaches to study the impact of hypoxia on transcriptional reprogramming of pancreatic cancer cells and investigate the role of MYB in the hypoxia-dependent processes. A large number of differentially expressed genes (DEGs) were identified in pancreatic cancer cells subjected to hypoxia (1% O2) and associated with multiple adaptive response pathways. Specifically, we found that pathways related to autophagy, cell migration, epithelial-to-mesenchymal transition, endocytosis, cytoskeleton reorganization were induced, while those associated with RNA processing, ribosome biogenesis, DNA replication and cell cycle were suppressed. To analyze the role of MYB in these adaptive responses, we compared the relative abundance of transcripts in MYB-overexpressing control and MYB knockout (KO) pancreatic cancer cells when cultured under normoxic or hypoxic conditions. We observed that the transcriptional output of MYB was drastically changed under hypoxia with a vast majority of genes being distinctly altered in response to the loss of MYB expression under normoxia and hypoxia. To examine if it resulted from altered genomic occupancy of MYB under normoxia and hypoxia, we compared MYB ChIP-seq peaks under these conditions. We observed a decrease in overall MYB-bound genomic regions under hypoxia despite the fact that we did not observe a decrease in nuclear MYB expression. More interestingly, the genomic occupancy of MYB shifted substantially from regions proximal to transcription start site to distal intergenic or intronic regions under hypoxia. Studies are currently underway to examine the mechanisms underlying the altered MYB genomic occupancy and its impact on adaptive physiological response of pancreatic cancer cells under hypoxia. Together, our findings bring unprecedented insight into the mechanistic role of MYB in hypoxia adaptation and pancreatic cancer pathobiology. Citation Format: Shashi Anand, Mohammad Aslam Khan, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh. MYB regulates a specific subset of hypoxia-induced genes and exhibits altered genomic occupancy under hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 392.

Small molecule mediators of host-T. cruzi-environment interactions in Chagas disease.

Small molecules (less than 1,500 Da) include major biological signals that mediate host-pathogen-microbiome communication. They also include key intermediates of metabolism and critical cellular building blocks. Pathogens present with unique nutritional needs that restrict pathogen colonization or promote tissue damage. In parallel, parts of host metabolism are responsive to immune signaling and regulated by immune cascades. These interactions can trigger both adaptive and maladaptive metabolic changes in the host, with microbiome-derived signals also contributing to disease progression. In turn, targeting pathogen metabolic needs or maladaptive host metabolic changes is an important strategy to develop new treatments for infectious diseases. Trypanosoma cruzi is a single-celled eukaryotic pathogen and the causative agent of Chagas disease, a neglected tropical disease associated with cardiac and intestinal dysfunction. Here, we discuss the role of small molecules during T. cruzi infection in its vector and in the mammalian host. We integrate these findings to build a theoretical interpretation of how maladaptive metabolic changes drive Chagas disease and extrapolate on how these findings can guide drug development.

ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism

Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein (LDL) cholesterol. Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in triglyceride-rich lipoprotein assembly and secretion remains unknown. CRISPR-associated protein 9 (CRISPR/Cas9) was used to target ANGPTL3 in HepG2 cells (ANGPTL3−/−) whereupon we observed ∼50% reduction of apolipoprotein B100 (ApoB100) secretion, accompanied by an increase in ApoB100 early presecretory degradation via a predominantly lysosomal mechanism. Despite defective particle secretion in ANGPTL3−/− cells, targeted lipidomic analysis did not reveal neutral lipid accumulation in ANGPTL3−/− cells; rather ANGPTL3−/− cells demonstrated decreased secretion of newly synthesized triglycerides and increased fatty acid oxidation. Furthermore, RNA sequencing demonstrated significantly altered expression of key lipid metabolism genes, including targets of peroxisome proliferator-activated receptor α, consistent with decreased lipid anabolism and increased lipid catabolism. In contrast, CRISPR/Cas9 LDL receptor (LDLR) deletion in ANGPTL3−/− cells did not result in a secretion defect at baseline, but proteasomal inhibition strongly induced compensatory late presecretory degradation of ApoB100 and impaired its secretion. Additionally, these ANGPTL3−/−;LDLR−/− cells rescued the deficient LDL clearance of LDLR−/− cells. In summary, ANGPTL3 deficiency in the presence of functional LDLR leads to the production of fewer lipoprotein particles due to early presecretory defects in particle assembly that are associated with adaptive changes in intrahepatic lipid metabolism. In contrast, when LDLR is absent, ANGPTL3 deficiency is associated with late presecretory regulation of ApoB100 degradation without impaired secretion. Our findings therefore suggest an unanticipated intrahepatic role for ANGPTL3, whose function varies with LDLR status.

Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.

Due to the unique characteristics of breast cancer initiation sites and significant alterations in tumor metabolism, breast cancer cells rely on lipid metabolic reprogramming to effectively regulate metabolic programs during the disease progression cascade. This adaptation enables them to meet the energy demands required for proliferation, invasion, metastasis, and responses to signaling molecules in the breast cancer microenvironment. In this review, we comprehensively examined the distinctive features of lipid metabolic reprogramming in breast cancer and elucidated the underlying mechanisms driving aberrant behavior of tumor cells. Additionally, we emphasize the potential role and adaptive changes in lipid metabolism within the breast cancer microenvironment, while summarizing recent preclinical studies. Overall, precise control over lipid metabolism rewiring and understanding of plasticity within the breast cancer microenvironment hold promising implications for developing targeted treatment strategies against this disease. Therefore, interventions targeting the lipid metabolism in breast cancer may facilitate innovative advancements in clinical applications.

Hormonal basis of seasonal metabolic changes in mammalian species.

Seasonal changes in external conditions (photoperiod, meteorological conditions, diet) cause adaptive changes in both energy and substrate metabolism in the animals of mammalian species. In summer, long days and a rich diet contribute to relative elevation in the levels of thyroid hormones (TH), but warmer weather lowers their levels. In winter, short days and a poor diet inhibit TH synthesis, but low temperatures increase their secretion. In addition, the results of our meta-analyses revealed a significant role of atmospheric pressure in circannual fluctuations of metabolic parameters in humans. The changes in photoperiod are generally viewed as a major factor contributing to seasonal rhythm regulation However, numerous data show that season-dependent metabolic changes in mammals could be also accounted for by meteorological factors and diet.

Exercise-induced fumarate accumulation: a potential mediator of mitochondrial biogenesis in mammalian skeletal muscle

Endurance exercise is known to induce mitochondrial biogenesis in mammalian skeletal muscles. However, the exact mechanism via which this exercise-induced mitochondria biogenesis occurs remains unclear. Extraneous physical activity induces several adaptive metabolic changes in the skeletal muscle including the activation purine nucleotide cycle (PNC) and utilization of amino acid as fuel sources. These metabolic adaptations are likely to cause accumulation of intra-muscular fumarate that might be a key mediator of exercise-induced mitochondrial biogenesis. This is because high intracellular levels of fumarate cause irreversible succination of Keap1, which leads to activation of nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) signalling. Activation of Nrf2 signalling in turn is known to play a role in contraction-induced mitochondria biogenesis. Accordingly, it is possible that therapeutic strategies that enhance skeletal muscle fumarate levels might potentially enhance muscle mitochondrial biogenesis, content and overall physical performance.

Biochemical Responses to the Long-Term Impact of Copper Sulfate (CuSO4) in Tobacco Plants.

Metabolic changes under stress are often studied in short-term experiments, revealing rapid responses in gene expression, enzyme activity, and the amount of antioxidants. In a long-term experiment, it is possible to identify adaptive changes in both primary and secondary metabolism. In this study, we characterized the physiological state of tobacco plants and assessed the amount and spectrum of phenolic compounds and the lignification of axial organs under excess copper stress in a long-term experiment (40 days). Plants were treated with 100 and 300 μM CuSO4, as well as a control (Knop solution). Copper accumulation, the size and anatomical structure of organs, stress markers, and the activity of antioxidant enzymes were studied. Lignin content was determined with the cysteine-assisted sulfuric method (CASA), and the metabolite profile and phenolic spectrum were determined with UHPLC-MS and thin-layer chromatography (TLC). Cu2+ mainly accumulated in the roots and, to a lesser extent, in the shoots. Copper sulfate (100 μM) slightly stimulated stem and leaf growth. A higher concentration (300 μM) caused oxidative stress; H2O2 content, superoxide dismutase (SOD), and guaiacol peroxidase (GPOX) activity increased in roots, and malondialdehyde (MDA) increased in all organs. The deposition of lignin increased in the roots and stems compared with the control. The content of free phenolics, which could be used as substrates for lignification, declined. The proportions of ferulic, cinnamic, and p-coumaric acids in the hydrolysate of bound phenolics were higher, and they tended toward additional lignification. The metabolic profile changed in both roots and stems at both concentrations, and changed in leaves only at a concentration of 300 μM. Thus, changes in the phenolic spectrum and the enhanced lignification of cell walls in the metaxylem of axial (root and stem) organs in tobacco can be considered important metabolic responses to stress caused by excess CuSO4.

Proteome-wide identification of S-sulfenylated cysteines response to salt stress in Brassica napus root

Reactive oxygen species (ROS) play a key role in a variety of biological processes, such as the perception of abiotic stress, the integration of different environmental signals, and the activation of stress response networks. Salt stress could induce an increased ROS accumulation in plants, disrupting intracellular redox homeostasis, leading to post-translational modifications (PTMs) of specific proteins, and eventually causing adaptive changes in metabolism. Here, we performed an iodoTMT-based proteomic approach to identify the sulfenylated proteins in B. napus root responsing to salt stress. Totally, 1 348 sulfenylated sites in 751 proteins were identified and these proteins were widely existed in different cell compartments and processes. Our study revealed that proteins with changed abundance and sulfenylation level in B. napus root under salt stress were mainly enriched in the biological processes of ion binding, glycolysis, ATP binding, and oxidative stress response. This study displays a landscape of sulfenylated proteins response to salt stress in B. napus root and provides some theoretical support for further understanding of the molecular mechanisms of redox regulation under salt stress in plants.

Alcohol blunts pregnancy-mediated insulin resistance and reduces fetal brain glucose despite elevated fetal gluconeogenesis, and these changes associate with fetal weight outcomes.

Prenatal alcohol exposure (PAE) impairs fetal growth and neurodevelopment. Although alcohol is well known to alter metabolism, its impact on these processes during pregnancy is largely unexplored. Here, we investigate how alcohol affects maternal-fetal glucose metabolism using our established mouse binge model of PAE. In the dam, alcohol reduces the hepatic abundance of glucose and glycolytic intermediates, and the gluconeogenic enzymes glucose-6-phosphtase and phosphoenolpyruvate carboxykinase. Fasting blood glucose is also reduced. In a healthy pregnancy, elevated maternal gluconeogenesis and insulin resistance ensures glucose availability for the fetus. Glucose and insulin tolerance tests reveal that alcohol impairs the dam's ability to acquire insulin resistance. Alcohol-exposed dams have enhanced glucose clearance (p < .05) in early gestation, after just two days of alcohol, and this persists through late term when fetal glucose needs are maximal. However, maternal plasma insulin levels, hepatic insulin signaling, and the abundance of glucose transporter proteins remain unchanged. In the PAE fetus, the expression of hepatic gluconeogenic genes is elevated, and there is a trend for elevated blood and liver glucose levels. In contrast, fetal brain and placental glucose levels remain low. This reduced maternal fasting glucose, reduced hepatic glucose, and elevated glucose clearance inversely correlated with fetal body and brain weight. Taken together, these data suggest that alcohol blunts the adaptive changes in maternal glucose metabolism that otherwise enhance fetal glucose availability. Compensatory attempts by the fetus to increase glucose pools via gluconeogenesis do not normalize brain glucose. These metabolic changes may contribute to the impaired fetal growth and brain development that typifies PAE.

The metabolic adaptation of bile acids and cholesterol after biliary atresia in lamprey via transcriptome-based analysis

Lamprey underwent biliary atresia (BA) at its metamorphosis stage. In contrast to patients with BA who develop progressive disease, lamprey can grow and develop normally, suggesting that lamprey has several adaptations for BA. Here we show that adaptive changes in bile acid and cholesterol metabolism are produced after lamprey BA. Among 1102 differentially expressed genes (DGEs) after BA in lamprey, many are enriched in gene ontology (GO) terms and pathways related to steroid metabolism. We find that among the DGEs related to bile acids and cholesterol metabolism, the expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1), sodium-dependent taurine cotransport polypeptide (NTCP) are significantly downregulated, whereas nuclear receptor farnesoid X receptor (FXR), multidrug resistance-associated protein 3 (MRP3), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), sterol O-acyltransferase 1 (SOAT1), and ATP binding cassette subfamily A member 1 (ABCA1) are remarkably upregulated. The changes in expression level are also validated by RT-qPCR. Furthermore, the level of high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in juvenile serum is higher compared to larvae. Taken together, the findings collectively indicate that after BA, lamprey may maintain bile acids and cholesterol homeostasis in liver tissue by inhibiting bile acids synthesis and uptake, promoting its efflux back to circulation, and enhancing cholesterol esterification for storage as lipid droplets and its egress to form nascent HDL (nHDL). Understanding the possible molecular mechanisms of lamprey metabolic adaptation sheds new light on the understanding of the development and treatment of diseases caused by abnormal bile acid and cholesterol metabolism in humans.

Adaptive Changes in Detoxification Metabolism and Transmembrane Transport of Bombyx mori Malpighian Tubules to Artificial Diet.

The high adaptability of insects to food sources has contributed to their ranking among the most abundant and diverse species on Earth. However, the molecular mechanisms underlying the rapid adaptation of insects to different foods remain unclear. We explored the changes in gene expression and metabolic composition of the Malpighian tubules as an important metabolic excretion and detoxification organ in silkworms (Bombyx mori) fed mulberry leaf and artificial diets. A total of 2436 differentially expressed genes (DEGs) and 245 differential metabolites were identified between groups, with the majority of DEGs associated with metabolic detoxification, transmembrane transport, and mitochondrial function. Detoxification enzymes, such as cytochrome P450 (CYP), glutathione-S-transferase (GST), and UDP-glycosyltransferase, and ABC and SLC transporters of endogenous and exogenous solutes were more abundant in the artificial diet group. Enzyme activity assays confirmed increased CYP and GST activity in the Malpighian tubules of the artificial diet-fed group. Metabolome analysis showed increased contents of secondary metabolites, terpenoids, flavonoids, alkaloids, organic acids, lipids, and food additives in the artificial diet group. Our findings highlight the important role of the Malpighian tubules in adaptation to different foods and provide guidance for further optimization of artificial diets to improve silkworm breeding.

Trigger Mechanisms of Cypermethrin-Induced Changes of Metabolism: An Experimental Study

Background: The purpose of this work was to study the triggering mechanisms of metabolic changes in experimental animals after a single injection of cypermethrin at a dose of 55 mg/kg of body weight. Methods and Results: Sixty rats were randomly divided into four groups (15 rats in each group). Rats of the control groups (G1 and G3) were injected with saline into the stomach. Animals of the experimental groups (G2 and G4) were injected once with the synthetic pyrethroid cypermethrin at a dose of 55 mg/kg of body weight, which is 1/5 LD50. Before being withdrawn from the experiment, blood was taken in vivo under anesthesia, and the liver was removed. The glucose, lactate, uric acid, and total bilirubin concentrations were determined in blood serum by unified research methods. The content of glutathione (GSH), malondialdehyde (MDA), and activity of glucose-6-phosphate dehydrogenase (G6PDH) was determined in erythrocyte hemolysates. In liver homogenates, the content of total protein, glycogen, uric acid, and inorganic phosphorus (Pi) was determined by unified methods, as well as MDA, GSH, activity of G6PDH, microsomal oxygenase, glutathione-S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR). Administration of cypermethrin to laboratory rats at a dose of 1/5 LD50 causes adaptive changes in metabolism. After one day, there was an increase in the content of glucose in the blood serum against the background of a deficiency of carbohydrates in the liver tissue. At the same time, there was an increase in anaerobic oxidation and an increase in purine catabolism, which was associated with the activation of lipid peroxidation (LP) of cell membranes and the depletion of the pool of antioxidants. GSH deficiency was exacerbated by an increase in the activity of antioxidant enzymes and xenobiotic biotransformation systems. Seven days after the administration of cypermethrin, rats retained a high rate of breakdown of purines to uric acid. This process was enhanced by a decrease in the RBC, a deficiency of carbohydrates, and inhibition of the activity of G6PDH, GPx, and GR. This ultimately led to the development of oxidative stress. Conclusion: The triggers for the development of oxidative stress under cypermethrin exposure are lactic acidosis and increased catabolism of purine mononucleotides, accompanied by an increase in the production of free radicals and inhibition of the function of the antioxidant system. A decrease in the blood RBC, carbohydrate deficiency, and suppression of the activity of the pentose cycle 7 days after the administration of cypermethrin aggravate this condition.

Regulation of the regulators: Transcription factors controlling biosynthesis of plant secondary metabolites during biotic stresses and their regulation by miRNAs.

Biotic stresses threaten to destabilize global food security and cause major losses to crop yield worldwide. In response to pest and pathogen attacks, plants trigger many adaptive cellular, morphological, physiological, and metabolic changes. One of the crucial stress-induced adaptive responses is the synthesis and accumulation of plant secondary metabolites (PSMs). PSMs mitigate the adverse effects of stress by maintaining the normal physiological and metabolic functioning of the plants, thereby providing stress tolerance. This differential production of PSMs is tightly orchestrated by master regulatory elements, Transcription factors (TFs) express differentially or undergo transcriptional and translational modifications during stress conditions and influence the production of PSMs. Amongst others, microRNAs, a class of small, non-coding RNA molecules that regulate gene expression post-transcriptionally, also play a vital role in controlling the expression of many such TFs. The present review summarizes the role of stress-inducible TFs in synthesizing and accumulating secondary metabolites and also highlights how miRNAs fine-tune the differential expression of various stress-responsive transcription factors during biotic stress.

Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism

ObjectiveSGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molecular effects of 5 weeks of dapagliflozin treatment on skeletal muscle metabolism in type 2 diabetes patients. MethodsTwenty-six type 2 diabetes mellitus patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. Skeletal muscle acetylcarnitine levels, intramyocellular lipid (IMCL) content and phosphocreatine (PCr) recovery rate were measured by magnetic resonance spectroscopy (MRS). Ex vivo mitochondrial respiration was measured in skeletal muscle fibers using high resolution respirometry. Intramyocellular lipid droplet and mitochondrial network dynamics were investigated using confocal microscopy. Skeletal muscle levels of acylcarnitines, amino acids and TCA cycle intermediates were measured. Expression of genes involved in fatty acid metabolism were investigated. ResultsMitochondrial function, mitochondrial network integrity and citrate synthase and carnitine acetyltransferase activities in skeletal muscle were unaltered after dapagliflozin treatment. Dapagliflozin treatment increased intramyocellular lipid content (0.060 (0.011, 0.110) %, p = 0.019). Myocellular lipid droplets increased in size (0.03 μm2 (0.01–0.06), p < 0.05) and number (0.003 μm−2 (−0.001–0.007), p = 0.09) upon dapagliflozin treatment. CPT1A, CPT1B and malonyl CoA-decarboxylase mRNA expression was increased by dapagliflozin. Fasting acylcarnitine species and C4–OH carnitine levels (0.4704 (0.1246, 0.8162) pmoles∗mg tissue−1, p < 0.001) in skeletal muscle were higher after dapagliflozin treatment, while acetylcarnitine levels were lower (−40.0774 (−64.4766, −15.6782) pmoles∗mg tissue−1, p < 0.001). Fasting levels of several amino acids, succinate, alpha-ketoglutarate and lactate in skeletal muscle were significantly lower after dapagliflozin treatment. ConclusionDapagliflozin treatment for 5 weeks leads to adaptive changes in skeletal muscle substrate metabolism favoring metabolism of fatty acid and ketone bodies and reduced glycolytic flux.The trial is registered with ClinicalTrials.gov, number NCT03338855.

Reconstructed Genome-Scale Metabolic Model Characterizes Adaptive Metabolic Flux Changes in Peripheral Blood Mononuclear Cells in Severe COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a mortal threat to human health. The elucidation of the relationship between peripheral immune cells and the development of inflammation is essential for revealing the pathogenic mechanism of COVID-19 and developing related antiviral drugs. The immune cell metabolism-targeting therapies exhibit a desirable anti-inflammatory effect in some treatment cases. In this study, based on differentially expressed gene (DEG) analysis, a genome-scale metabolic model (GSMM) was reconstructed by integrating transcriptome data to characterize the adaptive metabolic changes in peripheral blood mononuclear cells (PBMCs) in severe COVID-19 patients. Differential flux analysis revealed that metabolic changes such as enhanced aerobic glycolysis, impaired oxidative phosphorylation, fluctuating biogenesis of lipids, vitamins (folate and retinol), and nucleotides played important roles in the inflammation adaptation of PBMCs. Moreover, the main metabolic enzymes such as the solute carrier (SLC) family 2 member 3 (SLC2A3) and fatty acid synthase (FASN), responsible for the reactions with large differential fluxes, were identified as potential therapeutic targets. Our results revealed the inflammation regulation potentials of partial metabolic reactions with differential fluxes and their metabolites. This study provides a reference for developing potential PBMC metabolism-targeting therapy strategies against COVID-19.

Discrepancy in Sterol Usage between Two Polyphagous Caterpillars, Mythimna separata and Spodoptera frugiperda.

Simple SummaryMythimna separata and Spodoptera frugiperda are two destructive pests worldwide. In this study, for the first time, we evaluated their sterol metabolic capacity. The results showed that Spodoptera frugiperda required less sterol for normal growth, which helped them survive better when cholesterol was unavailable. Both insects consistently showed high fitness when they fed on cholestanol. Cholestanone enabled most individuals of S. frugiperda to pupate but caused remarkable lethality to M. separata at their early developmental stage. Comparative studies indicated that S. frugiperda was more efficient in converting ketone into available stanol than M. separata. Therefore, they perform differently in terms of their sterol demand and metabolism although these two species are closely related. The divergences in sterol nutritional biology between the two closely related insect species reflect adaptive and evolutive changes in sterol metabolism, which may help us to better understand the potential of using phytosterol-manipulated plants to control pests.Insects are sterol auxotrophs and typically obtain sterols from food. However, the sterol demand and metabolic capacity vary greatly among species, even for closely related species. The low survival of many insects on atypical sterols, such as cholestanol and cholestanone, raises the possibility of using sterol-modified plants to control insect herbivore pests. In this study, we evaluated two devastating migratory crop pests, Mythimna separata and Spodoptera frugiperda, in response to atypical sterols and explored the reasons that caused the divergences in sterol nutritional biology between them. Contrary to M. separata, S. frugiperda had unexpectedly high survival on cholestanone, and nearly 80% of the individuals pupated. Comparative studies, including insect response to multiple diets and larval body sterol/steroids analysis, were performed to explain their differences in cholestanone usage. Our results showed that, in comparison to M. separata, the superiority of S. frugiperda on cholestanone can be attributed to its higher efficiency of converting ketone into available stanol and its lower demand for sterols, which resulted in a better survival when cholesterol was unavailable. This research will help us to better understand insect sterol nutritional biology and the potential of using atypical sterols to control herbivorous insect pests.

S6.3c Adaptive dynamics in experimental populations of Aspergillus nidulans

S6.3 Fungal adaptation and evolution, September 22, 2022, 4:45 PM - 6:15 PM A total of 12 replicate populations initiated with a laboratory strain of the ascomycete fungus Aspergillus nidulans evolved on synthetic minimal glucose agar medium for 1 year, using weekly transfers of 1% of the produced asexual spores to fresh medium. This Aspergillus short-term evolution experiment (ASEX) was designed to understand how filamentous fungi adapt to growth on limited carbon in a spatially structured environment. We observed no systematic improvement in the fitness components tested and neither in the competitive fitness relative to the ancestor. Instead, we observed the repeated evolution of at least two morphotypes, with a fluffy-like (FL) or an ancestor-like (AL) colony morphology, leading to non-transitive fitness interactions among isolates in two selected populations. The genomic analyses of clones from all 12 populations at an early (week 10) and the final time point (week 52), show a clear role of natural selection during ASEX. We also observed a shared genetic basis and different timing of adaptation of AL and FL types. In addition, in most populations, both morphotypes do not form monophyletic groups, but they frequently disappear and re-evolve from ancestral forms of both types. Reduction in asexual spore yield, the most evident parallel phenotypic change found in all our evolved populations, is not due to the direct selection of genes involved in asexual reproduction. Instead, we argue that reduced spore yield is a pleiotropic effect of adaptive changes in metabolism.