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Water metabolism regulating mechanisms in hypokinesia
The range of daily fluctuations of the proportion of the amount of consumed water and its content in the body was evaluated by means of a water metabolism regulation factor. This index constitutes a relative measure of fluctuations of the constant of tritium water elimination from the body per 24 hours. It is established that under conditions of long term hypokinesia regulation of water metabolism is disturbed both in humans and in animals. Still more marked changes are observed 2 to 3 weeks after restoration of motor activity. The shifts noted are evidence of general biological regularity of disturbance of regulation systems in long term restriction of motor activity and in the early restoration period.
A Quantitative Study of Oxygen as a Metabolic Regulator
An acute reduction in oxygen delivery to a tissue is associated with metabolic changes aimed at maintaining ATP homeostasis. However, given the complexity of the human bio-energetic system, it is difficult to determine quantitatively how cellular metabolic processes interact to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). In particular, we are interested in determining mechanisms relating cellular oxygen concentration to observed metabolic responses at the cellular, tissue, organ, and whole body levels and in quantifying how changes in tissue oxygen availability affect the pathways of ATP synthesis and the metabolites that control these pathways. In this study; we extend a previously developed mathematical model of human bioenergetics, to provide a physicochemical framework that permits quantitative understanding of oxygen as a metabolic regulator. Specifically, the enhancement - sensitivity analysis - permits studying the effects of variations in tissue oxygenation and parameters controlling cellular respiration on glycolysis, lactate production, and pyruvate oxidation. The analysis can distinguish between parameters that must be determined accurately and those that require less precision, based on their effects on model predictions. This capability may prove to be important in optimizing experimental design, thus reducing use of animals.
A quantitative study of oxygen as a metabolic regulator
An acute reduction in oxygen delivery to a tissue is associated with metabolic changes aimed at maintaining ATP homeostasis. However, given the complexity of the human bioenergetic system, it is difficult to determine quantitatively how cellular metabolic processes interact to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). In particular, we are interested in determining mechanisms relating cellular oxygen concentration to observed metabolic responses at the cellular, tissue, organ, and whole body levels and in quantifying how changes in tissue oxygen availability affect the pathways of ATP synthesis and the metabolites that control these pathways. In this study, we extend a previously developed mathematical model of human bioenergetics, to provide a physicochemical framework that permits quantitative understanding of oxygen as a metabolic regulator. Specifically, the enhancement--sensitivity analysis--permits studying the effects of variations in tissue oxygenation and parameters controlling cellular respiration on glycolysis, lactate production, and pyruvate oxidation. The analysis can distinguish between parameters that must be determined accurately and those that require less precision, based on their effects on model predictions. This capability may prove to be important in optimizing experimental design, thus reducing use of animals.
A Quantitative Study of Oxygen as a Metabolic Regulator
An acute reduction in oxygen (O2) delivery to a tissue is generally associated with a decrease in phosphocreatine, increases in ADP, NADH/NAD, and inorganic phosphate, increased rates of glycolysis and lactate production, and reduced rates of pyruvate and fatty acid oxidation. However, given the complexity of the human bioenergetic system and its components, it is difficult to determine quantitatively how cellular metabolic processes interact to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in tissue O2 availability affect the pathways of ATP synthesis and the metabolites that control these pathways. In this study, we extend a previously developed mathematical model of human bioenergetics to provide a physicochemical framework that permits quantitative understanding of O2 as a metabolic regulator. Specifically, the enhancement permits studying the effects of variations in tissue oxygenation and in parameters controlling the rate of cellular respiration on glycolysis, lactate production, and pyruvate oxidation. The whole body is described as a bioenergetic system consisting of metabolically distinct tissue/organ subsystems that exchange materials with the blood. In order to study the dynamic response of each subsystem to stimuli, we solve the ordinary differential equations describing the temporal evolution of metabolite levels, given the initial concentrations. The solver used in the present study is the packaged code LSODE, as implemented in the NASA Lewis kinetics and sensitivity analysis code, LSENS. A major advantage of LSENS is the efficient procedures supporting systematic sensitivity analysis, which provides the basic methods for studying parameter sensitivities (i.e., changes in model behavior due to parameter variation). Sensitivity analysis establishes relationships between model predictions and problem parameters (i.e., initial concentrations, rate coefficients, etc). It helps determine the effects of uncertainties or changes in these input parameters on the predictions, which ultimately are compared with experimental observations in order to validate the model. Sensitivity analysis can identify parameters that must be determined accurately because of their large effect on the model predictions and parameters that need not be known with great precision because they have little or no effect on the solution. This capability may prove to be important in optimizing the design of experiments, thereby reducing the use of animals. This approach can be applied to study the metabolic effects of reduced oxygen delivery to cardiac muscle due to local myocardial ischemia and the effects of acute hypoxia on brain metabolism. Other important applications of sensitivity analysis include identification of quantitatively relevant pathways and biochemical species within an overall mechanism, when examining the effects of a genetic anomaly or pathological state on energetic system components and whole system behavior.
Harnessing redox proteomics to study metabolic regulation and stress response in lignin-fed Rhodococci
Abstract Background Rhodococci are studied for their bacterial ligninolytic capabilities and proclivity to accumulate lipids. Lignin utilization is a resource intensive process requiring a variety of redox active enzymes and cofactors for degradation as well as defense against the resulting toxic byproducts and oxidative conditions. Studying enzyme expression and regulation between carbon sources will help decode the metabolic rewiring that stymies lignin to lipid conversion in these bacteria. Herein, a redox proteomics approach was applied to investigate a fundamental driver of carbon catabolism and lipid anabolism: redox balance. Results A consortium of Rhodococcus strains was employed in this study given its higher capacity for lignin degradation compared to monocultures. This consortium was grown on glucose vs. lignin under nitrogen limitation to study the importance of redox balance as it relates to nutrient availability. A modified bottom–up proteomics workflow was harnessed to acquire a general relationship between protein abundance and protein redox states. Global proteomics results affirm differential expression of enzymes involved in sugar metabolism vs. those involved in lignin degradation and aromatics metabolism. As reported previously, several enzymes in the lipid biosynthetic pathways were downregulated, whereas many involved in β-oxidation were upregulated. Interestingly, proteins involved in oxidative stress response were also upregulated perhaps in response to lignin degradation and aromatics catabolism, which require oxygen and reactive oxygen species and generate toxic byproducts. Enzymes displaying little-to-no change in abundance but differences in redox state were observed in various pathways for carbon utilization (e.g., β‑ketoadipate pathway), lipid metabolism, as well as nitrogen metabolism (e.g., purine scavenging/synthesis), suggesting potential mechanisms of redox-dependent regulation of metabolism. Conclusions Efficient lipid production requires a steady carbon and energy flux while balancing fundamental requirements for enzyme production and cell maintenance. For lignin, we theorize that this balance is difficult to establish due to resource expenditure for enzyme production and stress response. This is supported by significant changes to protein abundances and protein cysteine oxidation in various metabolic pathways and redox processes.
Spatiotemporal 4D Whole-cell Modeling of a Minimal Autotroph Reveals Central Carbon Metabolism Regulated Locally by Protein Megacomplexes via Post-translational Modifications under Light Disturbance
Photosynthetic microorganisms rely on multiple pathways in central carbon metabolism to adapt to fluctuating light and energy availability across diel cycles. Mechanistic insight into the regulatory dynamics of this adaptation requires integrating processes spanning disparate timescales, from rapid redox-dependent post-translational modifications (PTMs) to slower changes in protein expression and metabolic pathway usage. To address this complexity beyond genome-based inference and traditional modeling, we develop a whole-cell four-dimensional (3D + time) model of the marine cyanobacterium Prochlorococcus marinus MED4 that explicitly represents the spatial organization of enzymatic and molecular processes in central carbon metabolism under light perturbation. We employ a perturbation-based research design to experimentally generate time-series, multi-omics measurements that provide molecular descriptors and cryo-ET derived 3D segmented volumes as constraints for this dynamic 4D framework. The integration of experiments and modeling across defined light regimes enables quantitative validation of system-level responses and forecasting under distinct light disturbances. We test the hypothesis that light-dependent redox PTMs regulating the structural assembly of a protein megacomplex, the “dark complex,” modulate metabolic flux at a conserved regulatory node of the Calvin–Benson cycle (CBC) in cyanobacteria. Our model shows that subcellular spatial organization buffers rapid light-induced changes in thylakoid reaction rates, which are followed by redox-PTM-mediated sequestration or release of CBC enzymes in the dark complex, ultimately impacting carbon fixation dynamics within carboxysomes. Comparison with an equivalently parameterized well-mixed stochastic model demonstrates that post-translational regulation not only buffers transcriptional noise and diffusion-driven fluctuations but also stabilizes phenotypic outcomes, underscoring the importance of spatial heterogeneity in phenotypic robustness. This ability to probe adaptive, spatiotemporally resolved mechanisms in photosynthetic machinery and central carbon metabolism addresses a critical gap in genotype-to-phenotype inference and expands modeling and design capabilities for understudied or genetically intractable autotrophs such as P. marinus MED4.
The global anaerobic metabolism regulator fnr is necessary for the degradation of food dyes and drugs by Escherichia coli
ABSTRACT The microbiome is an underappreciated contributor to intestinal drug metabolism with broad implications for drug efficacy and toxicity. While considerable progress has been made toward identifying the gut bacterial genes and enzymes involved, the role of environmental factors in shaping their activity remains poorly understood. Here, we focus on the gut bacterial reduction of azo bonds (R-N = N-R’), found in diverse chemicals in both food and drugs. Surprisingly, the canonical azoR gene in Escherichia coli was dispensable for azo bond reduction. Instead, azoreductase activity was controlled by the fumarate and nitrate reduction ( fnr ) regulator, consistent with a requirement for the anoxic conditions found within the gastrointestinal tract. Paired transcriptomic and proteomic analysis of the fnr regulon revealed that in addition to altering the expression of multiple reductases, FNR is necessary for the metabolism of L-Cysteine to hydrogen sulfide, enabling the degradation of azo bonds. Furthermore, we found that FNR indirectly regulates this process through the small noncoding regulatory RNA fnrS . Taken together, these results show how gut bacteria sense and respond to their intestinal environment to enable the metabolism of chemical groups found in both dietary and pharmaceutical compounds. IMPORTANCE This work has broad relevance due to the ubiquity of dyes containing azo bonds in food and drugs. We report that azo dyes can be degraded by human gut bacteria through both enzymatic and nonenzymatic mechanisms, even from a single gut bacterial species. Furthermore, we revealed that environmental factors, oxygen, and L-Cysteine control the ability of E. coli to degrade azo dyes due to their impacts on bacterial transcription and metabolism. These results open up new opportunities to manipulate the azoreductase activity of the gut microbiome through the manipulation of host diet, suggest that azoreductase potential may be altered in patients suffering from gastrointestinal disease, and highlight the importance of studying bacterial enzymes for drug metabolism in their natural cellular and ecological context.
Exploring Camelina sativa lipid metabolism regulation by combining gene co-expression and DNA affinity purification analyses
Camelina (Camelina sativa) is an annual oilseed plant that is gaining momentum as a biofuel cover crop. Understanding gene regulatory networks is essential to deciphering plant metabolic pathways, including lipid metabolism. Furthermore, we take advantage of a growing collection of gene expression datasets to predict transcription factors (TFs) associated with the control of Camelina lipid metabolism. We identified approximately 350 TFs highly co-expressed with lipid-related genes (LRGs). These TFs are highly represented in the MYB, AP2/ERF, bZIP, and bHLH families, including a significant number of homologs of well-known Arabidopsis lipid and seed developmental regulators. After prioritizing the top 22 TFs for further validation, we identified DNA-binding sites and predicted target genes for 16 out of the 22 TFs tested using DNA affinity purification followed by sequencing (DAP-seq). Enrichment analyses of targets supported the co-expression prediction for most TF candidates, and the comparison to Arabidopsis revealed some common themes, but also aspects unique to Camelina. Within the top potential lipid regulators, we identified CsaMYB1, CsaABI3AVP1-2, CsaHB1, CsaNAC2, CsaMYB3, and CsaNAC1 as likely involved in the control of seed fatty acid elongation and CsaABI3AVP1-2 and CsabZIP1 as potential regulators of the synthesis and degradation of triacylglycerols (TAGs), respectively. Altogether, the integration of co-expression data and DNA-binding assays permitted us to generate a high-confidence and short list of Camelina TFs involved in the control of lipid metabolism during seed development.
Continuous NF-κB pathway inhibition promotes expansion of human phenotypical hematopoietic stem/progenitor cells through metabolism regulation
Highlights: • Small molecular inhibition of NF-κB pathway efficiently expands human HSPCs. • NF-κB inhibition with TPCA-1 improves the self-renewal potential and biological function maintenance of expanded CD34{sup +} cells. • NF-κB pathway inhibition reprograms metabolism and enhances glycolysis. • Continuous NF-κB inhibition is required in the culture process to facilitate primitive HSC maintenance. Hematopoietic stem/progenitor cells (HSPCs) ex vivo expansion is critical in facilitating their widespread clinical application. NF-κB pathway is implicated in the energy homeostasis and metabolic adaptation. To explore the effect of NF-κB pathway on the ex vivo HSPC expansion and metabolism, the 50 nM–1 μM inhibitor of NF-κB pathway TPCA-1 was used to expand cord blood derived CD34{sup +} cells in serum-free culture. The expansion folds, function, mitochondrial profile and metabolism of HSPCs were determined. After 10 days of culture with 100 nM TPCA-1, the expansion of total cells CD34{sup +}CD38{sup −} cells and CD34{sup +}CD38{sup −}CD45RA{sup −}CD90{sup +}CD49f{sup +} cells were significantly increased compared to the cytokine priming alone. Notably, TPCA-1 treatment generated ~ 2-fold greater percentage of CD34{sup +}EPCR{sup +} and CD34{sup +}CD38{sup −}CD45RA{sup −}CD90{sup +}CD49f{sup +} cells compared to cytokine only conditions. Moreover, TPCA-1 expanded CD34{sup +} cells displayed enhanced serial colonies forming potential and secondary expansion capability. NF-κB inhibition increased the expression of self-renewal related genes, while downregulated the expression of mitochondrial biogenesis regulator (Pgc1α) and mitochondrial chaperones and proteases (ClpP, Hsp10, Hsp60). Mitochondrial mass and membrane potential were markedly decreased with TPCA-1 treatment, leading to the reduced mitochondrial reactive oxygen species (ROS) level in HSPCs. NF-κB inhibition displayed augmented glycolysis rate with compromising mitochondrial metabolism. This study demonstrated that NF-κB pathway inhibition improved glycolysis and limited ROS production that promoted the ex vivo expansion and maintenance of functional HSPCs.
Effects of cold stress on metabolic regulation in the overwintering larvae of the Chinese white pine beetle, Dendroctonus armandi
Abstract The Chinese white pine beetle, Dendroctonus armandi Tsai & Li (Coleoptera: Curculionidae, Scolytinae), is considered the most destructive forest pest in the Qinling and Bashan Mountains of China. In recent years, winter temperature has dropped in these regions, and extremely low temperatures are hard to survive for insects. Cold hardiness becomes a crucial strategy because temperature change often leads to fluctuations in insect abundance, and the metabolism rate is a key index of resistance to cold in overwintering insects. Therefore, we investigated the relationship between the change in respiratory rate and the activity of metabolism‐related mitochondrial enzymes in D. armandi larvae under cold conditions. We found that the respiratory rate decreased, and it was matched with the activity of glutamate dehydrogenase, aconitase, and lipase during overwintering. Among the various test times under cold conditions, the respiratory rate also decreased with decreasing temperature and increased under very low temperatures. At all cold stress periods, glutamate dehydrogenase and lipase showed increased activity at higher temperatures and decreased activity under lower temperatures, but the activity of NAD‐malic enzyme, NADP‐malic enzyme, mitochondrial isocitrate dehydrogenase, and aconitase were contrary. Under all low temperatures, the activity of enzymes – except for NADP‐malic enzyme, glutamate dehydrogenase, and lipase – increased in short‐term cold stress and decreased in long‐term cold stress at 4, 0, −4, −6, −8, and −10 °C. However, at −2 °C, the activity of enzymes showed a decreasing trend in short‐term treatments and an increasing trend in long‐term treatments, except for mitochondrial isocitrate dehydrogenase. The results not only improve our understanding of the metabolic mechanism of cold adaptation in D. armandi , but also provide an important experimental basis for further study and biological pest control.
A review of methods for the reconstruction and analysis of integrated genome-scale models of metabolism and regulation
The current survey aims to describe the main methodologies for extending the reconstruction and analysis of genome-scale metabolic models and phenotype simulation with Flux Balance Analysis mathematical frameworks, via the integration of Transcriptional Regulatory Networks and/or gene expression data. Although the surveyed methods are aimed at improving phenotype simulations obtained from these models, the perspective of reconstructing integrated genome-scale models of metabolism and gene expression for diverse prokaryotes is still an open challenge.
Cortical cell size regulates root metabolic cost
SUMMARY It has been hypothesized that vacuolar occupancy in mature root cortical parenchyma cells regulates root metabolic cost and thereby plant fitness under conditions of drought, suboptimal nutrient availability, and increased soil mechanical impedance. However, the mechanistic role of vacuoles in reducing root metabolic cost was unproven. Here we provide evidence to support this hypothesis. We first show that root cortical cell size is determined by both cortical cell diameter and cell length. Significant genotypic variation for both cortical cell diameter (~1.1‐ to 1.5‐fold) and cortical cell length (~ 1.3‐ to 7‐fold) was observed in maize and wheat. GWAS and QTL analyses indicate cortical cell diameter and length are heritable and under independent genetic control. We identify candidate genes for both phenes. Empirical results from isophenic lines contrasting for cortical cell diameter and length show that increased cell size, due to either diameter or length, is associated with reduced root respiration, nitrogen content, and phosphorus content.RootSlice, a functional‐structural model of root anatomy, predicts that an increased vacuolar: cytoplasmic ratio per unit cortical volume causes reduced root respiration and nutrient content. Ultrastructural imaging of cortical parenchyma cells with varying cortical diameter and cortical cell length confirms thein silicopredictions and shows that an increase in cell size is correlated with increased vacuolar volume and reduced cytoplasmic volume. Vacuolar occupancy and its relationship with cell size merits further investigation as a phene for improving crop adaptation to edaphic stress.
Xylanolytic metabolism is regulated by coordination of transcription factors XynR and XylR in extremely thermophilic Caldicellulosiruptorales
ABSTRACT Global transcription factors (TFs) control metabolic processes in bacteria to efficiently utilize available carbon. The orderCaldicellulosiruptoraleshas drawn interest due to the ability of its members to degrade components of lignocellulosic biomass. Regulatory reconstruction ofAnaerocellum (f. Caldicellulosiruptor) besciiidentified two major global transcription factors for xylan utilization, XynR and XylR, and the corresponding putative transcription factor binding sites. Recombinant versions of XynR (LacI family) and XylR (ROK family) were subjected to fluorescence polarization (FP) and biolayer interferometry (BLI) analysis to confirm the predicted binding sites. Four XynR sites and two XylR sites were validated, accounting for 20 of 26 genes regulated by XynR and six of seven genes regulated by XylR. Bioinformatic analysis of the individual genes controlled by the two regulators showed an inter-dependent scheme for xylan conversion; the transport of xylooligosaccharides (XOS) is dependent on XylR, while enzymes responsible for hydrolysis are controlled by both regulators. For xylose catabolism by the xylose isomerase-xylulose kinase pathway, regulation is also split, with XylR controlling xylose isomerase and XynR controlling xylokinase. The XynR/XylR regulator pair withinA. besciiis conserved in all sequenced species ofCaldicellulosiruptorales, suggesting similarities in regulating linear xylan conversion. In other xylanolytic thermophiles, XylR homologs control xylan degradation, compared to just 6 out of 26 genes forA. bescii. These results show that two separate regulatory schemes (dual repression) are coordinated byA. besciito effectively regulate the hemicellulose inventory and xylan catabolism. IMPORTANCE To take full advantage of extreme thermophiles as platform metabolic engineering microorganisms, the tools for genetic manipulation must be further developed, and strategies that exploit a better understanding of metabolic regulation need to be discerned.Anaerocellum bescii, the most studied of the extremely thermophilic fermentative anaerobic bacteria that can utilize microcrystalline cellulose, can degrade microcrystalline cellulose and hemicellulose and has been metabolically engineered to convert the resulting sugars to products such as ethanol and acetone. For xylan, in particular, two major global transcription factors (TFs), XynR and XylR, play a role in sugar metabolism, although their predicted regulatory interdependence from bioinformatics analysis has not been elucidated experimentally. Here, fluorescence polarization (FP) and biolayer interferometry (BLI) were used to explore this issue to support metabolic engineering efforts aimed at improving carbohydrate processing to industrial chemicals.
Bromodomain-containing protein 7 regulates matrix metabolism and apoptosis in human nucleus pulposus cells through the BRD7-PI3K-YAP1 signaling axis
Intervertebral disc degeneration (IDD) results from dysregulated metabolism of the extracellular matrix of the nucleus pulposus (NP) and involves the participation of inflammatory factors such as TNF-α. Bromodomain-containing protein 7 (BRD7) shows considerable potential for anti-inflammatory applications. Herein, we investigated the role of BRD7 in IDD. The immunohistochemistry results demonstrated decreased BRD7 expression in severely degenerated human NP tissues compared to those showing mild degeneration. Lentiviruses and adenoviruses were used to knock down or overexpress BRD7 and YAP1, respectively. Our results revealed that BRD7 knockdown promoted matrix degradation and suppressed PI3K and YAP1 expression, while BRD7 overexpression alleviated matrix degradation and promoted YAP1 and PI3K expression. In addition, PI3K inhibition augmented matrix degradation, enhanced apoptosis, and reduced YAP1 expression, whereas YAP1 overexpression promoted matrix synthesis, suppressed apoptosis and promoted PI3K expression. Besides, BRD7 overexpression reversed the reductions in sulfated glycosaminoglycan levels induced by TNF-α, but this effect was blocked by PI3K or YAP1 inhibitors. Moreover, YAP1 and PI3K were shown to interact through coimmunoprecipitation analysis. In summary, our results demonstrate that BRD7 can regulate matrix metabolism and apoptosis in human NP cells through the BRD7-PI3K-YAP1 signaling axis. This study might provide new insights into the prevention and treatment of IDD.
Programmable gene regulation for metabolic engineering using decoy transcription factor binding sites
Abstract Transcription factor decoy binding sites are short DNA sequences that can titrate a transcription factor away from its natural binding site, therefore regulating gene expression. In this study, we harness synthetic transcription factor decoy systems to regulate gene expression for metabolic pathways in Escherichia coli. We show that transcription factor decoys can effectively regulate expression of native and heterologous genes. Tunability of the decoy can be engineered via changes in copy number or modifications to the DNA decoy site sequence. Using arginine biosynthesis as a showcase, we observed a 16-fold increase in arginine production when we introduced the decoy system to steer metabolic flux towards increased arginine biosynthesis, with negligible growth differences compared to the wild type strain. The decoy-based production strain retains high genetic integrity; in contrast to a gene knock-out approach where mutations were common, we detected no mutations in the production system using the decoy-based strain. We further show that transcription factor decoys are amenable to multiplexed library screening by demonstrating enhanced tolerance to pinene with a combinatorial decoy library. Our study shows that transcription factor decoy binding sites are a powerful and compact tool for metabolic engineering.
Arabidopsis SnRK1 negatively regulates phenylpropanoid metabolism via Kelch domain-containing F-box proteins
Phenylpropanoid metabolism represents a substantial metabolic sink for the photosynthetically fixed carbon. The evolutionarily conserved Sucrose Non-Fermenting Related Kinase 1 (SnRK1) is a major metabolic sensor that reprograms metabolism upon carbon deprivation. However, it is not clear if and how SnRK1-mediated sugar signaling pathway controls phenylpropanoid metabolism. Here, we show that Arabidopsis SnRK1 negatively regulates phenylpropanoid biosynthesis via a group of Kelch domain-containing F-Box (KFB) proteins that are responsible for the ubiquitination and degradation of phenylalanine ammonia lyase (PAL). Down-regulation of AtSnRK1 significantly promoted the accumulation of soluble phenolics and lignin polymers and drastically increased PAL cellular accumulation but only slightly altered its transcription level. Co-expression of SnRK1α with PAL in Nicotiana benthamiana leaves resulted in the severe attenuation of the latter's protein level, but protein interaction assays suggested PAL is not a direct substrate of SnRK1. Furthermore, up- or down-regulation of AtSnRK1 positively affected KFB PALs gene expression, and energy starvation upregulated KFB PAL expression, which partially depends on AtSnRK1. Collectively, our study reveals that SnRK1 negatively regulates phenylpropanoid biosynthesis, and KFB PALs act as regulatory components of the SnRK1 signaling network, transcriptionally regulated by SnRK1 and subsequently mediating proteasomal degradation of PAL in response to the cellular carbon availability.
Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression
Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.