Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications

Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

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Tissue-specific metabolic reprogramming during wound induced de novo organ formation in tomato hypocotyl explants

10.1101/2021.04.29.441912 ◽

2021 ◽

Author(s):

Eduardo Larriba ◽

Ana Belén Sánchez García ◽

Cristina Martínez-Andújar ◽

Alfonso Albacete ◽

José Manuel Pérez-Pérez

Keyword(s):

De Novo ◽

Metabolic Reprogramming ◽

Apical Region ◽

List Type ◽

Basal Region ◽

Metabolic Switch ◽

Tissue Specific ◽

Hypocotyl Explants ◽

Organ Formation ◽

Organ Regeneration

SUMMARYPlants have remarkable regenerative capacity, which allows them to survive tissue damaging after biotic and abiotic stress. Some of the key transcription factors and the hormone crosstalk involved in wound-induced organ regeneration have been extensively studied in the model plant Arabidopsis thaliana. However, little is known about the role of metabolism in wound-induced organ regeneration.Here, we performed detailed transcriptome analysis and targeted metabolomics approach during de novo organ formation in tomato hypocotyl explants and found tissue-specific metabolic differences and divergent developmental pathways after wounding.Our results indicate that callus growth in the apical region of the hypocotyl depends on a specific metabolic switch involving the upregulation of the photorespiratory pathway and the differential regulation of photosynthesis-related genes and of the gluconeogenesis pathway.The endogenous pattern of ROS accumulation in the apical and basal region of the hypocotyl during the time-course were dynamically regulated, and contributed to tissue-specific wound-induced regeneration.Our findings provide a useful resource for further investigation on the molecular mechanisms involved in wound-induced organ formation in a crop species such as tomato.One-sentence SummaryMetabolic switch during wound-induced regeneration

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Systematic investigation of metabolic reprogramming in different cancers based on tissue-specific metabolic models

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720016440017 ◽

2016 ◽

Vol 14 (05) ◽

pp. 1644001 ◽

Cited By ~ 3

Author(s):

Fangzhou Shen ◽

Jian Li ◽

Ying Zhu ◽

Zhuo Wang

Keyword(s):

Renal Cancer ◽

Drug Targets ◽

Metabolic Flux ◽

Cancer Metabolism ◽

Metabolic Model ◽

Systematic Investigation ◽

Metabolic Reprogramming ◽

Measurement Technology ◽

Normal Cells ◽

Tissue Specific

Cancer cells have different metabolism in contrast to normal cells. The advancement in omics measurement technology enables the genome-wide characterization of altered cellular processes in cancers, but the metabolic flux landscape of cancer is still far from understood. In this study, we compared the well-reconstructed tissue-specific models of five cancers, including breast, liver, lung, renal, and urothelial cancer, and their corresponding normal cells. There are similar patterns in majority of significantly regulated pathways and enriched pathways in correlated reaction sets. But the differences among cancers are also explicit. The renal cancer demonstrates more dramatic difference with other cancer models, including the smallest number of reactions, flux distribution patterns, and specifically correlated pathways. We also validated the predicted essential genes and revealed the Warburg effect by in silico simulation in renal cancer, which are consistent with the measurements for renal cancer. In conclusion, the tissue-specific metabolic model is more suitable to investigate the cancer metabolism. The similarity and heterogenicity of metabolic reprogramming in different cancers are crucial for understanding the aberrant mechanisms of cancer proliferation, which is fundamental for identifying drug targets and biomarkers.

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Tissue-Specific Metabolic Reprogramming during Wound-Induced Organ Formation in Tomato Hypocotyl Explants

International Journal of Molecular Sciences ◽

10.3390/ijms221810112 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10112

Author(s):

Eduardo Larriba ◽

Ana Belén Sánchez-García ◽

Cristina Martínez-Andújar ◽

Alfonso Albacete ◽

José Manuel Pérez-Pérez

Keyword(s):

Molecular Mechanisms ◽

De Novo ◽

Metabolic Reprogramming ◽

Apical Region ◽

Crop Species ◽

Metabolic Switch ◽

Tissue Specific ◽

Hypocotyl Explants ◽

Organ Formation ◽

Organ Regeneration

Plants have remarkable regenerative capacity, which allows them to survive tissue damage after exposure to biotic and abiotic stresses. Some of the key transcription factors and hormone crosstalk mechanisms involved in wound-induced organ regeneration have been extensively studied in the model plant Arabidopsis thaliana. However, little is known about the role of metabolism in wound-induced organ formation. Here, we performed detailed transcriptome analysis and used a targeted metabolomics approach to study de novo organ formation in tomato hypocotyl explants and found tissue-specific metabolic differences and divergent developmental pathways. Our results indicate that successful regeneration in the apical region of the hypocotyl depends on a specific metabolic switch involving the upregulation of photorespiratory pathway components and the differential regulation of photosynthesis-related gene expression and gluconeogenesis pathway activation. These findings provide a useful resource for further investigation of the molecular mechanisms involved in wound-induced organ formation in crop species such as tomato.

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40 YEARS of IGF1: Understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0076 ◽

2018 ◽

Vol 61 (1) ◽

pp. T187-T198 ◽

Cited By ~ 10

Author(s):

Rhonda D Kineman ◽

Mercedes del Rio-Moreno ◽

André Sarmento-Cabral

Keyword(s):

Lipid Metabolism ◽

Nutrient Flux ◽

The Body ◽

Whole Body ◽

Metabolic Function ◽

Tissue Specific ◽

Functional Homology ◽

Carbohydrate And Lipid Metabolism ◽

Age Dependent ◽

Igf1 Receptor

It is clear that insulin-like growth factor-1 (IGF1) is important in supporting growth and regulating metabolism. The IGF1 found in the circulation is primarily produced by the liver hepatocytes, but healthy mature hepatocytes do not express appreciable levels of the IGF1 receptor (IGF1R). Therefore, the metabolic actions of IGF1 are thought to be mediated via extra-hepatocyte actions. Given the structural and functional homology between IGF1/IGF1R and insulin receptor (INSR) signaling, and the fact that IGF1, IGF1R and INSR are expressed in most tissues of the body, it is difficult to separate out the tissue-specific contributions of IGF1/IGF1R in maintaining whole body metabolic function. To circumvent this problem, over the last 20 years, investigators have taken advantage of the Cre/loxP system to manipulate IGF1/IGF1R in a tissue-dependent, and more recently, an age-dependent fashion. These studies have revealed that IGF1/IGF1R can alter extra-hepatocyte function to regulate hormonal inputs to the liver and/or alter tissue-specific carbohydrate and lipid metabolism to alter nutrient flux to liver, where these actions are not mutually exclusive, but serve to integrate the function of all tissues to support the metabolic needs of the organism.

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Analysis of microRNA expression during the torpor-arousal cycle of a mammalian hibernator, the 13-lined ground squirrel

Physiological Genomics ◽

10.1152/physiolgenomics.00005.2016 ◽

2016 ◽

Vol 48 (6) ◽

pp. 388-396 ◽

Cited By ~ 19

Author(s):

Cheng-Wei Wu ◽

Kyle K. Biggar ◽

Bryan E. Luu ◽

Kama E. Szereszewski ◽

Kenneth B. Storey

Keyword(s):

Skeletal Muscle ◽

Ground Squirrel ◽

Muscle Development ◽

Expression Profiles ◽

Ground Squirrels ◽

Microrna Expression ◽

Metabolic Reprogramming ◽

Skeletal Muscle Atrophy ◽

Tissue Specific ◽

Go Annotation

Hibernation is a highly regulated stress response that is utilized by some mammals to survive harsh winter conditions and involves a complex metabolic reprogramming at the cellular level to maintain tissue protections at low temperature. In this study, we profiled the expression of 117 conserved microRNAs in the heart, muscle, and liver of the 13-lined ground squirrel ( Ictidomys tridecemlineatus) across four stages of the torpor-arousal cycle (euthermia, early torpor, late torpor, and interbout arousal) by real-time PCR. We found significant differential regulation of numerous microRNAs that were both tissue specific and torpor stage specific. Among the most significant regulated microRNAs was miR-208b, a positive regulator of muscle development that was found to be upregulated by fivefold in the heart during late torpor (13-fold during arousal), while decreased by 3.7-fold in the skeletal muscle, implicating a potential regulatory role in the development of cardiac hypertrophy and skeletal muscle atrophy in the ground squirrels during torpor. In addition, the insulin resistance marker miR-181a was upregulated by 5.7-fold in the liver during early torpor, which supports previous suggestions of hyperinsulinemia in hibernators during the early stages of the hibernation cycle. Although microRNA expression profiles were largely unique between the three tissues, GO annotation analysis revealed that the putative targets of upregulated microRNAs tend to enrich toward suppression of progrowth-related processes in all three tissues. These findings implicate microRNAs in the regulation of both tissue-specific processes and general suppression of cell growth during hibernation.

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Metabolomic Evaluation of Tissue-Specific Defense Responses in Tomato Plants Modulated by PGPR-Priming against Phytophthora capsici Infection

Plants ◽

10.3390/plants10081530 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1530

Author(s):

Msizi I. Mhlongo ◽

Lizelle A. Piater ◽

Paul A. Steenkamp ◽

Nico Labuschagne ◽

Ian A. Dubery

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

High Performance Liquid Chromatography ◽

Liquid Chromatography ◽

High Performance ◽

Phytophthora Capsici ◽

Metabolic Reprogramming ◽

Disease Suppression ◽

Tissue Specific ◽

Stems And Leaves

Plant growth-promoting rhizobacteria (PGPR) can stimulate disease suppression through the induction of an enhanced state of defense readiness. Here, untargeted ultra-high performance liquid chromatography–mass spectrometry (UHPLC–MS) and targeted ultra-high performance liquid chromatography coupled to triple-quadrupole mass spectrometry (UHPLC–QqQ-MS) were used to investigate metabolic reprogramming in tomato plant tissues in response to priming by Pseudomonas fluorescens N04 and Paenibacillus alvei T22 against Phytophthora capsici. Roots were treated with the two PGPR strains prior to stem inoculation with Ph. capsici. Metabolites were methanol-extracted from roots, stems and leaves at two–eight days post-inoculation. Targeted analysis by UHPLC–QqQ-MS allowed quantification of aromatic amino acids and phytohormones. For untargeted analysis, UHPLC–MS data were chemometrically processed to determine signatory biomarkers related to priming against Ph. capsici. The aromatic amino acid content was differentially reprogrammed in Ps. fluorescens and Pa. alvei primed plants responding to Ph. capsici. Furthermore, abscisic acid and methyl salicylic acid were found to be major signaling molecules in the tripartite interaction. LC–MS metabolomics analysis showed time-dependent metabolic changes in the primed-unchallenged vs. primed-challenged tissues. The annotated metabolites included phenylpropanoids, benzoic acids, glycoalkaloids, flavonoids, amino acids, organic acids, as well as oxygenated fatty acids. Tissue-specific reprogramming across diverse metabolic networks in roots, stems and leaves was also observed, which demonstrated that PGPR priming resulted in modulation of the defense response to Ph. capsici infection.

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Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2021.05.013 ◽

2021 ◽

Author(s):

Zhonghua Wang ◽

Wenqing Fu ◽

Meiling Huo ◽

Bingshu He ◽

Yaqi Liu ◽

...

Keyword(s):

Mass Spectrometry ◽

Diabetic Nephropathy ◽

Mass Spectrometry Imaging ◽

Metabolic Reprogramming ◽

Tissue Specific

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Uteroplacental nutrient flux and evidence for metabolic reprogramming during sustained hypoxemia

Physiological Reports ◽

10.14814/phy2.15033 ◽

2021 ◽

Vol 9 (18) ◽

Author(s):

Amanda K. Jones ◽

Paul J. Rozance ◽

Laura D. Brown ◽

Ramón A. Lorca ◽

Colleen G. Julian ◽

...

Keyword(s):

Nutrient Flux ◽

Metabolic Reprogramming

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Genome Scale Modeling to Study the Metabolic Competition between Cells in the Tumor Microenvironment

Cancers ◽

10.3390/cancers13184609 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4609

Author(s):

Itziar Frades ◽

Carles Foguet ◽

Marta Cascante ◽

Marcos J. Araúzo-Bravo

Keyword(s):

Steady State ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Building Blocks ◽

Linear Constraints ◽

Metabolic Reprogramming ◽

Tissue Specific ◽

Metabolic Fluxes ◽

Genome Scale

The tumor’s physiology emerges from the dynamic interplay of numerous cell types, such as cancer cells, immune cells and stromal cells, within the tumor microenvironment. Immune and cancer cells compete for nutrients within the tumor microenvironment, leading to a metabolic battle between these cell populations. Tumor cells can reprogram their metabolism to meet the high demand of building blocks and ATP for proliferation, and to gain an advantage over the action of immune cells. The study of the metabolic reprogramming mechanisms underlying cancer requires the quantification of metabolic fluxes which can be estimated at the genome-scale with constraint-based or kinetic modeling. Constraint-based models use a set of linear constraints to simulate steady-state metabolic fluxes, whereas kinetic models can simulate both the transient behavior and steady-state values of cellular fluxes and concentrations. The integration of cell- or tissue-specific data enables the construction of context-specific models that reflect cell-type- or tissue-specific metabolic properties. While the available modeling frameworks enable limited modeling of the metabolic crosstalk between tumor and immune cells in the tumor stroma, future developments will likely involve new hybrid kinetic/stoichiometric formulations.

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