An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming

It has been known adipocytes increase p53 expression and activity in obesity, however, only canonical p53 functions (i.e. senescence and apoptosis) are attributed to inflammation-associated metabolic phenotypes. Whether or not p53 is directly involved in mature adipocyte metabolic regulation remains unclear. Here we show p53 protein expression can be up-regulated in adipocytes by nutrient starvation without activating cell senescence, apoptosis, or a death-related p53 canonical pathway. Inducing the loss of p53 in mature adipocytes significantly reprograms energy metabolism and this effect is primarily mediated through a AMP-activated protein kinase (AMPK) pathway and a novel downstream transcriptional target, lysosomal acid lipase (LAL). The pathophysiological relevance is further demonstrated in a conditional and adipocyte-specific p53 knockout mouse model. Overall, these data support a non-canonical p53 function in the regulation of adipocyte energy homeostasis and indicate that the dysregulation of this pathway may be involved in developing metabolic dysfunction in obesity.

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AMPK promotes induction of a tumor suppressor FLCN through activation of TFEB independently of mTOR

10.1101/499921 ◽

2018 ◽

Author(s):

Caterina Collodet ◽

Marc Foretz ◽

Maria Deak ◽

Laurent Bultot ◽

Sylviane Metairon ◽

...

Keyword(s):

Gene Expression ◽

Tumor Suppressor ◽

Energy Homeostasis ◽

Transcriptome Profiling ◽

Metabolic Reprogramming ◽

Double Knockout ◽

Transcription Factor Eb ◽

Pathway Analyses ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a central energy sensor and master regulator of energy homeostasis. AMPK not only elicits acute metabolic responses, but also promotes metabolic reprogramming and adaptions in the long-term through regulation of specific transcription factors/co-activators. We performed a whole-genome transcriptome profiling in wild-type and AMPK-deficient mouse embryonic fibroblasts (MEF) and primary hepatocytes that had been treated with two distinct classes of small-molecule AMPK activators, namely 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or 991. This led to the identification of distinct compound-dependent gene expression signatures and to the discovery of several AMPK-regulated genes, including Flcn encoding a tumor suppressor and nutrient sensor folliculin (FLCN). Gene set enrichment and pathway analyses identified the lysosomal pathway and the associated transcription factor EB (TFEB) as key transcriptional mediator responsible for AMPK-dependent gene expression changes. AMPK-induced Flcn expression was abolished in TFEB/TFE3 double knockout MEF and the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. Mechanistically, we have found that AMPK promotes the dephosphorylation and nuclear localization of TFEB independently of mTOR activity. Collectively, we identified the AMPK-TFEB-FLCN axis as a potential key regulator for cellular and metabolic homeostasis. Moreover, data from zebrafish with physiologically and pharmacologically activated AMPK supports the existence of the AMPK-TFEB-FLCN cascade in vivo.

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Metabolic control of regulatory T cell (Treg) survival and function by Lkb1

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1715363114 ◽

2017 ◽

Vol 114 (47) ◽

pp. 12542-12547 ◽

Cited By ~ 47

Author(s):

Nanhai He ◽

Weiwei Fan ◽

Brian Henriquez ◽

Ruth T. Yu ◽

Annette R. Atkins ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Cellular Metabolism ◽

Autoimmune Disorder ◽

T Cell Subsets ◽

Quiescent T Cells ◽

And Function ◽

Amp Activated Protein Kinase

The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder. Tregs lacking Lkb1 have defective mitochondria, compromised OXPHOS, depleted cellular ATP, and altered cellular metabolism pathways that compromise their survival and function. Furthermore, we demonstrate that the function of LKB1 in Tregs is largely independent of the AMP-activated protein kinase, but is mediated by the MAP/microtubule affinity-regulating kinases and salt-inducible kinases. Our results define a metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis and tolerance.

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Taurine Reprograms Mammary-Gland Metabolism and Alleviates Inflammation Induced by Streptococcus uberis in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.696101 ◽

2021 ◽

Vol 12 ◽

Author(s):

Riguo Lan ◽

Zhixin Wan ◽

Yuanyuan Xu ◽

Zhenglei Wang ◽

Shaodong Fu ◽

...

Keyword(s):

Metabolic Regulation ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Mammary Glands ◽

Metabolic Reprogramming ◽

Cellular Damage ◽

Economic Losses ◽

Metabolic Dysfunction ◽

Metabolic Homeostasis ◽

Streptococcus Uberis

Streptococcus uberis (S. uberis) is an important pathogen causing mastitis, which causes continuous inflammation and dysfunction of mammary glands and leads to enormous economic losses. Most research on infection continues to be microbial metabolism-centric, and many overlook the fact that pathogens require energy from host. Mouse is a common animal model for studying bovine mastitis. In this perspective, we uncover metabolic reprogramming during host immune responses is associated with infection-driven inflammation, particularly when caused by intracellular bacteria. Taurine, a metabolic regulator, has been shown to effectively ameliorate metabolic diseases. We evaluated the role of taurine in the metabolic regulation of S. uberis-induced mastitis. Metabolic profiling indicates that S. uberis exposure triggers inflammation and metabolic dysfunction of mammary glands and mammary epithelial cells (the main functional cells in mammary glands). Challenge with S. uberis upregulates glycolysis and oxidative phosphorylation in MECs. Pretreatment with taurine restores metabolic homeostasis, reverses metabolic dysfunction by decrease of lipid, amino acid and especially energy disturbance in the infectious context, and alleviates excessive inflammatory responses. These outcomes depend on taurine-mediated activation of the AMPK–mTOR pathway, which inhibits the over activation of inflammatory responses and alleviates cellular damage. Thus, metabolic homeostasis is essential for reducing inflammation. Metabolic modulation can be used as a prophylactic strategy against mastitis.

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Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

International Journal of Molecular Sciences ◽

10.3390/ijms22158295 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8295

Author(s):

Michael G. Appiah ◽

Eun Jeong Park ◽

Yuichi Akama ◽

Yuki Nakamori ◽

Eiji Kawamoto ◽

...

Keyword(s):

Cancer Progression ◽

Immune Cells ◽

Metabolic Regulation ◽

Inflammatory Diseases ◽

Cellular Level ◽

Multiple Organ ◽

Metabolic Reprogramming ◽

Target Cells ◽

Metabolic Dysfunction ◽

Metabolic Signaling

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.

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Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab014 ◽

2021 ◽

Vol 80 (5) ◽

pp. 467-475

Author(s):

Yu-Qing Li ◽

C Shun Wong

Keyword(s):

Cell Fate ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Neuronal Development ◽

Adenosine Monophosphate ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Wild Type ◽

Newborn Neuron ◽

Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

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Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

Nature Communications ◽

10.1038/s41467-021-21617-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jennifer K. Dowling ◽

Remsha Afzal ◽

Linden J. Gearing ◽

Mariana P. Cervantes-Silva ◽

Stephanie Annett ◽

...

Keyword(s):

Metabolic Regulation ◽

Mitochondrial Dynamics ◽

Interleukin 10 ◽

Metabolic Reprogramming ◽

In Vivo Model ◽

Macrophage Polarisation ◽

Inflammatory Status ◽

Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

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Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽

10.3390/cancers13143465 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3465

Author(s):

Aya Saleh ◽

Ruth Perets

Keyword(s):

Cancer Progression ◽

Target Genes ◽

P53 Protein ◽

Genetic Alterations ◽

Common Mutation ◽

Missense Mutations ◽

P53 Expression ◽

Histologic Subtype ◽

Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Cells ◽

10.3390/cells10040903 ◽

2021 ◽

Vol 10 (4) ◽

pp. 903

Author(s):

Xiao-Mei Zhang ◽

De-Gao Chen ◽

Shengwen Calvin Li ◽

Bo Zhu ◽

Zhong-Jun Li

Keyword(s):

Metabolic Regulation ◽

Transcriptional Profiling ◽

Tumor Development ◽

Metabolic Reprogramming ◽

Cancer Therapies ◽

Functional Heterogeneity ◽

Tumor Associated Macrophages ◽

Metabolic Remodeling ◽

And Function ◽

Mapping Models

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

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A Bibenzyl Component Moscatilin Mitigates Glycation-Mediated Damages in an SH-SY5Y Cell Model of Neurodegenerative Diseases through AMPK Activation and RAGE/NF-κB Pathway Suppression

Molecules ◽

10.3390/molecules25194574 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4574

Author(s):

Mei Chou Lai ◽

Wayne Young Liu ◽

Shorong-Shii Liou ◽

I-Min Liu

Keyword(s):

Neurodegenerative Diseases ◽

Cell Model ◽

P53 Expression ◽

Pheochromocytoma Cells ◽

Beneficial Effects ◽

Compound C ◽

Species Production ◽

Amp Activated Protein Kinase ◽

Exposure Ages

Moscatilin can protect rat pheochromocytoma cells against methylglyoxal-induced damage. Elimination of the effect of advanced glycation end-products (AGEs) but activation of AMP-activated protein kinase (AMPK) are the potential therapeutic targets for the neurodegenerative diseases. Our study aimed to clarify AMPK signaling’s role in the beneficial effects of moscatilin on the diabetic/hyperglycemia-associated neurodegenerative disorders. AGEs-induced injury in SH-SY5Y cells was used as an in vitro neurodegenerative model. AGEs stimulation resulted in cellular viability loss and reactive oxygen species production, and mitochondrial membrane potential collapse. It was observed that the cleaved forms of caspase-9, caspase-3, and poly (ADP-ribose) polymerase increased in SH-SY5Y cells following AGEs exposure. AGEs decreased Bcl-2 but increased Bax and p53 expression and nuclear factor kappa-B activation in SH-SY5Y cells. AGEs also attenuated the phosphorylation level of AMPK. These AGEs-induced detrimental effects were ameliorated by moscatilin, which was similar to the actions of metformin. Compound C, an inhibitor of AMPK, abolished the beneficial effects of moscatilin on the regulation of SH-SY5Y cells’ function, indicating the involvement of AMPK. In conclusion, moscatilin offers a promising therapeutic strategy to reduce the neurotoxicity or AMPK dysfunction of AGEs. It provides a potential beneficial effect with AGEs-related neurodegenerative diseases.

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β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

Metabolites ◽

10.3390/metabo10090346 ◽

2020 ◽

Vol 10 (9) ◽

pp. 346

Author(s):

Adrian Benito ◽

Nabil Hajji ◽

Kevin O’Neill ◽

Hector C. Keun ◽

Nelofer Syed

Keyword(s):

Metabolic Regulation ◽

Marker Gene ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Glycolytic Flux ◽

Dihydroxyacetone Phosphate ◽

Glycolytic Intermediate ◽

Critical Set ◽

The Tca Cycle ◽

Bv2 Cells

Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of β-hydroxybutyrate (BHB) in human (HMC3) and murine (BV2) microglia cells and the interplay with glucose in resting and LPS-activated BV2 cells. We found that BHB is imported and oxidised in the TCA cycle in both cell lines with a subsequent increase in the cytosolic NADH:NAD+ ratio. In BV2 cells, stimulation with LPS upregulated the glycolytic flux, increased the cytosolic NADH:NAD+ ratio and promoted the accumulation of the glycolytic intermediate dihydroxyacetone phosphate (DHAP). The addition of BHB enhanced LPS-induced accumulation of DHAP and promoted glucose-derived lactate export. BHB also synergistically increased LPS-induced accumulation of succinate and other key immunometabolites, such as α-ketoglutarate and fumarate generated by the TCA cycle. Finally, BHB upregulated the expression of a key pro-inflammatory (M1 polarisation) marker gene, NOS2, in BV2 cells activated with LPS. In conclusion, we identify BHB as a potentially immunomodulatory metabolic substrate for microglia that promotes metabolic reprogramming during pro-inflammatory response.

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