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  1. Article ; Online: Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

    Cikes, Domagoj / Leutner, Michael / Cronin, Shane J F / Novatchkova, Maria / Pfleger, Lorenz / Klepochová, Radka / Lair, Benjamin / Lac, Marlène / Bergoglio, Camille / Viguerie, Nathalie / Dürnberger, Gerhard / Roitinger, Elisabeth / Grivej, Mihaela / Rullman, Eric / Gustafsson, Thomas / Hagelkruys, Astrid / Tavernier, Geneviève / Bourlier, Virginie / Knauf, Claude /
    Krebs, Michael / Kautzky-Willer, Alexandra / Moro, Cedric / Krssak, Martin / Orthofer, Michael / Penninger, Josef M

    Nature aging

    2024  Volume 4, Issue 1, Page(s) 80–94

    Abstract: Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. ... ...

    Abstract Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.
    MeSH term(s) Aged ; Animals ; Humans ; Mice ; Aging/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Glucose/metabolism ; Metabolic Networks and Pathways ; Muscle, Skeletal/metabolism ; Phospholipases/metabolism ; Glycerylphosphorylcholine/metabolism
    Chemical Substances Glucose (IY9XDZ35W2) ; GPCPD1 protein, human (EC 3.1.-) ; Phospholipases (EC 3.1.-) ; Glycerylphosphorylcholine (60M22SGW66)
    Language English
    Publishing date 2024-01-18
    Publishing country United States
    Document type Journal Article
    ISSN 2662-8465
    ISSN (online) 2662-8465
    DOI 10.1038/s43587-023-00551-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ChREBPβ is dispensable for the control of glucose homeostasis and energy balance.

    Recazens, Emeline / Tavernier, Geneviève / Dufau, Jérémy / Bergoglio, Camille / Benhamed, Fadila / Cassant-Sourdy, Stéphanie / Marques, Marie-Adeline / Caspar-Bauguil, Sylvie / Brion, Alice / Monbrun, Laurent / Dentin, Renaud / Ferrier, Clara / Leroux, Mélanie / Denechaud, Pierre-Damien / Moro, Cedric / Concordet, Jean-Paul / Postic, Catherine / Mouisel, Etienne / Langin, Dominique

    JCI insight

    2022  Volume 7, Issue 4

    Abstract: Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes 2 isoforms: ChREBPα, the full-length form (translocation into ... ...

    Abstract Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes 2 isoforms: ChREBPα, the full-length form (translocation into the nucleus is under the control of glucose), and ChREBPβ, a constitutively nuclear shorter form. ChREBPβ gene expression in white adipose tissue is strongly associated with insulin sensitivity. Here, we investigated the consequences of ChREBPβ deficiency on insulin action and energy balance. ChREBPβ-deficient male and female C57BL6/J and FVB/N mice were produced using CRISPR/Cas9-mediated gene editing. Unlike global ChREBP deficiency, lack of ChREBPβ showed modest effects on gene expression in adipose tissues and the liver, with variations chiefly observed in brown adipose tissue. In mice fed chow and 2 types of high-fat diets, lack of ChREBPβ had moderate effects on body composition and insulin sensitivity. At thermoneutrality, ChREBPβ deficiency did not prevent the whitening of brown adipose tissue previously reported in total ChREBP-KO mice. These findings revealed that ChREBPβ is dispensable for metabolic adaptations to nutritional and thermic challenges.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Blood Glucose/metabolism ; Cells, Cultured ; Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Energy Metabolism/genetics ; Female ; Gene Expression Regulation ; Male ; Mice ; Mice, Inbred C57BL ; RNA/genetics
    Chemical Substances Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Blood Glucose ; Mlxipl protein, mouse ; RNA (63231-63-0)
    Language English
    Publishing date 2022-02-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.153431
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cyclic AMP-binding protein Epac1 acts as a metabolic sensor to promote cardiomyocyte lipotoxicity.

    Laudette, Marion / Sainte-Marie, Yannis / Cousin, Grégoire / Bergonnier, Dorian / Belhabib, Ismahane / Brun, Stéphanie / Formoso, Karina / Laib, Loubna / Tortosa, Florence / Bergoglio, Camille / Marcheix, Bertrand / Borén, Jan / Lairez, Olivier / Fauconnier, Jérémy / Lucas, Alexandre / Mialet-Perez, Jeanne / Moro, Cédric / Lezoualc'h, Frank

    Cell death & disease

    2021  Volume 12, Issue 9, Page(s) 824

    Abstract: Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis ... ...

    Abstract Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the β-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca
    MeSH term(s) Adenylyl Cyclases/metabolism ; Amino Acid Sequence ; Animals ; Animals, Newborn ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Catecholamines/metabolism ; Cyclic AMP/metabolism ; Guanine Nucleotide Exchange Factors/chemistry ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; L-Lactate Dehydrogenase/metabolism ; Lipoylation/drug effects ; Mitochondria/drug effects ; Mitochondria/metabolism ; Models, Biological ; Myocytes, Cardiac/metabolism ; Oxidation-Reduction ; Palmitic Acid/toxicity ; Phosphoproteins/metabolism ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Solubility ; Stress, Physiological/drug effects ; Rats
    Chemical Substances Catecholamines ; Epac protein, mouse ; Guanine Nucleotide Exchange Factors ; Phosphoproteins ; Palmitic Acid (2V16EO95H1) ; Cyclic AMP (E0399OZS9N) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17) ; Adenylyl Cyclases (EC 4.6.1.1)
    Language English
    Publishing date 2021-09-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-04113-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: CD36 Drives Metastasis and Relapse in Acute Myeloid Leukemia.

    Farge, Thomas / Nakhle, Jean / Lagarde, Damien / Cognet, Guillaume / Polley, Nathaniel / Castellano, Rémy / Nicolau, Marie-Laure / Bosc, Claudie / Sabatier, Marie / Sahal, Ambrine / Saland, Estelle / Jeanson, Yannick / Guiraud, Nathan / Boet, Emeline / Bergoglio, Camille / Gotanègre, Mathilde / Mouchel, Pierre-Luc / Stuani, Lucille / Larrue, Clément /
    Sallese, Marie / De Mas, Véronique / Moro, Cedric / Dray, Cédric / Collette, Yves / Raymond-Letron, Isabelle / Ader, Isabelle / Récher, Christian / Sarry, Jean-Emmanuel / Cabon, Florence / Vergez, François / Carrière, Audrey

    Cancer research

    2023  Volume 83, Issue 17, Page(s) 2824–2838

    Abstract: Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and ... ...

    Abstract Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.
    Significance: CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
    MeSH term(s) Humans ; Animals ; Mice ; Leukemia, Myeloid, Acute/pathology ; Treatment Outcome ; Prognosis ; Recurrence ; Blast Crisis/pathology ; Chronic Disease
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-22-3682
    Database MEDical Literature Analysis and Retrieval System OnLINE

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