The enhancement of fat oxidation during the active phase and suppression of body weight gain in glycerol-3-phosphate dehydrogenase 1 deficient mice

Sayama, Neo; Inoue, Mizuki; Morita, Akihito; Miura, Shinji

doi:10.1080/09168451.2020.1792268

Cited by 4 publications

(4 citation statements)

References 28 publications

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“…This enzyme catalyzes the reversible conversion of dihydroxyaceton phosphate (DHAP) to glycerol-3-phosphate (G3P) by oxidizing NADH to NAD+. Since GPD1 connects glycolysis to lipid metabolism (Sato et al, 2020) oligodendrocytes may benefit from coupling the regeneration of NAD + to the generation of G3P as a phospholipid precursor in lipid biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

“…This enzyme catalyzes the reversible conversion of dihydroxyaceton phosphate (DHAP) to glycerol‐3‐phosphate (G3P) by oxidizing NADH to NAD+. Since GPD1 connects glycolysis to lipid metabolism (Sato et al, 2020) oligodendrocytes may benefit from coupling the regeneration of NAD + to the generation of G3P as a phospholipid precursor in lipid biosynthesis. Cytosolic GPD1 in oligodendrocytes may thus provide an additional way to make NAD+ regeneration partly independent from the action of mitochondrial NADH shuttles and may thus substitute for the lack of LDH reaction in oligodendrocytes to a certain extent.…”

Section: Discussionmentioning

confidence: 99%

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Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

Späte,

Zhou,

Sun

et al. 2024

Glia

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Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type‐specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also “funnel” lactate through their “myelinic” channels between gap junction‐coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

Späte,

Zhou,

Sun

et al. 2024

Glia

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show abstract

“…Despite the metabolite alterations (in G3P, DHAP, and the lactate/pyruvate ratio), the exercise tolerance and pancreatic islet function of the mutant mice were normal. On the other hand, later studies revealed that mice without GPD1 had higher fatty acid oxidation in skeletal muscle, leading to higher exercise endurance and less weight gain 33 , 34 , possibly regulated by EP300 interacting inhibitor of differentiation 1 (EID1) 35 . Although other roles of GPD1, such as protection from cell death upon treatment with oxidants, have been reported with a cell line 36 , 37 , confirmation is necessary in in vivo systems.…”

Section: Glycerol 3-phosphate Dehydrogenases: Individual Enzymes and ...mentioning

confidence: 99%

Glycerol 3-phosphate dehydrogenases (1 and 2) in cancer and other diseases

Oh,

Mai,

Kim

et al. 2024

Exp Mol Med

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The glycerol 3-phosphate shuttle (GPS) is composed of two different enzymes: cytosolic NAD+-linked glycerol 3-phosphate dehydrogenase 1 (GPD1) and mitochondrial FAD-linked glycerol 3-phosphate dehydrogenase 2 (GPD2). These two enzymes work together to act as an NADH shuttle for mitochondrial bioenergetics and function as an important bridge between glucose and lipid metabolism. Since these genes were discovered in the 1960s, their abnormal expression has been described in various metabolic diseases and tumors. Nevertheless, it took a long time until scientists could investigate the causal relationship of these enzymes in those pathophysiological conditions. To date, numerous studies have explored the involvement and mechanisms of GPD1 and GPD2 in cancer and other diseases, encompassing reports of controversial and non-conventional mechanisms. In this review, we summarize and update current knowledge regarding the functions and effects of GPS to provide an overview of how the enzymes influence disease conditions. The potential and challenges of developing therapeutic strategies targeting these enzymes are also discussed.

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“…Moreover, hypoxia-inducible factor 1 subunit alpha (HIF-1α) directly regulates GPD1 at the transcriptional level, thereby inhibiting mitochondrial function and lipid metabolism [ 15 ]. In addition, GPD1 deficiency induces enhanced fat oxidation and inhibits weight gain [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Non-Histone Lysine Crotonylation Is Involved in the Regulation of White Fat Browning

Liu

Liang

et al. 2022

IJMS

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Lysine crotonylation modification is a novel acylation modification that is similar to acetylation modification. Studies have found that protein acetylation plays an important regulatory part in the occurrence and prevention of obesity and is involved in the regulation of glucose metabolism, tricarboxylic acid cycle, white fat browning and fatty acid metabolism. Therefore, we speculate that protein crotonylation may also play a more vital role in regulating the browning of white fat. To verify this conjecture, we identified 7254 crotonyl modification sites and 1629 modified proteins in iWAT of white fat browning model mice by affinity enrichment and liquid chromatography–mass spectrometry (LC-MS/MS). We selected five representative proteins in the metabolic process, namely glycerol-3-phosphate dehydrogenase 1 (GPD1), fatty acid binding protein 4 (FABP4), adenylate kinase 2 (AK2), triosephosphate isomerase 1 (TPI1) and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 8 (NDUFA8). Through qPCR, Western blotting, immunofluorescence staining, Oil Red O staining and HE staining, we demonstrated that GPD1 and FABP4 inhibited white fat browning, while AK2, TPI1 and NDUFA8 promoted white fat browning. GPD1 and FABP4 proteins were downregulated by crotonylation modification, while AK2, TPI1 and NDUFA8 proteins were upregulated by crotonylation modification. Further detection found that the crotonylation modification of GPD1, FABP4, AK2, TPI1 and NDUFA8 promoted white fat browning, which was consistent with the sequencing results. These results indicate that the protein crotonylation is involved in regulating white fat browning, which is of great significance for controlling obesity and treating obesity-related diseases.

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The enhancement of fat oxidation during the active phase and suppression of body weight gain in glycerol-3-phosphate dehydrogenase 1 deficient mice

Cited by 4 publications

References 28 publications

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

Downregulated expression of lactate dehydrogenase in adult oligodendrocytes and its implication for the transfer of glycolysis products to axons

Glycerol 3-phosphate dehydrogenases (1 and 2) in cancer and other diseases

Non-Histone Lysine Crotonylation Is Involved in the Regulation of White Fat Browning

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