2022
DOI: 10.3390/metabo12010056
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Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver

Abstract: Hypoxia poses a major physiological challenge for mammals and has significant impacts on cellular and systemic metabolism. As with many other small rodents, naked mole-rats (NMRs; Heterocephalus glaber), who are among the most hypoxia-tolerant mammals, respond to hypoxia by supressing energy demand (i.e., through a reduction in metabolic rate mediated by a variety of cell- and tissue-level strategies), and altering metabolic fuel use to rely primarily on carbohydrates. However, little is known regarding specif… Show more

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Cited by 18 publications
(12 citation statements)
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“…In liver, FOXP1 binding sites were enriched in Up enhancer shifts (Figure 3B), and we also found a concordant recruitment of Up promoters and enhancers at the Foxp1 gene locus (Figure 3E, Tables S3 and S9), suggesting a coordinated upregulation of this pathway in mole-rats. FOXP1 is a known regulator of hepatic glucose homeostasis [44], and its regulatory rewiring in mole-rats may contribute to their enhanced glucose utilization compared to other rodents [7, 16].…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…In liver, FOXP1 binding sites were enriched in Up enhancer shifts (Figure 3B), and we also found a concordant recruitment of Up promoters and enhancers at the Foxp1 gene locus (Figure 3E, Tables S3 and S9), suggesting a coordinated upregulation of this pathway in mole-rats. FOXP1 is a known regulator of hepatic glucose homeostasis [44], and its regulatory rewiring in mole-rats may contribute to their enhanced glucose utilization compared to other rodents [7, 16].…”
Section: Resultsmentioning
confidence: 99%
“…Most phenotypic changes across mammals are thought to arise from differences in gene regulation. African mole-rats are a group of rodents displaying unusual longevity [1] and evolutionary adaptations to their subterranean environment (reviewed in [2,3]), including cooperative behaviour [4,5], resistance to hypoxia [6][7][8], anoxia [9] and hypercapnia [8], metabolic adaptations [9,10] and pain insensitivity [11]. These unusual traits have prompted genome sequencing of both the naked mole-rat [12] (Heterocephalus glaber) and the Damaraland mole-rat [13] (Fukomys damarensis), and genomic investigations on speciesspecific changes in protein sequences and signatures of positive selection [14,15].…”
Section: Introductionmentioning
confidence: 99%
“…Also in stark contrast to all previous studies in adult mammals, inhibition of glutamatergic signaling in adult naked mole rats tends to decrease V E in normoxia but has no impact on the acute HVR. 39 Given the apparently minimal role for glutamate receptor inhibition on naked mole-rat breathing, it is notable that the concentration of glutamate in the brain decreases in naked mole-rats exposed to in vivo hypoxia, 73 and that naked mole-rats express a neonatal combination of glutamatergic N-methyl-d-aspartate receptor (NMDAR) subunits. 74 Taken together, these observations suggest that although naked mole-rats have functional NMDARs, their overall activation and also their conductance to excitatory ions are likely reduced, and thus this signaling pathway has considerably lower potential to impact the HVR in naked mole-rats than in the CNS of other adult mammals.…”
Section: Neonatal Cns Control Of Ventilation In Naked Mole-ratsmentioning
confidence: 99%
“…Biosynthesis of amino acids V (17) V (20) Retrograde endocannabinoid signalling V (21) V (30) Thermogenesis V (25) V (33) Endocytosis V (26) V (29) Pyruvate metabolism V (13) V (14) Non-alcoholic fatty liver disease V (21) V (26) cGMP-PKG signalling pathway V (21) V (28) Bacterial invasion of epithelial cells V (15) V (15) Cardiac muscle contraction…”
Section: Data Availability Statementmentioning
confidence: 99%
“…At the same time, brain Na + /K + -ATPase activity is selectively downregulated in some regions of the brain to conserve energy [26], and brain mitochondrial ATP generation becomes more tightly coupled to O 2 consumption (i.e., becomes more efficient). As a result, ATP concentration is maintained in the naked mole-rat brain in hypoxia, and deleterious glutamate release and downstream excitotoxicity, which are hallmarks of the hypoxia-intolerant mammal brain [27,28], are avoided in the hypoxic naked mole-rat brain [9,[29][30][31]. Furthermore, naked mole-rat brain mitochondria retain respiratory capacity and membrane integrity following ischaemia, indicating tolerance-related modification in respiratory pathway control compared to mouse brains [7].…”
Section: Introductionmentioning
confidence: 99%