The loss of P2X7 receptor expression leads to increase intestinal glucose transit and hepatic steatosis

Arguin, Guillaume; Bourzac, Jean-François; Placet, Morgane; Molle, Caroline M.; Paquette, Michel; Rousseau, Jacques; Plourde, Mélanie; Gendron, Fernand‐Pierre

doi:10.1038/s41598-017-13300-8

Cited by 21 publications

(23 citation statements)

References 70 publications

(84 reference statements)

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“…Furthermore, the reduced expression of pro-inflammatory genes and reduced levels of plasma cytokines CCL2 and IL6 in P2rx7 KO vs. WT mice may indicate a role for P2X7 in liver upon nutritional inflammatory stimulus. Surprisingly, a recent study reported dyslipidemia and hepatic steatosis along with increased weight gain in P2rx7 KO mice [54]. In this study, lipogenic pathways were shown to be affected, indicating that P2X7 deficiency may deregulate liver function under severe hepatic pathological conditions.…”

Section: E N T P D 1 ( C D 3 9 ) N T 5 E ( C D 7 3 ) P 2 R X 4 P 2 R contrasting

confidence: 51%

The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues

Tian

Heine

Evangelakos

et al. 2020

Purinergic Signalling

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Several studies suggest a role of extracellular adenine nucleotides in regulating adipose tissue functions via the purinergic signaling network. Metabolic studies in mice with global deletion of the purinergic receptor P2X7 on the C57BL/6 background indicate that this receptor has only a minor role in adipose tissue for diet-induced inflammation or cold-triggered thermogenesis. However, recent data show that a polymorphism (P451L) present in C57BL/6 mice attenuates P2X7 receptor function, whereas BALB/c mice express the fully functional P451 allele. To determine the potential role of P2rx7 under metabolic and thermogenic stress conditions, we performed comparative studies using male P2rx7 knockout (KO) and respective wild-type controls on both BALB/c and C57BL/6 backgrounds. Our data show that adipose P2rx7 mRNA levels are increased in obese mice. Moreover, P2rx7 deficiency results in reduced levels of circulating CCL2 and IL6 with a moderate effect on gene expression of pro-inflammatory markers in white adipose tissue and liver of BALB/c and C57BL/6 mice. However, P2X7 expression does not alter body weight, insulin resistance, and hyperglycemia associated with high-fat diet feeding on both genetic backgrounds. Furthermore, deficiency of P2rx7 is dispensable for energy expenditure at thermoneutral and acute cold exposure conditions. In summary, these data show that—apart from a moderate effect on inflammatory cytokines—P2X7 plays only a minor role in inflammatory and thermogenic effects of white and brown adipose tissue even on the BALB/c background.

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Section: E N T P D 1 ( C D 3 9 ) N T 5 E ( C D 7 3 ) P 2 R X 4 P 2 R contrasting

confidence: 51%

The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues

Tian

Heine

Evangelakos

et al. 2020

Purinergic Signalling

View full text Add to dashboard Cite

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“…The P2X7 receptor, with its wide-ranging proposed physiological roles in inflammatory disease, cancer, neurological disorders (Bartlett et al, 2014 ; Roger et al, 2015 ; Pevarello et al, 2017 ) and, most recently, metabolic disease (Arguin et al, 2017 ), has been a focus within the pharmaceutical industry and several potent and selective P2X7 antagonists have been developed (Park and Kim, 2017 ). Many of these were thought to be orthosteric, but painstaking and elegant recent work by Alsopp et al, using structure-function and molecular modeling (Allsopp et al, 2017 ), and by Karasawa and Kawate, using functional assay and crystallization of giant panda P2X7 in complex with a series of P2X7 antagonists (Karasawa and Kawate, 2016 ) has clearly demonstrated that these compounds bind to an allosteric site in the extracellular domain distinct from the ATP binding pocket (Figure 4A ).…”

Section: Modulator Binding In P2x Receptor Crystal Structuresmentioning

confidence: 99%

The Molecular Determinants of Small-Molecule Ligand Binding at P2X Receptors

2018

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P2X receptors are trimeric eukaryotic ATP-gated cation channels. Extracellular ATP—their physiological ligand—is released as a neurotransmitter and in conditions of cell damage such as inflammation, and substantial evidence implicates P2X receptors in diseases including neuropathic pain, cancer, and arthritis. In 2009, the first P2X crystal structure, Danio rerio P2X4 in the apo- state, was published, and this was followed in 2012 by the ATP-bound structure. These structures transformed our understanding of the conformational changes induced by ATP binding and the mechanism of ligand specificity, and enabled homology modeling of mammalian P2X receptors for ligand docking and rational design of receptor modulators. P2X receptors are attractive drug targets, and a wide array of potent, subtype-selective modulators (mostly antagonists) have been developed. In 2016, crystal structures of human P2X3 in complex with the competitive antagonists TNP-ATP and A-317491, and Ailuropoda melanoleuca P2X7 in complex with a series of allosteric antagonists were published, giving fascinating insights into the mechanism of channel antagonism. In this article we not only summarize current understanding of small-molecule modulator binding at P2X receptors, but also use this information in combination with previously published structure-function data and molecular docking experiments, to hypothesize a role for the dorsal fin loop region in differential ATP potency, and describe novel, testable binding conformations for both the semi-selective synthetic P2X7 agonist 2′-(3′)-O-(4-benzoyl)benzoyl ATP (BzATP), and the P2X4-selective positive allosteric modulator ivermectin. We find that the distal benzoyl group of BzATP lies in close proximity to Lys-127, a residue previously implicated in BzATP binding to P2X7, potentially explaining the increased potency of BzATP at rat P2X7 receptors. We also present molecular docking of ivermectin to rat P2X4 receptors, illustrating a plausible binding conformation between the first and second transmembrane domains which not only tallies with previous mutagenesis studies, but would also likely have the effect of stabilizing the open channel structure, consistent with the mode of action of this positive allosteric modulator. From our docking simulations and analysis of sequence homology we propose a series of mutations likely to confer ivermectin sensitivity to human P2X1.

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“…P2X7 null mice (P2X7KO) are hyperglycemic, and show glucose intolerance after chronic exposure to high fat/high sucrose diet [11]. Hyperglycemia and concomitant increase of serum insulin levels supports the idea of possible insulin resistance in P2X7KO mice, in which it was also observed hepatic steatosis and facilitated glucose delivery into the bloodstream [12]. The critical involvement of P2X7 in regulating energy metabolism has been further demonstrated in P2X7KO mice showing G. Giacovazzo and S. Apolloni are equal first authors.…”

Section: Introductionmentioning

confidence: 96%

Loss of P2X7 receptor function dampens whole body energy expenditure and fatty acid oxidation

Giacovazzo

Apolloni

Coccurello

2018

Purinergic Signalling

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The established role of ATP-responsive P2X7 receptor in inflammatory, neurodegenerative, and immune diseases is now expanding to include several aspects of metabolic dysregulation. Indeed, P2X7 receptors are involved in β cell function, insulin secretion, and liability to diabetes, and loss of P2X7 function may increase the risk of hepatic steatosis and disrupt adipogenesis. Recently, body weight gain, abnormal lipid accumulation, adipocyte hyperplasia, increased fat mass, and ectopic fat distribution have been found in P2X7 KO mice. Here, we hypothesized that such clinical picture of dysregulated lipid metabolism might be the result of altered in vivo energy metabolism. By indirect calorimetry, we assessed 24 h of energy expenditure (EE) and respiratory exchange ratio (RER) as quotient of carbohydrate to fat oxidation in P2X7 KO mice. Moreover, we assessed the same parameters in aged-matched WT counterparts that underwent a 7-day treatment with the P2X7 antagonist A804598. We found that loss of P2X7 function elicits a severe decrease of EE that was less pronounced in A804598-treated mice. In parallel, P2X7KO mice show a drastic increase of RER, thus indicating the occurrence of a greater ratio of carbohydrate to fat oxidation. Decreased EE and fat oxidation is predictive of body weight gain, which was here confirmed. Taken together, our data provide evidence that P2X7 loss of function produces defective energy homeostasis that, together with disrupted adipogenesis, might help to explain accumulation of adipose tissue and contribute to disclose the potential role of P2X7 in metabolic diseases.

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The loss of P2X7 receptor expression leads to increase intestinal glucose transit and hepatic steatosis

Cited by 21 publications

References 70 publications

The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues

The P2X7 ion channel is dispensable for energy and metabolic homeostasis of white and brown adipose tissues

The Molecular Determinants of Small-Molecule Ligand Binding at P2X Receptors

Loss of P2X7 receptor function dampens whole body energy expenditure and fatty acid oxidation

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