Stimulation of P2X7 Enhances Whole Body Energy Metabolism in Mice

Abstract

The P2X7 receptor, a member of the ionotropic purinergic P2X family of extracellular ATP-gated receptors, exerts strong trophic effects when tonically activated in cells, in addition to cytotoxic effects after a sustained activation. Because of its widespread distribution, P2X7 regulates several cell- and tissue-specific physiological functions, and is involved in a number of disease conditions. A novel role has recently emerged for P2X7 in the regulation of glucose and energy metabolism. In previous work, we have demonstrated that genetic depletion, and to a lesser extent also pharmacological inhibition of P2X7, elicits a significant decrease of the whole body energy expenditure and an increase of the respiratory exchange ratio. In the present work, we have investigated the effects of P2X7 stimulation in vivo on the whole body energy metabolism. Adult mice were daily injected with the specific P2X7 agonist 2′(3′)-O-(4-Benzoylbenzoyl)adenosine 5′-triphosphate for 1 week and subjected to indirect calorimetric analysis for 48 h. We report that 2′(3′)-O-(4-Benzoylbenzoyl)adenosine 5′-triphosphate increases metabolic rate and O 2 consumption, concomitantly decreasing respiratory rate and upregulating NADPH oxidase 2 in gastrocnemius and tibialis anterior muscles. Our results indicate a major impact on energy homeostasis and muscle metabolism by activation of P2X7.

The P2X7 receptor localizes to the mitochondria, modulates mitochondrial energy metabolism and enhances physical performance

“…Trophic, growth-promoting activity of the P2X7R has been now demonstrated in several in vitro and in vivo systems (Di Virgilio et al 2018) (Lara et al 2020). Furthermore, accruing indirect evidence supports the view that the P2X7R modulates cell and whole body energy homeostasis being involved in dysmetabolisms, obesity and hormonal dysfunctions (Giacovazzo et al 2019) (Novak and Solini 2018) (Solini and Novak 2019) (Giacovazzo, Apolloni, and Coccurello 2018). A cardio-protective activity for the P2X7R has also been proposed (Vessey, Li, and Kelley 2010).…”

“…Since during physical activity or at sites of inflammation the extracellular ATP concentration is several fold increased (Forrester 1966, Wilhelm et al 2010), the P2X7R might be considered a bioenergetics sensor enabling the intracellular ATP synthetic apparatus to sense extracellular ATP levels, and thus meet the increased energy demand. Along these lines, stimulation of the P2X7R has been previously shown to enhance energy metabolism in mice (Giacovazzo et al 2019). In this study P2X7R subcellular localization and its effect on mitochondrial energy metabolism was investigated.…”

Mechanism of insulin resistance in obesity: a role of ATP

“…The P2Y1 activation leads to the inhibition of glucagon secretion. Among the ATP receptors, the activation of P2X7 by a pharmacological agent induces energy expenditure in mice [90], and the inactivation by gene KO does not change body weight and insulin sensitivity in KO mice [91]. However, this ATP-based pathway deserves to be explored further especially in the models of obesity.…”

Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors

“…Furthermore, it is now evident that ATP is continuously released in the brain and extracellular levels are altered in response to metabolic demand [ 25 , 47 , 51 ], linked to reciprocal changes in the levels of phosphorylated AMP-activated protein kinase (P-AMPK), well known for its role in cellular energy sensing and regulation [ 25 ]. Controlled activation ofP2X7R supports mitochondrial ATP synthesis in multiple ways, including facilitating glucose uptake by regulating glucose transporter expression and function [ 4 ], and stimulation ofP2X7R has been shown to enhance energy metabolism in mice [ 34 ]. In addition, circadian regulation of extracellular ATP levels suggests that ATP may be an important circadian output in thesuprachiasmatic nucleus and other brain regions [ 77 ].…”