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

Abstract

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.

Stimulation of P2X7 Enhances Whole Body Energy Metabolism in Mice

“…To investigate the role of P2X7 activation in the regulation of energy homeostasis, we have assessed the metabolic rate and the respiratory quotient of C57BL/6J mice treated once a day for 7 consecutive days with vehicle (PBS) or the best selective and specific available P2X7 agonist BzATP, by means of continuous IC analysis during the last 48 h of treatment in standard nutritional conditions (Figure 1A). To overcome sex-mixed results with low reproducibility, we have used only the female gender because of previously reported data (Giacovazzo et al, 2018). Our results indicate that BzATP at the concentration of 1 mg/Kg (i.e., within a range demonstrated to be effective in rodents (Gubert et al, 2016), shows quick absorption without accumulation in the peritoneal space.…”

“…In a previous work, we have demonstrated that genetic depletion and, to a lesser extent, also pharmacological inhibition of P2X7 elicits a pronounced decrease of the whole body EE and a significant increase of the RER, thus indicating a prevalent increase of carbohydrate oxidation. The relative sparing of fatty acids storage and concomitant defective energy homeostasis were also associated to body weight gain (Giacovazzo et al, 2018). Given the increasing importance of P2X7 in the regulation of cellular energy metabolism, either during physiological or tumor conditions (Amoroso et al, 2012; Savio et al, 2018), in the present work we have investigated by IC the effects of P2X7 activation in mice that underwent 7-days treatment with the best available selective and specific P2X7 agonist BzATP.…”

P2X7 Receptor-Dependent Layer-Specific Changes in Neuron-Microglia Reactivity in the Prefrontal Cortex of a Phencyclidine Induced Mouse Model of Schizophrenia

“…Before the first treatment, P2rx7 −/− animals had a higher body mass compared to the P2rx7 +/+ animals (Giacovazzo et al, 2018), which normalized after the 1 day ( Figure 10E).…”

P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes

“…In addition to depression, P2X7 receptor is closely related to the occurrence of diabetes and some diabetes comorbidities [64]. P2X7 receptors regulate insulin secretion by participating in pancreatic β cell function, and the abnormality of P2X7 function causes the imbalance in energy homeostasis and increases the accumulation of adipose tissues, which have potential effects on metabolic diseases [65]. P2X7 receptor knockout and P2X7 receptor inhibitor BBG can prevent diabetes induced by streptozocin [66].…”