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Updated: Feb 10, 2026
Determining Basal Energy Expenditure and the Capacity of Thermogenic Adipocytes to Expend Energy in Obese Mice
Published on: November 11, 2021
Loss of P2X7 receptor function dampens whole body energy expenditure and fatty acid oxidation
Giacomo Giacovazzo1,2, Savina Apolloni2, Roberto Coccurello3,4
1Institute of Cell Biology and Neurobiology (IBCN), National Research Council (C.N.R.), Rome, Italy.
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.
Insights
Loss of the P2X7 receptor impairs energy metabolism, leading to reduced energy expenditure and increased carbohydrate oxidation. This contributes to weight gain and metabolic dysfunction, highlighting P2X7
Area of Science:
- Metabolic disease research
- Cellular and molecular biology
- Physiology
Background:
- The P2X7 receptor (P2X7R) is implicated in inflammatory, immune, and neurodegenerative diseases.
- Emerging evidence links P2X7R to metabolic dysregulation, including diabetes, hepatic steatosis, and adipogenesis.
- P2X7 receptor knockout (KO) mice exhibit obesity, abnormal lipid accumulation, and altered fat distribution.
Purpose of the Study:
- To investigate the role of P2X7 receptor function in in vivo energy metabolism.
- To determine if P2X7R deficiency impacts energy expenditure and substrate oxidation.
- To explore the link between P2X7R-mediated energy metabolism and obesity.
Main Methods:
- Indirect calorimetry was used to measure 24-hour energy expenditure (EE) and respiratory exchange ratio (RER) in P2X7 KO mice.
- The same parameters were assessed in wild-type (WT) mice treated with a P2X7 antagonist (A804598).
- RER was used to quantify the ratio of carbohydrate to fat oxidation.
Main Results:
- P2X7 receptor deficiency caused a significant decrease in energy expenditure (EE).
- P2X7 KO mice exhibited a marked increase in RER, indicating a shift towards carbohydrate oxidation.
- Treatment with a P2X7 antagonist partially replicated the EE decrease observed in P2X7 KO mice.
- The observed metabolic changes correlate with increased body weight gain and adipose tissue accumulation.
Conclusions:
- Loss of P2X7 receptor function leads to defective energy homeostasis.
- Impaired energy expenditure and altered substrate utilization contribute to obesity and metabolic disease.
- The P2X7 receptor represents a potential therapeutic target for metabolic disorders.
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