Abstract
Whole-body energy metabolism entails the highly regulated balance between food intake, nutrient breakdown, energy generation (ATP), and energy storage for the preservation of vital functions and body mass. Purinergic signaling has attracted increasing attention in the regulatory mechanisms not only for the reverse processes of white adipose tissue lipogenesis and lipolysis, but also for brown adipocyte-dependent thermogenesis and leptin production. This regulatory role has remarkable implications in the handling of body's energy expenditure and energy reservoir. Hence, selected purinergic receptors can play a relevant function in lipid metabolism, endocrine activity, glucose uptake, ATP-dependent increased expression of uncoupling protein 1, and browning of adipose tissue. Indeed, purinergic P2 receptors regulate adipogenesis and lipid metabolism and are involved in adipogenic differentiation. In particular, the ionotropic ATP-activated P2X7 subtype is involved in fat distribution, as well as in the modulation of inflammatory pathways in white adipose tissue. Within this context, very recent evidence has established a direct function of P2X7 in energy metabolism. Specifically, either genetic deletion (P2X7 knockout mice) or subchronic pharmacological inhibition of the receptor produces a decrease of whole-body energy expenditure and, concurrently, an increase of carbohydrate oxidation. As further evidence, lipid accumulation, increased fat mass distribution, and weight gain are reported in P2X7-depleted mice. Conversely, the stimulation of P2X7 enhances energy expenditure. Altogether, this knowledge supports the role of P2X7 signaling in the fight against obesity and insulin resistance, as well as in the promotion of adaptive thermogenesis.
Highlights
At difference with the primary function of intracellular nucleotides that provides the energy supply for cell viability and survival, extracellular nucleotides such as ATP can act as signaling molecules when released into the extracellular compartment
We have highlighted the major involvement of P2X7 in determining and regulating fat distribution, white adipose tissue (AT) inflammation, energy metabolism, and nonshivering thermogenesis
Functional P2X7 receptors are found expressed in visceral and subcutaneous AT, and the alteration of P2X7 function greatly contributes to AT inflammation and adiposity
Summary
At difference with the primary function of intracellular nucleotides that provides the energy supply for cell viability and survival, extracellular nucleotides such as ATP can act as signaling molecules when released into the extracellular compartment. It is accepted that the study of excessive white AT storage (i.e., adiposity) is of major importance for the comprehension of maladaptive chronic inflammatory response and the generation of low-grade systemic inflammation and obesity comorbidities, such as type 2 diabetes, dyslipidemia, Abbreviations: AT, Adipose tissue; BzATP, 3′-O-(4-Benzoyl)benzoyl ATP; EE, energy expenditure; FFAs, free fatty acids; HFD, high-fat diet; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist; NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein 3; ROS, reactive oxygen species; SERCA, sarco(endo)plasmic reticulum Ca2+ATPase; TNF-α, tumor necrosis factor α; UCP1, uncoupling protein 1; UCP3, uncoupling protein 3.
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