P2X receptor-ion channels in the inflammatory response in adipose tissue and pancreas  potential triggers in onset of type 2 diabetes?

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Highlights

  • Obesity is one of the main factors driving type 2 diabetes.

  • Adipose tissue and pancreas are chronically inflamed in these conditions.

  • ATP sensitive P2X7 receptors-ion channels are key players in inflammasome activation.

  • P2X7 receptors are expressed in adipocytes, β-cells and macrophages.

  • P2X7-inflammasome and cell cross-talk perpetuate tissue stress and dysfunction.

Type 2 diabetes is reaching an alarming prevalence worldwide. Its complex pathogenesis certainly includes a pivotal role of low-grade inflammation, which could be triggered by excessive purinergic signaling. In this complex scenario, extracellular ATP impairs the function of two key players: β-cell and adipose tissue. In the former, P2Y and possibly some P2X receptors-ion channels regulate insulin secretion, but it is still debated whether excessive ATP can via P2X receptors impair β-cell function directly or whether cell damage is due to an excessive systemic release of cytokines. In human adipocytes, the P2X7 receptor promotes the release of inflammatory cytokines, at least in part via inflammasome activation, likely contributing to systemic insulin resistance. This receptor-inflammasome system is also strongly activated in macrophages infiltrating both pancreas and adipose tissue, mediating a deleterious cross-talk that perpetuates the damage.

Introduction

The worldwide epidemic increase in incidence of obesity and type 2 diabetes can be attributed to, among other causes, increased food consumption and decreased energy expenditure. The complex pathogenesis of type 2 diabetes involves several tissues and organs. Over the last decades it has become clear that nutrient overload activates inflammatory responses in adipose tissue, pancreas, liver, skeletal muscle, gut and hypothalamus, which contribute to impaired insulin secretion and function, altered incretin hormone balance, dysfunctional cross-talk between the brain and the peripheral tissues. These processes add to the accepted characteristics of type 2 diabetes of impaired glucose sensing/glucose uptake and insulin release/insulin sensitivity [1, 2], all concurring to the development of impaired glucose tolerance and associated comorbidities like obesity, hypertension and dyslipidemia [3, 4•].

Nucleotides play an essential role in a balanced energy metabolism, as they take part in most metabolic reactions; they are building blocks of nucleic acids, act as coenzymes and most pertinently, they are secreted/released from many tissues and participate in the so-called purinergic signaling. This extracellular signaling involves mechanisms for ATP release, purinergic receptors of P2Y and P2X families, ecto-enzymes hydrolyzing ATP/nucleotides stepwise to adenosine, adenosine receptors and adenosine transporters returning adenosine to the cells. Under physiological conditions, it is assumed that extracellular ATP levels contribute to the regulation of several processes, like epithelial transport, neurotransmission and even insulin secretion. A persistently elevated extracellular ATP perpetuates an increased tone of the purinergic signaling, which may participate in the inflammatory responses that characterize several metabolic disorders. Under these conditions, ATP might act as a ‘stress signal’, also known as damage-associated molecular pattern (DAMP) signal in sterile inflammation, and for its action it requires the activation of P2X receptors-ion channels (see below).

In this review, we will explore how purinergic signaling, especially P2X receptor-ion channels, can constitute an important factor linking metabolism and inflammation in the development of obesity and type 2 diabetes (T2D). We will consider this topic from the viewpoint of two key organs, pancreas and adipose tissue, focusing on the role of β-cells, adipocytes and macrophages and the interplay between these (Figure 1).

Section snippets

P2X receptors  ion channels

The extracellular ATP binds to P2 types of receptors: P2Y receptors (G-coupled proteins that also interact with ADP, UTP, UDP and UDP-glucose) and P2X receptors (ligand-gated ion channels binding only ATP). Seven types of P2X ligand-gated ion channels (P2X1 to P2X7) are so far known, with somewhat different ligand affinity and ion selectivity (for Na+, Ca2+ and K+, and some like P2X5 also have finite permeability to Cl) [5]. Opening of these channels would have the following effect on cells  Na+

β-cells and pancreas

Insulin is the key hormone in the maintenance of metabolic homeostasis; the regulation of its secretion by β-cells is a complex process that involves a number of ion channels, in particular KATP channels that are sensitive to intracellular ATP/ADP. There is now solid evidence that extracellular ATP and other nucleotides/sides regulate β-cell functions. Most importantly, extracellular nucleotides/sides can evoke insulin secretion, also independently of glucose, and this response is preserved in

Adipose tissue and adipocytes

Several P2Y receptors positively influence adipogenic differentiation of stem cells [46, 47]; the role of P2XRs, especially P2X7R is less defined [48]. Data from in vitro and animal models suggest an anti-adipogenic effect of P2X7R, that is, increased body weight, adipocyte hyperplasia and ectopic fat accumulation in male P2X7R KO mice [49], and differentiation of mesenchymal stem cells toward the osteoblast, rather than adipocyte lineage after P2X7R stimulation [50]. In humans, white

Role of macrophages in pancreas and adipose tissue (Figure 2)

Macrophages play a key role in the islet inflammation seen in T2D, and also in adipose tissue inflammation in obesity. Both conditions are associated with increased numbers of macrophages [61, 62, 63], which can be recruited in response to, for example, MCP-1 secreted by enlarging adipocytes, and/or can polarize from physiological M2 state to pro-inflammatory M1 state, for example, in islets [64]. The best studied mechanism that causes β-cell dysfunction is the IL-1β system, and interference

Concluding remarks

Low-grade chronic inflammation in adipose tissue and pancreatic islets is regarded as one of the key factors in development of obesity and T2D. In this review, we have proposed that excessive energy uptake, and unmatched energy expenditure could impose metabolic stress that would be reflected in increased tone of purinergic signaling. In particular, low affinity P2X7 receptor-ion channels require relatively high levels of extracellular ATP. It is accepted that such ATP levels could arise from

Conflict of interest

The authors have no conflict of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Studies in Novak's laboratory that inspired this review were funded by the Independent Research Fund Denmark/Natural Sciences (4002-00162B). The authors would like to acknowledge networking support by the COST Action BM-1406.

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