Adipocyte P2X7 receptors expression: A role in modulating inflammatory response in subjects with metabolic syndrome?

Adipose tissue contains self-renewing multipotent cells termed mesenchymal stromal cells. In situ, these cells serve to expand adipose tissue by adipogenesis, but their multipotency has gained interest for use in tissue regeneration. Little is known regarding the repertoire of receptors expressed by adipose-derived mesenchymal stromal cells (AD-MSCs). The purpose of this study was to undertake a comprehensive analysis of purinergic receptor expression. Mesenchymal stromal cells were isolated from human subcutaneous adipose tissue and confirmed by flow cytometry. The expression profile of purinergic receptors was determined by quantitative real-time PCR and immunocytochemistry. The molecular basis for adenine and uracil nucleotide-evoked intracellular calcium responses was determined using Fura-2 measurements. All the known subtypes of P2X and P2Y receptors, excluding P2X2, P2X3 and P2Y 12 receptors, were detected at the mRNA and protein level. ATP, ADP and UTP elicited concentration-dependent calcium responses in mesenchymal cells (N = 7-9 donors), with a potency ranking ADP (EC 50 1.3 ± 1.0 μM) > ATP (EC 50 2.2 ± 1.1 μM) = UTP (3.2 ± 2.8 μM). Cells were unresponsive to UDP (< 30 μM) and UDPglucose (< 30 μM). ATP responses were attenuated by selective P2Y 2 receptor antagonism (AR-C118925XX; IC 50 1.1 ± 0.8 μM, 73.0 ± 8.5% max inhibition; N = 7 donors), and UTP responses were abolished. ADP responses were attenuated by the selective P2Y 6 receptor antagonist, MRS2587 (IC 50 437 ± 133nM, 81.0 ± 8.4% max inhibition; N = 6 donors). These data demonstrate that adenine and uracil nucleotides elicit intracellular calcium responses in human AD-MSCs with a predominant role for P2Y 2 and P2Y 6 receptor activation. This study furthers understanding about how human adipose-derived mesenchymal stromal cells can respond to external signalling cues.

Section: +contrasting

confidence: 50%

P2Y2 and P2Y6 receptor activation elicits intracellular calcium responses in human adipose-derived mesenchymal stromal cells

Ali

Turner

Fountain

2018

“…Morphometric analysis of adipocytes from fat pads of WT and P2X7 KO mice Since P2X7 is expressed in adipocytes [34] and the difference in total body mass was associated with a significant increase in adipose tissue, we examined the fat pads in WT and KO mice. Epididymal fat pads of WT and KO male mice (9 and 12 months of age) were isolated and weighed post-mortem.…”

Section: Resultsmentioning

confidence: 99%

“…An increase in adipose tissue mass can result from greater adipocyte size (hypertrophy), greater adipocyte cell number (hyperplasia), or both [52]. Previous studies have shown that both visceral and subcutaneous adipocytes express P2X7 receptors [34,53]. Adipocyte size and density were similar in WT and KO, indicating that the increase in mass was due to adipocyte hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

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Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

Beaucage

Xiao

Pollmann

et al. 2013

The P2X7 receptor is an ATP-gated cation channel expressed by a number of cell types. We have shown previously that disruption of P2X7 receptor function results in downregulation of osteogenic markers and upregulation of adipogenic markers in calvarial cell cultures. In the present study, we assessed whether loss of P2X7 receptor function results in changes to adipocyte distribution and lipid accumulation in vivo. Male P2X7 loss-of-function (KO) mice exhibited significantly greater body weight and epididymal fat pad mass than wild-type (WT) mice at 9 months of age. Fat pad adipocytes did not differ in size, consistent with adipocyte hyperplasia rather than hypertrophy. Histological examination revealed ectopic lipid accumulation in the form of adipocytes and/or lipid droplets in several non-adipose tissues of older male KO mice (9-12 months of age). Ectopic lipid was observed in kidney, extraorbital lacrimal gland and pancreas, but not in liver, heart or skeletal muscle. Specifically, lacrimal gland and pancreas from 12-month-old male KO mice had greater numbers of adipocytes in perivascular, periductal and acinar regions. As well, lipid droplets accumulated in the renal tubular epithelium and lacrimal acinar cells. Blood plasma analyses revealed diminished total cholesterol levels in 9-and 12-month-old male KO mice compared with WT controls. Interestingly, no differences were observed in female mice. Moreover, there were no significant differences in food consumption between male KO and WT mice. Taken together, these data establish novel in vivo roles for the P2X7 receptor in regulating adipogenesis and lipid metabolism in an age-and sex-dependent manner.

“…P2Y 2 , P2Y 6 and P2Y 12 receptors, and all P2X receptor subtypes except P2X6, were identified as the nucleotide receptors on brown fat cells [297]. Human adipocytes express functionally active P2X7 receptors that mediate release of inflammatory cytokines; adipocytes from patients with metabolic syndrome show enhanced P2X7 receptor expression [336].…”

Section: P1 Receptorsmentioning

confidence: 99%

Purinergic signalling in endocrine organs

Burnstock

2013

There is widespread involvement of purinergic signalling in endocrine biology. Pituitary cells express P1, P2X and P2Y receptor subtypes to mediate hormone release. Adenosine 5′-triphosphate (ATP) regulates insulin release in the pancreas and is involved in the secretion of thyroid hormones. ATP plays a major role in the synthesis, storage and release of catecholamines from the adrenal gland. In the ovary purinoceptors mediate gonadotrophin-induced progesterone secretion, while in the testes, both Sertoli and Leydig cells express purinoceptors that mediate secretion of oestradiol and testosterone, respectively. ATP released as a cotransmitter with noradrenaline is involved in activities of the pineal gland and in the neuroendocrine control of the thymus. In the hypothalamus, ATP and adenosine stimulate or modulate the release of luteinising hormone-releasing hormone, as well as arginine-vasopressin and oxytocin. Functionally active P2X and P2Y receptors have been identified on human placental syncytiotrophoblast cells and on neuroendocrine cells in the lung, skin, prostate and intestine. Adipocytes have been recognised recently to have endocrine function involving purinoceptors.