The involvement of purinergic signalling in obesity.

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hyperthyroidism 1 endocrinologydiseases
metabolic syndrome 3 endocrinologydiseases
obesity 74 endocrinologydiseases
osteoporosis 1 endocrinologydiseases
Insulin 3 endocrinologydiseasesdrugs
amphetamine 1 endocrinologydiseasesdrugs
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Insulin 16424 glycogen synthase in rat fat cells [[49]].Fig. 2Factors influencing leptin synthesis and secretion. Insulin -mediated glucose uptake determines the rate of glucose metabolism in adipose tissue, and the subsequent
Insulin 28447 increased adipogenesis [[101]]. There is impaired glucose tolerance in A1 receptor knockout mice [[102]]. Insulin , as well as adenosine, is antilipolytic in rats [[103]]. Also in rats, adenosine modulation of the stimulation
Insulin 29281 therapeutic target for the treatment of obesity-related insulin resistance and type 2 diabetes [[106]]. Insulin resistance in obese Zucker rats is tissue specific, and BWA1433, an adenosine receptor antagonist, improved
amphetamine 12320 One neuronal circuit inhibits food intake, via α-melanocyte-stimulating hormone, and cocaine- and amphetamine -regulated transcripts [[36]]. The other neuronal circuit stimulates food intake, via the expression
Select Disease Character Offset Disease Term Instance
hyperinsulinemia 25250 suggested that animal and human obesity is associated with reduction of tissue Na+/K+-ATPase, linked to hyperinsulinemia , influencing thermogenesis and energy balance [[84]].Typical signs of Cushing’s syndrome and side
hyperthyroidism 29813 rats respond to adenosine, but not to adrenaline, with increased glycerol release [[109]]. Short-term hyperthyroidism modulates adenosine receptors and adenylate cyclase in rat adipocytes [[110]]. Studies of membranes
metabolic syndrome 19284 addition, Rossi and colleagues, in line with this evidence, demonstrated that patients affected by metabolic syndrome showed an enhancement of P2X7 receptor expression and inflammasome activation compared to control patients
metabolic syndrome 25433 of Cushing’s syndrome and side effects of prolonged glucocorticoid treatment are features of the metabolic syndrome , such as central obesity with insulin resistance and dyslipidaemia. Changes in AMP-activated protein
metabolic syndrome 36097 options are palliative and limited. An excess of body fat is associated with cardiovascular disorders and metabolic syndrome s, including insulin-independent diabetes and dyslipidemia; therefore, a combination of lifestyle changes
obesity 72 Title: Purinergic SignallingThe involvement of purinergic signalling in obesity Geoffrey BurnstockDaniela GentilePublication date (epub): 4/2018Publication date (pmc-release): 4/2018Publication
obesity 452 dysregulation of energy balance. Currently, no wholly successful pharmacological treatments are available for obesity and related adverse consequences. In recent years, hints obtained from several experimental animal models
obesity 737 ion channels (P2X), G protein-coupled receptors (P2Y) and adenosine receptors (P1), is involved in obesity , both at peripheral and central levels. This review has drawn together, for the first time, the evidence
obesity 949 for a promising, much needed novel therapeutic purinergic signalling approach for the treatment of obesity with a ‘proof of concept’ that hopefully could lead to further investigations and clinical trials
obesity 1081 concept’ that hopefully could lead to further investigations and clinical trials for the management of obesity .IntroductionObesity, defined as abnormal or excessive fat accumulation, represents a major health issue,
obesity 1630 (BMI > 30 kg/m2) (http://www.who.int/mediacentre/factsheets/fs311/en/). The imbalance of energy underlying obesity is due to several factors, including genetic predisposition, individual metabolism, excessive caloric
obesity 3578 the potential to greatly increase the total body fat mass and may contribute to the development of obesity in adults [[5]].Regulation of energy homeostasis is highly controlled by the central nervous system
obesity 4373 of either the parasympathetic or sympathetic branches, or both, may contribute to the development of obesity and related metabolic comorbidities [[8]]. Depression of sympathetic and parasympathetic activity has
obesity 4758 increase in white adipocyte cell number and fat pad mass [[9]].Currently, therapeutic strategies against obesity have been largely ineffective, such as 5-hydroxytryptamine modulators, β3 adrenoceptor agonists, lipase
obesity 4988 melanocortin 4 inhibitors, leptin agonists and ghrelin antagonists [[10]]. The development of novel anti- obesity drugs based on our current understanding of energy homeostasis is required. The present review explores
obesity 5153 homeostasis is required. The present review explores the possible involvement of purinergic signalling in obesity .Purinergic signalling [i.e. adenosine 5′-triphosphate (ATP) acting as an extracellular signalling
obesity 6713 thermogenic genes making them specialised in energy expenditure and therefore a potential target for anti- obesity therapies [[14]]. There are also beige cells, which are inducible ‘brown-like’ adipocytes that develop
obesity 6928 in white fat in response to various activators. The activities of brown and beige fat cells reduced obesity in mice, an effect similar to that seen in lean humans [[14]], in addition to causing antidiabetic effects
obesity 9235 thermogenesis in brown adipocytes via A2A receptors, and A2A agonists were shown to counteract HFD-induced obesity in mice [[25]].Purinergic control of white adipocytesWhite adipocytes are the major energy reservoir
obesity 10520 white adipocyte exocytosis/secretion [[29]]. Disturbance of adiponectin secretion in individuals with obesity highlights the control of adipokinase release by ATP. Reduction in the plasma level of adiponectin in
obesity 10644 control of adipokinase release by ATP. Reduction in the plasma level of adiponectin in subjects with obesity precedes the reduction in insulin sensitivity and onset of diabetes [[30]].Adenosine monophosphate (AMP)
obesity 10946 adiponectin, has fat-reducing effects in mammalian white adipose tissue and is a potential target for obesity treatment [[31]]. The authors suggested that chronic AMP kinase activation acts by remodelling adipocyte
obesity 11475 involves the phospholipase C-protein kinase C pathway [[32]].Hypothalamic purinergic nervous control of obesity In the last decade, many studies have highlighted a fundamental role of the CNS, in particular the arcuate
obesity 12564 agouti-related peptide (AgRP) [[37]]. Several studies aimed at finding novel approaches for the management of obesity have focused on the critical role of AgRP neurons in the regulation of appetite, reporting that their
obesity 13991 (see Fig. 1). Moreover, both conventional and AgRP-restricted P2Y6-deficient animals exhibit reduced obesity as well as improved whole-body insulin sensitivity when exposed to long-term HFD feeding. Thus, although
obesity 14237 needed, P2Y6 receptors could represent a potential therapeutic target for the prevention and treatment of obesity and related insulin resistance. Furthermore, since P2Y6 receptors are also expressed on activated microglia
obesity 14408 receptors are also expressed on activated microglia in the hippocampus of rats [[43]] and considering that obesity promotes hypothalamic inflammation, including the activation of microglia [[44]], this purinergic receptor
obesity 15280 directly controlled by the peripheral supply of the precursor metabolite uridine, typically increased in obesity /diabetes. Pharmacological blocking of P2Y6 receptor activation in the CNS, with the selective P2Y6 receptor
obesity 15553 from [[41]] and reproduced with permission from Elsevier)Regulatory roles of ATP and P2 receptors in obesity In a review entitled ‘Leptin and the control of obesity’, it was stated that ‘ATP is a major stimulus
obesity 15610 Elsevier)Regulatory roles of ATP and P2 receptors in obesityIn a review entitled ‘Leptin and the control of obesity ’, it was stated that ‘ATP is a major stimulus for leptin production and secretion’ [[10], [45],
obesity 16065 addition, there is strong evidence that the vagus nerve is involved in the development of diet-induced obesity (see [[48]]) and, since ATP is also a cotransmitter with acetylcholine in vagal nerves, it may be involved
obesity 17526 cotransmitter from sympathetic nerves, mediates the long-term effects of leptin on blood pressure involved in obesity hypertension [[51]]. ATP has antihyperlipidaemic activity by decreasing serum triglyceride levels in
obesity 17792 suggesting that ATP supplementation could provide an effective approach to control triglyceride levels in obesity [[52]]. A later paper provided evidence that ATP stimulated lipogenesis in rat adipocytes via a P2 receptor
obesity 19857 P2X7 receptor antagonists significantly decreased carbon tetrachloride exacerbation of liver injury in obesity paved the way for future investigations using the antagonists as potential therapeutic molecules in
obesity 19993 investigations using the antagonists as potential therapeutic molecules in treating steatohepatitis in obesity in its early phase [[61]]. Of note, in metabolically unhealthy obese subjects, stromal vascular cells
obesity 20252 involved in the chronic inflammation of visceral adipose tissue underlying the metabolic changes in obesity [[62]]. In P2X7 knockout mice, there is abnormal fat distribution, suggesting that P2X7 receptors mediate
obesity 22517 abundant in a variety of tissues and species. KATP channel activity is coupled with insulin resistance in obesity and type 2 diabetes in mammals [[72]]. Indeed, insulin activates KATP channels in hypothalamic neurons
obesity 23217 suggested that KATP channel-deficient mice exhibit hyperphagia but are resistant to the induction of obesity by a HFD [[75]].ATP-binding cassette transportersATP-binding cassette (ABC) transporters (ABCA1, ABCG1,
obesity 23620 variant was reported to affect high-density lipoprotein cholesterol levels and to be associated with obesity and obesity-related comorbidities in the Mexican population [[78]]. The ABC transporter G8 gene was
obesity 23632 reported to affect high-density lipoprotein cholesterol levels and to be associated with obesity and obesity -related comorbidities in the Mexican population [[78]]. The ABC transporter G8 gene was shown to be
obesity 24496 possibilitiesCell surface H+-ATP synthase has been claimed to be a potential molecular target for anti- obesity drugs. Of note, treatment with small molecule inhibitors of H+-ATP synthase or antibodies against H+-ATP
obesity 25178 not significantly increased in those of obese rats [[83]].It has been suggested that animal and human obesity is associated with reduction of tissue Na+/K+-ATPase, linked to hyperinsulinemia, influencing thermogenesis
obesity 25469 effects of prolonged glucocorticoid treatment are features of the metabolic syndrome, such as central obesity with insulin resistance and dyslipidaemia. Changes in AMP-activated protein kinase have been proposed
obesity 25680 as a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity in individuals with Cushing’s syndrome [[85]].Regulatory role of adenosine and P1 receptors in obesityIn
obesity 25785 obesity in individuals with Cushing’s syndrome [[85]].Regulatory role of adenosine and P1 receptors in obesity In early studies on rat adipocytes, adenosine was shown to inhibit lipolysis elicited by noradrenaline
obesity 27284 play an important role, has been examined [[96]]. Agonists to A1 receptors are in clinical trials for obesity . The A2 adenosine receptor subtype, which is positively coupled to adenylate cyclase, was shown to be
obesity 29056 and insulin resistance [[105]]. Over-expression of A1 receptors in adipose tissue protects mice from obesity -related insulin resistance, and it was suggested that A1 receptor activation should be considered as
obesity 29217 A1 receptor activation should be considered as a potential therapeutic target for the treatment of obesity -related insulin resistance and type 2 diabetes [[106]]. Insulin resistance in obese Zucker rats is tissue
obesity 30217 in brown adipose tissue of rats [[113]].In brown subcutaneous abdominal fat cells from subjects with obesity , the antilipolytic effect of an adenosine analogue was markedly attenuated as compared to that in fat
obesity 30481 in the P1 receptor number in adipocyte plasma membranes and reduced adenosine sensitivity in human obesity were reported [[115]]. Inhibition of isoprenaline-stimulated lipolysis by an adenosine receptor agonist
obesity 31039 central depression mechanisms. An adenosine deaminase polymorphism was shown to be associated with obesity , and adenosine receptor agonists were recommended as therapeutic targets for obesity and dyslipidemia
obesity 31124 associated with obesity, and adenosine receptor agonists were recommended as therapeutic targets for obesity and dyslipidemia [[118]]. Data was presented to suggest that inhibition of lipolysis by adenosine appears
obesity 31283 suggest that inhibition of lipolysis by adenosine appears to be greater in African-American women with obesity and that this might possibly be one explanation for the observation that African-American women with
obesity 31392 and that this might possibly be one explanation for the observation that African-American women with obesity have more difficulty in losing weight than Caucasian women with obesity [[118]].A HFD induced changes
obesity 31464 African-American women with obesity have more difficulty in losing weight than Caucasian women with obesity [[118]].A HFD induced changes in glucose homeostasis, inflammation and obesity. A2B receptors were upregulated
obesity 31543 Caucasian women with obesity [[118]].A HFD induced changes in glucose homeostasis, inflammation and obesity . A2B receptors were upregulated in lean mice by a HFD, while A2B receptor knockout mice under this diet
obesity 31673 upregulated in lean mice by a HFD, while A2B receptor knockout mice under this diet developed greater obesity and signs of type 2 diabetes [[119]]. The authors showed further that in human subjects with obesity,
obesity 31774 obesity and signs of type 2 diabetes [[119]]. The authors showed further that in human subjects with obesity , A2B receptor expression correlated strongly with expression of the insulin receptor substrate 2, and
obesity 31977 2, and suggested that A2B receptor agonists have potential for the treatment of type 2 diabetes and obesity . A recent study by Antonioli and coworkers reported that A2B receptors participate to obesity-related
obesity 32071 diabetes and obesity. A recent study by Antonioli and coworkers reported that A2B receptors participate to obesity -related enteric dysmotility, modulating the activity of excitatory tachykininergic nerves in HFD mice
obesity 32314 and adipogenesis is available [[121]]. High plasma levels of adenosine were found in children with obesity [[122]] and in overweight pregnant women [[123]]. Non-alcoholic fatty liver disease is an obesity-related
obesity 32412 with obesity [[122]] and in overweight pregnant women [[123]]. Non-alcoholic fatty liver disease is an obesity -related condition. A study provided insight into the lipolytic actions of caffeine (a P1 receptor antagonist)
obesity 33112 ectonucleotidase CD73 and A2A receptors in inflammation observed in patients with type 2 diabetes and obesity mediated via apoptosis [[126]]. Adenosine protects rats from a HFD by reducing glucose and insulin levels,
obesity 33627 mice. Therefore, P2Y6 receptors are a potential therapeutic target for the prevention and treatment of obesity .A2A receptor agonists, acting on adipocytes, counteract HFD-induced obesity in mice, indicating A2A
obesity 33703 prevention and treatment of obesity.A2A receptor agonists, acting on adipocytes, counteract HFD-induced obesity in mice, indicating A2A receptors as a potential drug target for anti-obesity therapies.P2Y11 receptors
obesity 33781 counteract HFD-induced obesity in mice, indicating A2A receptors as a potential drug target for anti- obesity therapies.P2Y11 receptors have stimulatory effects on lipolysis in adipocytes. Therefore, these receptors
obesity 34032 P2X7 receptors, which mediate inflammation, and KATP are beginning to be explored for the treatment of obesity .Growing lines of evidence suggest that a subtle balance of adipogenic and osteogenic differentiation
obesity 34287 homeostasis and a loss of adipo-osteogenic balance leads to pathophysiological conditions, such as obesity .P2Y1 receptors are responsible for the extracellular ATP-mediated intracellular triglyceride accumulation
obesity 35215 loss. Antagonism of P2Y13 receptors might constitute a novel therapeutic strategy in patients with obesity affected by intestinal dysmotility.Adipocyte ABC transporter G1 promoted triglyceride storage and fat
obesity 35477 therapeutic target in the control of fat accumulation.A1 receptor agonists are in clinical trials for obesity . Over-expression of A1 receptors in adipose tissue protects mice from obesity-related insulin resistance.A2B
obesity 35555 in clinical trials for obesity. Over-expression of A1 receptors in adipose tissue protects mice from obesity -related insulin resistance.A2B receptors prevent HFD-induced hallmarks of type 2 diabetes, adipose tissue
obesity 35899 signalling offers proof-of-concept potential for the development of novel therapeutic approaches to treat obesity , mostly from studies in animal models. Currently, pharmacological obesity treatment options are palliative
obesity 35973 therapeutic approaches to treat obesity, mostly from studies in animal models. Currently, pharmacological obesity treatment options are palliative and limited. An excess of body fat is associated with cardiovascular
obesity 36341 the most efficacious approach to achieving sustained weight loss for the majority of patients with obesity . In particular, strategies to combat obesity may include drugs that regulate bodyweight acting through
obesity 36386 sustained weight loss for the majority of patients with obesity. In particular, strategies to combat obesity may include drugs that regulate bodyweight acting through CNS pathways or via peripheral adiposity signals
obesity 36897 P2Y receptors and ionotropic P2X7 receptors, which are all thought to contribute to the pathology of obesity . The enormous flexibility and diversity of the purinergic system can be exploited in drug design for
obesity 37059 purinergic system can be exploited in drug design for therapeutic intervention and the development of anti- obesity drugs, although further understanding is needed. Indeed, the development of selective agonists and antagonists
obesity 37368 the interactions of purinergic signalling with other established signalling systems in relation to obesity . Hopefully, the potential use of purinergic compounds that are orally bioavailable and stable in vivo
obesity 37499 potential use of purinergic compounds that are orally bioavailable and stable in vivo for the treatment of obesity will soon be prepared by medicinal chemists that can be used in clinical trials
osteoporosis 6357 tachycardia. Clinical trials are currently in progress to explore purinergic agents for the treatment of osteoporosis , chronic cough, visceral pain, bladder incontinence, cancer and neurodegenerative diseases (see [[13]]).Purinergic

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