Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

Mh, Son; Hd, Kim; Yn, Chae; Mk, Kim; Cy, Shin; Gj, Ahn; Sh, Choi; Ek, Yang; Kj, Park; Hw, Chae; Moon, Hi-Soo; Sh, Kim; Yg, Shin; Sh, Yoon

doi:10.1038/ijo.2009.253

Cited by 54 publications

(43 citation statements)

References 32 publications

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“…The previously published, peripherally restricted compound URB447 has approximately 100 times lower CB 1 R affinity (IC 50 , 313 nM) and lacks CB 1 /CB 2 selectivity (51), and another recently published compound with reduced brain penetrance has similarly low CB 1 R affinity (159 nM) (52). An article describing another peripherally restricted CB 1 R antagonist with nanomolar potency and a high degree of selectivity for CB 1 over CB 2 receptors appeared after the present study had been submitted for publication.…”

Section: Figurementioning

confidence: 99%

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Tam¹,

Vemuri²,

Liu³

et al. 2010

J. Clin. Invest.

152

272

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Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB 1 R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB 1 R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB 1 R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB 1 R in peripheral tissues, including the liver, as verified through the use of CB 1 R-deficient mice with or without transgenic expression of CB 1 R in the liver. These results suggest that targeting peripheral CB 1 R has therapeutic potential for alleviating cardiometabolic risk in obese patients. IntroductionEndocannabinoids are endogenous lipid mediators that interact with the same G protein-coupled receptors - CB 1 R and CB 2 R - that recognize plant-derived cannabinoids, and they regulate a broad range of physiological functions. CB 1 Rs are expressed at very high levels in the brain but are also present at much lower yet functionally relevant concentrations in various peripheral tissues, whereas the expression of CB 2 Rs is largely limited to cells of the immune and hematopoietic systems. Activation of CB 1 R results in increased appetite, insulin resistance, and increased hepatic lipogenesis, which suggests the involvement of the endocannabinoid/ CB 1 R system in obesity and its metabolic consequences (1). Indeed, obesity and its metabolic complications are characterized by an overactive endocannabinoid system (2-5), and chronic treatment with CB 1 R antagonists leads to weight loss and improved cardiometabolic risk profile in obese rodents (6, 7) and humans (8-11). However, concern over neuropsychiatric side effects, including anxiety, depression, and suicidal ideation (12), prevented approval of the first-in-class CB 1 R antagonist rimonabant in the United States and led to its withdrawal from the European market as well as the withdrawal of related compounds from preclinical development (13). Although the exact role of the endocannabinoid system in the control of mood and anxiety-like behaviors is not clear, CB 1 R in the prefrontal cortex, amygdala, and the mesolimbic dopaminergic reward pathway have been linked to the control of these behaviors (14). On the other hand, CB 1 Rs are also present in peripheral tissues including the liver (15-17), skeletal muscle (18,19), endocrine

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Section: Figurementioning

confidence: 99%

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Tam¹,

Vemuri²,

Liu³

et al. 2010

J. Clin. Invest.

152

272

View full text Add to dashboard Cite

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“…A number of studies have demonstrated that CB 1 antagonists and inverse agonists are an effective anti-obesity therapeutic (Van Gaal et al 2005, Janiak et al 2007, Rosenstock et al 2008, Nam et al 2012, Tam et al 2012. However, characterisation of the physiological effects of CB 1 antagonism in the periphery is limited outside of metabolically active tissues (Sink et al 2008, Son et al 2010, Merroun et al 2013. Therefore, it is essential to determine whether antagonism of CB 1 in the periphery alters disease progression in other tissues to ensure a full investigation of its potential as a therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

Jenkin¹,

O’Keefe²,

Simcocks³

et al. 2015

Journal of Endocrinology

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Modulation of the endocannabinoid system as an anti-obesity therapeutic is well established; however, the direct effects of cannabinoid receptor 1 (CB 1 ) antagonism on renal function and structure in a model of diet-induced obesity (DIO) are unknown. The aim of this study was to characterise the renal effects of the CB 1 antagonist AM251 in a model of DIO. Male Sprague-Dawley rats were fed a low-or high-fat diet (HFD: 40% digestible energy from lipids) for 10 weeks to elicit DIO (nZ9). In a different cohort, rats were fed a HFD for 15 weeks. After 9 weeks consuming a HFD, rats were injected daily for 6 weeks with 3 mg/kg AM251 (nZ9) or saline via i.p. injection (nZ9). After 10 weeks consuming a HFD, CB 1 and megalin protein expression were significantly increased in the kidneys of obese rats. Antagonism of CB 1 with AM251 significantly reduced weight gain, systolic blood pressure, plasma leptin, and reduced albuminuria and plasma creatinine levels in obese rats. Importantly, there was a significant reduction in tubular cross-section diameter in the obese rats treated with AM251. An improvement in albuminuria was likely due to the reduction in tubular size, reduced leptinaemia and maintenance of megalin expression levels. In obese rats, AM251 did not alter diastolic blood pressure, sodium excretion, creatinine clearance or expression of the fibrotic proteins VEGFA, TGFB1 and collagen IV in the kidney. This study demonstrates that treatment with CB 1 antagonist AM251 improves renal outcomes in obese rats.

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“…L'aumento de novo della lipogenesi epatica, è stata documentata nel topo DIO (62,63), così come nei soggetti con NAFLD (64,65), e può essere mediata dagli endocannabinoidi. Infatti, in studi condotti nei roditori, l'espressione del gene lipogenico e il tasso di lipogenesi epatica de novo, risultavano aumentati dagli agonisti CB 1 e diminuiti dagli antagonisti (66,67,68,69). Una dieta ricca di grassi aumenta l'espressione epatica dei CB 1 (70) e i livelli di AEA.…”

Section: Endocannabinoidi E Fibrosi Epaticaunclassified

Che cosa so di... Il ruolo della Cannabis e dei Cannabinoidi nelle malattie del fegato: review della letteratura

Vivo¹,

Bellinato²,

Marucco³

et al. 2017

Mission

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IntroduzioneL'utilizzo della cannabis a scopo terapeutico risale a migliaia di anni prima di Cristo, oggi il suo utilizzo è illegale in quasi tutti i paesi occidentali, ma da anni esiste un forte movimento, attivo soprattutto negli Stati Uniti, a favore della sua reintroduzione anche a scopo ricreativo. Ad oggi, sono 20 Stati e il Distretto di Columbia, ad aver approvato regolamenti che hanno permesso di depenalizzare o legalizzare la produzione e l'uso della cannabis a fini terapeutici. Secondo i dati pubblicati dall'International Narcotics Control Board (Narcotic Drugs: Estimated world requirements for 2015; statistics for 2013), i Paesi produttori di cannabis oltre gli Stati Uniti, sono: Canada, Regno Unito, Olanda, Danimarca, Francia, Romania, Repubblica Ceca e Israele.In Italia con il decreto del 9 novembre 2015, il Ministro della Salute ha rilasciato la concessione delle autorizzazioni per la coltivazione, la produzione, la fabbricazione, l'impiego, il commercio, l'esportazione, l'importazione, il transito, l'acquisto, la vendita e la detenzione delle sostanze stupefacenti o psicotrope prestando particolare attenzione ai medicinali di origine vegetale a base di cannabis. La rimborsabilità a carico del Servizio sanitario regionale prevede che la produzione nazionale di sostanze e preparazioni di origine vegetale a base di cannabis, avvenga presso lo Stabilimento chimico farmaceutico militare di Firenze e sia subordinata alle indicazioni emanate da parte delle Regioni o Province autonome. Le regioni che attualmente hanno approvato l'utilizzo della cannabis a scopo terapeutico sono rappresentate da: Puglia, Toscana, Veneto, Liguria, Marche, Friuli Venezia Giulia, Abruzzo, Sicilia, Umbria, Basilicata, Emilia Romagna, Piemonte e Valle D'Aosta. La prescrizione medica di questi preparati non deve essere considerata una terapia propriamente detta, bensì un trattamento sintomatico di supporto ai trattamenti standard, quando questi ultimi non hanno prodotto gli effetti desiderati, hanno provocato effetti secondari non tollerabili, o necessitano di incrementi posologici che potrebbero determinare la comparsa di effetti collaterali . Mission 46.......................................................................................................................................................................................................... SummaryIn many States of USA and some Italian regions, marijuana has been legalized as medical drug. So, a process of cannabis decriminalization is in place throughout the West. The debate about cannabis goes on politically and socially with contrasting aspects. Both as regards the recreational use, it should be recalled that is considered harmful (to a different extent) by virtually all the experts; both in terms of therapeutic use, considered promising by many researchers, but for which the results really sure still seem limited to a few ambit. This paper provides a review to groped to shed light on this topic both on the legal peculiarities and medical prescribing, and espe...

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Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

Cited by 54 publications

References 32 publications

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

Che cosa so di... Il ruolo della Cannabis e dei Cannabinoidi nelle malattie del fegato: review della letteratura

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