CB1 Signaling in Forebrain and Sympathetic Neurons Is a Key Determinant of Endocannabinoid Actions on Energy Balance

Quarta, Carmelo; Bellocchio, Luigi; Mancini, Giacomo; Mazza, Roberta; Cervino, Cristina; Braulke, Luzie J.; Fekete, Csaba; Latorre, Rocco; Nanni, Cristina; Bucci, Marco; Clemens, Laura E.; Heldmaier, Gerhard; Watanabe, Masahiko; Leste-Lassere, Thierry; Maître, Marlène; Tedesco, Laura; Fanelli, Flaminia; Reuss, Stefan; Schimrigk, К.; Srivastava, Rai Ajit K.; Monory, Krisztina; Valerio, Alessandra; Grandis, Annamaria; Giorgio, Roberto De; Pasquali, Renato; Nisoli, Enzo; Cota, Daniela; Lutz, Beat; Marsicano, Giovanni; Pagotto, Uberto

doi:10.1016/j.cmet.2010.02.015

Cited by 190 publications

(195 citation statements)

References 32 publications

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“…Interestingly, we found that androgenic decreased (DT) negatively, while estrogenic increased (DE 2 ) positively, correlated with the number of MetS components. The existence of correlations between sex hormone levels and body fat distribution could also be envisaged but not demonstrated in this study because of the technical difficulties in applying to rabbits the micro-CT system used with small rodents (Quarta et al 2010). Moreover, testosterone dosing in HFD rabbits improved insulin sensitivity (reduction of glycemia, improvement of glucose tolerance, and reduction of VAT).…”

Section: Discussionmentioning

confidence: 98%

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Maneschi¹,

Morelli²,

Filippi³

et al. 2012

Journal of Endocrinology

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We recently demonstrated that testosterone dosing ameliorated the metabolic profile and reduced visceral adipose tissue (VAT) in a high-fat diet (HFD)-induced rabbit model of metabolic syndrome (MetS). We studied the effects of HFD and in vivo testosterone dosing on VAT function and the adipogenic capacity of rabbit preadipocytes isolated from VAT of regular diet (RD), HFD, and testosterone-treated HFD rabbits. VAT was studied by immunohistochemistry, western blot, and RT-PCR. Isolated rPADs were exposed to adipocyte differentiating mixture (DIM) to evaluate adipogenic potential. Adipocyte size was significantly increased in HFD VAT compared with RD, indicating adipocyte dysfunction, which was normalized by testosterone dosing. Accordingly, perilipin, an anti-lipolytic protein, was significantly increased in HFD VAT, when compared with other groups. HFD VAT was hypoxic, while testosterone dosing normalized VAT oxygenation. In VAT, androgen receptor expression was positively associated with mRNA expression of GLUT4 (SLC2A4) (insulin-regulated glucose transporter) and STAMP2 (STEAP4) (androgen-dependent gene required for insulin signaling). In testosterone-treated HFD VAT, STAMP2 mRNA was significantly increased when compared with the other groups. Moreover, GLUT4 membrane translocation was significantly reduced in HFD VAT, compared with RD, and increased by testosterone. In DIM-exposed preadipocytes from HFD, triglyceride accumulation, adipocyte-specific genes, insulin-stimulated triglyceride synthesis, glucose uptake, and GLUT4 membrane translocation were reduced compared with preadipocytes from RD and normalized by in vivo testosterone dosing. In conclusion, testosterone dosing in a MetS animal model positively affects VAT functions. This could reflect the ability of testosterone in restoring insulin sensitivity in VAT, thus counteracting metabolic alterations.

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Section: Discussionmentioning

confidence: 98%

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Maneschi¹,

Morelli²,

Filippi³

et al. 2012

Journal of Endocrinology

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“…Energy expenditure enhanced by blockade of central CB1 antagonists is primarily mediated by sympathetic activation via central nervous system action. 6,7,31 In contrast to rimonabant, acute treatment with BPR697 did not elevate energy expenditure, which is well correlated with its poor central nervous system penetration. This result indicates the weight loss from BPR697 is not due to enhancement of energy expenditure.…”

Section: Discussionmentioning

confidence: 99%

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Lin

Shia

et al. 2011

Int J Obes

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OBJECTIVE: Fatty acid oxidation has been implicated in amelioration of obesity by burning off excessive accumulated lipid. BPR697, a peripheral cannabinoid receptor 1 (CB1) antagonist, elevated fat oxidation without added energy expenditure. Its impact on food intake, body weight changes and metabolic alterations were examined in rats fed standard chow and in diet-induced obesity (DIO) mice. MATERIALS AND METHODS: CB1 agonist-induced hypothermia and analgesia responses were measured to examine the brain activity of BPR697. The acute effects of BPR697 on food intake, body weight change and post-absorptive metabolic profiles were investigated in rats. Energy utilization with BPR697 was examined by indirect calorimetry. Chronic treatment of DIO mice was used to evaluate the long-term effects of BPR697. RESULTS: Distribution of BPR697 was significantly biased in favor of the periphery instead of the brain, as shown by its low brain/plasma concentration ratio and confirmed by the negative response of BPR697 in CB1 agonist-induced hypothermia and analgesia. When administered to rats at 20 mg kg À1 , BPR697 showed a unique spectrum of effects with significant weight loss without altered food intake. Furthermore, BPR697 increased serum levels of free fatty acids and ketone bodies and reduced hepatic lipid accumulation with preservation of liver glycogen in postprandial rats. Indirect calorimetric profiling of BPR697 revealed a similar trend, shifting whole-body energy catabolism toward fat oxidation, but without elevated energy expenditure. In DIO mice with chronic treatment, animals treated with BPR697 at 20 mg kg À1 resisted weight gain and showed a reduction of high-fat-induced cardiometabolic abnormalities such as hyperglycemia, abdominal fat and liver steatosis. CONCLUSION: The induction of fatty acid oxidation without concomitant elevation of energy expenditure by the peripheral CB1 antagonist BPR697 is sufficient to cause substantial weight loss in chow-fed rats. In the presence of high-dietary fat intake, BPR697 resists weight gain and alleviates obesity-related cardiometabolic risk factors. Keywords: fatty acid oxidation; peripheral CB1 antagonist; food intake; body weight; cardiometabolic risk factors INTRODUCTION Energy homeostasis, the balance between energy intake and energy expenditure, is regulated by coordinated interaction between the central nervous system and peripheral tissues. Elucidation of the metabolic factors influencing energy balance, and lipid and glucose metabolism has been a major focus of research interest, and many studies of the underlying mechanisms have revealed the importance of communication between the central nervous system and the periphery. 1--3 Among various factors involved in energy balance, endocannabinoids (for example, anandamide and 2-arachidonoylglycerol) mediate a positive energy balance via activation of their receptor, cannabinoid receptor 1 (CB1). The brain CB1 receptor, a G proteincoupled receptor, is present at a high level in brain tissue, and enhances appetite a...

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“…In fact, the endocannabinoid system (ECS), which comprises the cannabinoid receptors, the endogenous ligands and the enzymes responsible for synthesis and degradation of endocannabinoids, is present in all strategic tissues controlling energy balance (Cota & Woods 2005) and it has been involved in the pathogenesis of obesity (Di Marzo et al 2009, Quarta et al 2010. Besides its important role in the hypothalamus and brain reward system in controlling food intake, elements of the ECS are also expressed in key peripheral tissues controlling metabolism, i.e.…”

Section: Introductionmentioning

confidence: 99%

A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans

Romero-Zerbo¹,

Rafacho²,

Díaz-Arteaga³

et al. 2011

Journal of Endocrinology

105

100

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The cannabinoid CB1 receptor is a well-known player in energy homeostasis and its specific antagonism has been used in clinical practice for the treatment of obesity. The G protein-coupled receptor GPR55 has been recently proposed as a new cannabinoid receptor and, by contrast, its pharmacology is still enigmatic and its physiological role is largely unexplored, with no reports investigating its putative role in metabolism. Thus, we aim to investigate in rats the presence, distribution and putative physiological role of GPR55 in a key metabolic tissue, the endocrine pancreas. We found high Gpr55 mRNA content in pancreatic islets and considerable protein distribution in insulin-secreting b-cells. Activation of GPR55 by the agonist O-1602 increased calcium transients (P!0 . 01) and insulin secretion (P!0 . 001) stimulated by glucose. This latter effect was blunted in Gpr55 KO mice suggesting that O-1602 is acting, at least in part, through GPR55. Indeed, acute in vivo experiments showed that GPR55 activation increases glucose tolerance (P!0 . 05) and plasma insulin levels (P!0 . 05), suggesting an in vivo physiological relevance of GPR55 systemic stimulation. Taken together, these results reveal the expression of GPR55 receptors in the endocrine pancreas as well as its function at stimulus-secretion coupling of insulin secretion, suggesting a role in glucose homeostasis. In this context, it may also represent a new target for consideration in the management of type 2 diabetes and related diseases.

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CB1 Signaling in Forebrain and Sympathetic Neurons Is a Key Determinant of Endocannabinoid Actions on Energy Balance

Cited by 190 publications

References 32 publications

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

A role for the putative cannabinoid receptor GPR55 in the islets of Langerhans

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