The endocannabinoid system controls food intake via olfactory processes

Soria-Gómez, Edgar; Bellocchio, Luigi; Reguero, Leire; Lepousez, Gabriel; Martin, Claire; Bendahmane, Mounir; Ruehle, Sabine; Remmers, Floortje; Desprez, Tiffany; Matías, Isabelle; Wiesner, Theresa; Cannich, Astrid; Nissant, Antoine; Wadleigh, Aya; Pape, Hans‐Christian; Chiarlone, Anna; Quarta, Carmelo; Verrier, Danièle; Vincent, Peggy; Massa, Federico; Lutz, Beat; Guzmán, Manuel; Gurden, Hirac; Ferreira, Guillaume; Lledo, Pierre−Marie; Grandes, Pedro; Marsicano, Giovanni

doi:10.1038/nn.3647

Cited by 237 publications

(280 citation statements)

References 51 publications

(116 reference statements)

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“…There is substantial evidence that eCB signaling within the brain, particularly within the hypothalamus (as well as the nucleus accumbens and olfactory bulb) (23,(44)(45)(46)(47)(48)(49), promotes feeding behavior and its regulation by satiety state. Similarly, there is experimental evidence for both central and peripheral sites of action by which eCB signaling can modulate metabolic processes (12,13,50,51), particularly through the regulation of sympathetic tone in adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome

Bowles¹,

Karatsoreos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB 1 receptor as well as mice treated with the global CB 1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB 1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB 1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism.corticosterone | 2-AG | anandamide | obesity | liver O besity and associated cardiometabolic diseases, such as type 2 diabetes, represent major contributors to morbidity and mortality (1, 2). Persistent exposure to environmental and psychological stress and the concomitant increase in circulating glucocorticoids (GCs; the primary stress hormones) are believed to be contributing factors to the epidemic of obesity and metabolic syndrome (3-6). Furthermore, patients receiving exogenous GCs subsequent to an organ transplant or for the treatment of inflammatory-related illnesses show several symptoms of the metabolic syndrome (7). Despite this relationship, the mechanisms by which GCs produce these changes in weight regulation and metabolism remain unclear.It has been clearly shown that GCs can mobilize the endocannabinoid (eCB) system, which is essential for many of the effects of GCs, including negative feedback regulation of the hypothalamic-pituitary-adrenal axis, suppression of sexual behavior, and alterations in memory consolidation (8-11). eCBs are also potent regulators of feeding and metabolism, with effects that parallel those of GCs, such as increased feeding, reduced energy expenditure, fat accumulation ...

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Section: Discussionmentioning

confidence: 99%

A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome

Bowles¹,

Karatsoreos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Brain deletion of the CB1 gene in Glu-CB1-KO and GABA-CB1-KO has been demonstrated previously (Monory et al, 2006(Monory et al, , 2007Soria-Gómez et al, 2014;Bellocchio et al, 2010). Here we focused on brain structures relevant to the present study (Figure 1).…”

Section: Cb1 Immunohistochemistrymentioning

confidence: 91%

“…The progeny of these couples were, therefore, either 'floxed' with or without the Cre recombinase expression. Mice not expressing Cre recombinase are here defined as Glu-CB1-WT and GABA-CB1-WT controls, whereas their mutant littermates are called Glu-CB1-KO (CB1loxP/loxP; Nex-cre mice) and GABA-CB1-KO (CB1loxP/loxP; Dlx5/6-cre mice), respectively (Bellocchio et al, 2010;Monory et al, 2006Monory et al, , 2007Soria-Gómez et al, 2014).…”

Section: Animalsmentioning

confidence: 99%

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

Martín‐García

Bourgoin

Cathala

et al. 2015

Neuropsychopharmacol

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The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

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“…Endocannabinoids in the olfactory cortex increase odor detection and food intake in fasted mice, by decreasing, via CB1 abundantly expressed on axon terminals, the activity of cortical glutamatergic neurons that project from olfactory cortex areas to the main olfactory bulb food (811).…”

Section: Appetite and Feeding Behaviormentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

342

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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The endocannabinoid system controls food intake via olfactory processes

Cited by 237 publications

References 51 publications

A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome

A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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