Dysregulation of the Endocannabinoid System in Obesity

Franz Volhard Clinical Research Center, Medical Faculty of the Charité, Berlin, Germany.
Journal of Neuroendocrinology (Impact Factor: 3.14). 06/2008; 20 Suppl 1(s1):110-5. DOI: 10.1111/j.1365-2826.2008.01683.x
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An activation of the endocannabinoid system (ECS) in obesity with increased concentrations of endocannabinoids in several tissues and in the circulation is described in this review. This increased availability of endocannabinoids might stimulate cannabinoid receptors in a pathophysiological manner. The successful use of the cannabinoid receptor CB(1) inverse agonists rimonabant and taranabant for weight loss and the treatment of obesity-associated metabolic disorders might well be through blocking this overstimulation of cannabinoid receptors. At present, no single mechanism has been identified that explains the increased bioavailability of endocannabinoids in obesity. Both increased synthesis and decreased degradation appear to operate in a species- and tissue-dependent manner, but many pieces of the puzzle still need to be collected. For example, most data show decreased fatty acid amide hydrolase (FAAH) expression and/or activity as a result of obesity or high-fat intake, but the endocannabinoid predominantly increased in tissues is 2-arachidonoylglycerol (2-AG), which is not degraded by FAAH in vivo. Furthermore, the influence of dietary fatty acids on the synthesis of endocannabinoids needs to be studied in much more detail. Although weight loss does not seem to influence activation of the endocannabinoid system (ECS) in human obesity, suggesting an underlying mechanisms independent of body weight, no such mechanism at the genetic level has yet been identified either. Thus, activation of the ECS is a hallmark of abdominal obesity, and explains the success of pharmacological CB(1) blockade, but serious attempts have to be made to clarify the underlying mechanisms of this activation.

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Available from: Stefan Engeli, Sep 22, 2014
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    • "As eCB levels in tissues are tightly controlled by a balance between synthesis and degradation, dysregulation of this control can lead to pathological conditions such as obesity and T2D (Fig. 3). Indeed, the eCB system is severely altered in obesity, which may result in increased eCB levels and CB 1 activity in the brain, liver, adipose tissue and skeletal muscles [46], and decreased levels of enzymes and receptors in other organs, such as the stomach, kidneys and heart (Fig. 3 "
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    ABSTRACT: The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D.
    Diabetes & Metabolism 09/2014; 40(4). DOI:10.1016/j.diabet.2014.02.004 · 3.27 Impact Factor
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    • "Endocannabinoids are involved in food intake, pain sensation and memory formation, amongst others [8,11]. EC system dysregulation is connected to several pathological conditions [10], such as Alzheimer’s, Parkinson’s, and Huntington’s disease, obesity, ischemic brain damage and epileptic seizures [12-15]. Endocannabinoids are released from the postsynaptic neurons and serve as retrograde signaling molecules [16]. "
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    ABSTRACT: Epilepsy is one of the most common chronic neurological disorders in dogs characterized by recurrent seizures. The endocannabinoid (EC) system plays a central role in suppressing pathologic neuronal excitability and in controlling the spread of activity in an epileptic network. Endocannabinoids are released on demand and their dysregulation has been described in several pathological conditions. Recurrent seizures may lead to an adverse reorganization of the EC system and impairment of its protective effect. In the current study, we tested the hypothesis that cerebrospinal fluid (CSF) concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2AG) are altered in epileptic dogs. Concentrations of AEA and total AG (sum of 2AG and 1AG) were measured in 40 dogs with idiopathic epilepsy and in 16 unaffected, healthy control dogs using liquid chromatography combined with tandem mass spectrometry. AEA and total AG were measured at 4.94 (3.18- 9.17) pM and 1.43 (0.90- 1.92) nM in epileptic dogs and at 3.19 (2.04 - 4.28) pM and 1.76 (1.08 - 2.69) nM in the control group, respectively (median, 25 - 75% percentiles in brackets). The AEA difference between epileptic and healthy dogs was statistically significant (p < 0.05). Values correlated with seizure severity and duration of seizure activity. Dogs with cluster seizures and/or status epilepticus and with seizure activity for more than six months displayed the highest EC concentrations. In conclusion, we present the first endocannabinoid measurements in canine CSF and confirm the hypothesis that the EC system is altered in canine idiopathic epilepsy.
    BMC Veterinary Research 12/2013; 9(1):262. DOI:10.1186/1746-6148-9-262 · 1.78 Impact Factor
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    • "At the central stages of the nervous system, it has been well described that the endocannabinoid system plays a dual role in the regulation of food intake as well as in the homeostatic and nonhomeostatic (or hedonic) energy regulation (Matias et al., 2008). Additionally, selective inverse agonists of CB 1 receptors have been developed for weight loss and the treatment of obesity-associated metabolic disorders (Engeli, 2008). It is obvious that the central processes involved in linking olfaction to food intake would hardly stay unaffected by an increased or decreased sensitivity of ORNs. "
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