“Pathophysiological conditions such as obesity and type 2 diabetes (T2D) are reportedly associated to over-activation of the endocannabinoid system (ECS). Therefore, modulation of the ECS offers potential therapeutic benefits on those diseases. GPR55, the receptor for L-α-lysophosphatidylinositol (LPI) that has also affinity for various cannabinoid ligands, is distributed at the central and peripheral level and it is involved in several physiological processes. This review summarizes the localization and role of GPR55 in tissues that are crucial for the regulation of glucose metabolism, and provides an update on its contribution in obesity and insulin resistance. The therapeutic potential of targeting the GPR55 receptor is also discussed.” https://www.ncbi.nlm.nih.gov/pubmed/28457969]]>
Category Archives: Obesity
Cannabinoid type 1 receptor-containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus.
“Phytocannabinoids, such as THC and endocannabinoids, are well known to promote feeding behavior and to control energy metabolism through cannabinoid type 1 receptors (CB1R). However, the underlying mechanisms are not fully understood.
Generally, cannabinoid-conducted retrograde dis-inhibition of hunger-promoting neurons has been suggested to promote food intake, but so far it has not been demonstrated due to technical limitations.
Our immunohistochemical and ultrastructural study demonstrates the morphological substrate for cannabinoid-conducted feeding behavior via retrograde dis-inhibition of hunger-promoting AgRP/NPY neurons.”
https://www.ncbi.nlm.nih.gov/pubmed/28377876Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats.
“Weight gain is an important side effect of most atypical antipsychotic drugs such as olanzapine. Moreover, although many animal models with metabolic side effects have been well defined, the interaction with other pathways has to be considered. The endocannabinoid system and the CB1 receptor (CB1R) are among the most promising central and peripheral targets involved in weight and energy balance. In this study we developed a rat model based 15-days treatment with olanzapine that shows weight gain and an alteration of the blood parameters involved in the regulation of energy balance and glucose metabolism. Consequently, we analysed whether, and by which mechanism, a co-treatment with the novel CB1R neutral antagonist NESS06SM, could attenuate the adverse metabolic effects of olanzapine compared to the reference CB1R inverse agonist rimonabant. Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour. Furthermore, rimonabant and NESS06SM restored the metabolic enzymes in the liver and fat tissue altered by olanzapine. Therefore, CB1 receptor antagonist/inverse agonist compounds could be good candidate agents for the treatment of weight gain induced by olanzapine.” https://www.ncbi.nlm.nih.gov/pubmed/28377074]]>
The CB1 Receptor as the Cornerstone of Exostasis.
“The type-1 cannabinoid receptor (CB1) is the main effector of the endocannabinoid system (ECS), which is involved in most brain and body functions. In this Perspective, we provide evidence indicating that CB1 receptor functions are key determinants of bodily coordinated exostatic processes. First, we will introduce the concepts of endostasis and exostasis as compensation or accumulation for immediate or future energy needs and discuss how exostasis has been necessary for the survival of species during evolution. Then, we will argue how different specific biological functions of the CB1 receptor in the body converge to provide physiological exostatic processes. Finally, we will introduce the concept of proactive evolution-induced diseases (PEIDs), which helps explain the seeming paradox that an evolutionary-selected physiological function can become the cause of epidemic pathological conditions, such as obesity. We propose here a possible unifying theory of CB1 receptor functions that can be tested by future experimental studies.” https://www.ncbi.nlm.nih.gov/pubmed/28334603]]>
Overactivation of the endocannabinoid system alters the anti-lipolytic action of insulin in mouse adipose tissue.
“Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT). The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate. For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R-/- mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways. Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R-/-suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the anti-lipolytic action of insulin. Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target. This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test whether the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28325733]]>
MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future.
“The endocannabinoid system (ECS), including cannabinoid type 1 and type 2 receptors (CB1R and CB2R), endogenous ligands called endocannabinoids and their related enzymatic machinery, is known to have a role in the regulation of energy balance.
Past information generated on the ECS, mainly focused on the involvement of this system in the central nervous system regulation of food intake, while at the same time clinical studies pointed out the therapeutic efficacy of brain-penetrant CB1R antagonists like rimonabant for obesity and metabolic disorders.
Rimonabant was removed from the market in 2009 and its obituary written due to its psychiatric side effects. However, in the meanwhile a number of investigations had started to highlight the roles of the peripheral ECS in the regulation of metabolism, bringing up new hope that the ECS might still represent target for treatment.
Accordingly, peripherally-restricted CB1R antagonists or inverse agonists have shown to effectively reduce body weight, adiposity, insulin resistance and dyslipidemia in obese animal models.
Very recent investigations have further expanded the possible toolbox for the modulation of the ECS, by demonstrating the existence of endogenous allosteric inhibitors of CB1R, the characterization of the structure of the human CB1R, and the likely involvement of CB2R in metabolic disorders. Here we give an overview of these findings, discussing what the future may hold in the context of strategies targeting the ECS in metabolic disease.”
https://www.ncbi.nlm.nih.gov/pubmed/28246151
“Obesity is a risk factor for increased severity of acute 
“GPR55 is a G-protein coupled receptor (GPCR) that has been identified as a new