After the withdrawal of the first generation of cannabinoid type 1 receptor antagonists for the treatment of obesity and metabolic disease, newly identified mechanisms point again to the ECS as attractive therapeutic target.

Inhibition of ECS activity has beneficial metabolic consequences by reducing adiposity, dyslipidemia, insulin resistance, and hepatic steatosis.

The ECS adjusts behavior and metabolism to food availability. Its activity is advantageous when access to food is limited or cannot be predicted, but becomes harmful when food is abundant, favoring the development of obesity and metabolic disease.

The endocannabinoid system (ECS) exerts a multi-organ energy-stowing function by promoting consumption of palatable food, stimulating fat mass expansion, and inhibiting energy expenditure and thermogenesis.

The endocannabinoid system (ECS) functions to adjust behavior and metabolism according to environmental changes in food availability. Its actions range from the regulation of sensory responses to the development of preference for the consumption of calorically-rich food and control of its metabolic handling. ECS activity is beneficial when access to food is scarce or unpredictable. However, when food is plentiful, the ECS favors obesity and metabolic disease. We review recent advances in understanding the roles of the ECS in energy balance, and discuss newly identified mechanisms of action that, after the withdrawal of first generation cannabinoid type 1 (CB 1 ) receptor antagonists for the treatment of obesity, have made the ECS once again an attractive target for therapy.

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Anandamide increases the differentiation of rat adipocytes and causes PPARgamma and CB1 receptor upregulation.

Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age.

Co-administration of SR141716 with peptide YY3-36 or oxyntomodulin has additive effects on food intake in mice.

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Diacylglycerol lipase alpha knockout mice demonstrate metabolic and behavioral phenotypes similar to those of cannabinoid receptor 1 knockout mice.

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The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice.

Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors.

The neutral cannabinoid CB(1) receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat.

Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113.

A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents.

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Peripheral effects of FAAH deficiency on fuel and energy homeostasis: role of dysregulated lysine acetylation.

Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function.

The cDNA 385C to A missense polymorphism of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) is associated with overweight/obesity but not with binge eating disorder in overweight/obese women.

Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH).

Genetic variation in cannabinoid receptor 1 (CNR1) is associated with derangements in lipid homeostasis, independent of body mass index.

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Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa.

Hedonic eating is associated with increased peripheral levels of ghrelin and the endocannabinoid 2-arachidonoyl-glycerol in healthy humans: a pilot study.

Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells.

Simultaneous postprandial deregulation of the orexigenic endocannabinoid anandamide and the anorexigenic peptide YY in obesity.

Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects.

Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity.

Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes.

Regulation of MAP kinase-directed mitogenic and protein kinase B-mediated signaling by cannabinoid receptor type 1 in skeletal muscle cells.

Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.

Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice.

CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice.

The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids.

Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia.

Adipocye-specific CB1 conditional knock-out mice: new insights in the study of obesity and metabolic syndrome.

Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways.

Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation.

CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.

CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance.

Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB(1) receptor blockade.

Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility.

Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus.

Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit.

Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol.

Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

The gastric CB1 receptor modulates ghrelin production through the mTOR pathway to regulate food intake.

Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype.

Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine.

Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice.

Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance.

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Endogenous cannabinoids in the brain and peripheral tissues: regulation of their levels and control of food intake.

Glossary

a compound that binds to a receptor at a site distinct from the active (or orthosteric) site and induces a conformational change in the receptor, thereby increasing or reducing the affinity of the receptor for its ligands.

a class of G-protein-coupled receptors activated by endogenous or exogenous cannabinoids. Two CBR subtypes have been cloned and characterized so far: the CB 1 R and the CB 2 R.

a preparation of the Cannabis sativa plant used as a psychoactive drug or medicine. The main psychoactive component of cannabis is tetrahydrocannabinol (THC).

anticipatory responses elicited by the autonomic nervous system to enhance digestion and metabolism of a meal. Cephalic-phase responses can arise from cognitive or sensory stimuli regarding food.

endogenous lipid-derived agonists for G-protein-coupled CBRs. They include anandamide (AEA) and 2-arachidonoylglycerol (2-AG).

a bioactive peptide fragment derived from the hemoglobin α1 chain which has been proposed to work as an endogenous allosteric modulator of CB 1 R.

a compound that has effects similar to those of an antagonist, but also causes a distinct set of downstream biological responses. Inverse agonists not only block the effects of binding agonists like a classical antagonist, but also inhibit the intrinsic or basal activity of the receptor.

a hormone produced mainly by adipocytes that regulates energy balance, metabolism, and immune and reproductive functions.

a system crucially involved in the regulation of energy balance that in the CNS includes POMC and AgRP neurons of the hypothalamic arcuate nucleus, which respectively produce melanocortin agonists and antagonists acting on melanocortin receptors in target brain areas.

a typical craving for palatable food after consuming marijuana-containing products.

steroids that are produced in the brain after local synthesis or by conversion of peripherally derived adrenal or gonadal steroids.

the process by which signaling molecules called neurotransmitters are released by a presynaptic neuron, cross the synapse, and activate the receptors of a postsynaptic neuron.

a compound that competitively binds to a receptor at the same binding site (active site) as the endogenous ligand or agonist, and attenuates the effects of the agonist by causing a functional reduction in signal transduction. It displays no intrinsic activity for activating the receptor.

a compound that increases appetite and food intake.

a family of N-terminally extended peptides that seem to act as endogenous negative allosteric modulators of CB 1 R.

a 241 amino acid polypeptide whose cleavage produces α-melanocyte-stimulating hormone (α-MSH), adrenocorticotrophic hormone (ACTH), and β-endorphin, which actively participate in the regulation of energy balance and metabolism.

fatty acids that contain more than one double bond in their structure. These include omega-3 (or n-3) and omega-6 (or n-6), also known as essential fatty acids.

production of heat by the organism, principally occurring in the brown adipose tissue.