Endocannabinoids and the control of energy balance

doi:10.1016/j.tem.2006.11.006

Trends in Endocrinology & Metabolism

Volume 18, Issue 1, January–February 2007, Pages 27-37

https://doi.org/10.1016/j.tem.2006.11.006 Get rights and content

Two receptors have been cloned to date for the psychotropic compound Δ⁹-tetrahydrocannabinol, and termed cannabinoid CB₁ and CB₂ receptors. Their endogenous ligands, the endocannabinoids, have also been identified. CB₁ receptors and endocannabinoids are present in brain structures controlling energy intake and in peripheral cells (hepatocytes, adipocytes, pancreatic islet cells) regulating energy homeostasis. CB₂ receptors are more abundant in lymphocytes and macrophages, and participate in immune and inflammatory reactions. Metabolic hormones and peptides regulate the levels of the endocannabinoids and, hence, the activity of cannabinoid receptors in several tissues in a seemingly coordinated way. The endocannabinoids, particularly after stress and brief food deprivation, act in turn as local modulators of the expression and action of neurotransmitters, hormones and adipokines involved in metabolic control. Endocannabinoid overactivity seems to accompany metabolic and eating disorders and to contribute to the development of abdominal obesity, dyslipidemia and hyperglycemia. Accordingly, clinical trials have shown that CB₁ receptor antagonists are efficacious at reducing not only food intake, but also abdominal adiposity and its metabolic sequelae.

Section snippets

From Cannabis to the endocannabinoid system

In the history of their discovery, the endocannabinoids in many ways resemble the endorphins. It all started in the mid-1960s, with the identification of the major psychoactive component of Cannabis sativa and marijuana, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) [1] (Figure 1). The next major achievement was the finding that Δ⁹-THC works by binding to specific plasma membrane proteins, the ‘cannabinoid receptors’. Although the existence of several receptors for Δ⁹-THC and/or its synthetic analogs (

Endocannabinoid ‘tone’, stress and food intake

The cloning of cannabinoid CB₁ receptors enabled the development of potent, metabolically stable and selective CB₁ agonists and antagonists (Figure 1) and of transgenic CB₁ receptor-deficient mice. This led to the demonstration that these receptors are responsible for the well-known appetite-inducing actions of cannabis and Δ⁹-THC and for analogous effects of the endocannabinoids 9, 10. In the framework of what seems to be a general strategy, whereby the ECS is transiently activated in the

Endocannabinoid control over hypothalamic neurotransmitters and neuropeptides

CB₁ receptors are distributed in the hypothalamus in a way that suggests that they directly regulate the expression of orexigenic or anorexigenic signals [24]; that is: (i) in neurons of the ARC expressing cocaine- and amphetamine-regulated transcript (CART, an anorexigenic mediator); (ii) in lateral hypothalamus (LHA) neurons containing the orexigenic melanin-concentrating hormone (MCH) and orexins; and (iii) in the PVN, in neurons expressing the anorexigenic corticotropin-releasing hormone

Peripheral endocannabinoid control of metabolism

As mentioned earlier, endocannabinoids and CB₁ receptors are present in peripheral cells and tissues controlling energy homeostasis, including the gut [35], the liver and hepatocytes [36], white adipose tissue (WAT) 37, 38 and adipocytes 24, 37, 39, 40, skeletal muscle [41] and the pancreas 37, 42. This suggests the existence of an as-yet poorly investigated role of the ECS in the peripheral control of nutrient assimilation, processing and storage, as summarized in the following paragraphs.

Endocannabinoid overactivity in obesity and hyperglycaemia, and its consequences

There is increasing evidence for overactivity of the ECS during conditions of unbalanced energy homeostasis (e.g. obesity and hyperglycemia), and for its causative role in these disorders (Table 1, Box 3). In lean animals, CB₁ receptor antagonists appear to be more efficacious in the presence of a demonstrated higher tone of the ECS in those brain areas controlling food intake (e.g. following brief periods of food deprivation or when the animals are exposed to palatable foods). Therefore, the

Therapeutic implications of ECS function and dysfunction in the control of metabolism

We have summarized here the available evidence pointing to the important role of the ECS in the control not only of energy intake, but also of energy accumulation and expenditure, and of glucose and fatty acid metabolism at the level of several peripheral organs. Based on this evidence, new endocannabinoid-based drugs are already being developed and marketed for the treatment of obesity and related metabolic disorders. Rimonabant, the first CB₁ receptor antagonist and inverse agonist to be

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The cannabinoid receptor CB1R is expressed in pancreatic β-cells; CB1R increased activity is associated with diabetes, obesity, cardiovascular disorders as well as decreased insulin secretion and insulin resistance. CB1R was shown to signal through G-protein coupling as well as β-arrestins in β-cells. Peripherally restricted CB1R inverse agonists purportedly have beneficial effects on insulin secretion in β-cells, without the unwanted effects in the central nervous system. Here we show that a peripherally restricted CB1R inverse agonist, MRI-1891, augments glucose stimulated insulin secretion in isolated human pancreatic islets and mouse islets. The insulin secretion enhancing effect of MRI-1891 is comparable to exendin-4, an analogue of the glucagon like peptide-1 (GLP1). Moreover, MRI-1891 treatment protects isolated human islet cells against cytokine-induced apoptosis, similar to exendin-4. Thus, MRI-1891, a new class of CB1R inverse agonist, may be considered a potential therapeutic for both type 1 and type 2 diabetes because of its ability to protect pancreatic β-cells from cytokine toxicity and to promote insulin secretion.
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Neuroendocrine mechanisms play a key role in the regulation of eating behavior. In individuals with binge eating disorder (BED), alterations in these mechanisms signaling hunger and satiety have been observed. It has been investigated that these alterations may underlie the development and maintenance of compulsive overeating in BED. The present narrative review examined the current literature related to the neurobiological processes involved in feeding dysregulation in BED with the aim of updating the most relevant aspects with special attention to neuroendocrine signaling. Studies have shown both central and peripheral endocrine dysfunctions in hormones participating in homeostatic and hedonic pathways in BED. Most studies have been especially focused on orexigenic signals, pointing out the existence of a hyperactivated mechanism promoting hunger. Fewer studies have explored anorexigenic pathways, but the findings so far seem to suggest an abnormal satiety threshold. Despite this, to date, it is unable to identify whether these alterations are typical of the BED pathophysiology or are related to an obesogenic pattern due to most studies included patients with BED and obesity. The identification of endophenotypes in BED may provide a new approach to aberrant eating behavior, favoring the implementation of biological therapeutic targets.
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Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a “nutritional programming” of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.
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Trends in Endocrinology & Metabolism

ReviewEndocannabinoids and the control of energy balance

Section snippets

From Cannabis to the endocannabinoid system

Endocannabinoid ‘tone’, stress and food intake

Endocannabinoid control over hypothalamic neurotransmitters and neuropeptides

Peripheral endocannabinoid control of metabolism

Endocannabinoid overactivity in obesity and hyperglycaemia, and its consequences

Therapeutic implications of ECS function and dysfunction in the control of metabolism

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Brain Res. Brain Res. Rev.

Neuropharmacology

Neurosci. Lett.

Neuron

Curr. Opin. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

FEBS Lett.

Physiol. Behav.

Lancet

Lancet

Prostaglandins Leukot. Essent. Fatty Acids

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

Biochim. Biophys. Acta

Isolation, structure, and partial synthesis of an active constituent of hashish

J. Am. Chem. Soc.

Pharmacological actions of cannabinoids

Handb. Exp. Pharmacol.

Cannabinoid-based drugs as anti-inflammatory therapeutics

Nat. Rev. Immunol.

Identification and functional characterization of brainstem cannabinoid CB2 receptors

Science

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

Science

The endocannabinoid system and its therapeutic exploitation

Nat. Rev. Drug Discov.

Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors

Psychopharmacology (Berl.)

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

Br. J. Pharmacol.

Plant, synthetic, and endogenous cannabinoids in medicine

Annu. Rev. Med.

Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis

Neuropsychopharmacology

Leptin-regulated endocannabinoids are involved in maintaining food intake

Nature

Appetite suppression and weight loss after the cannabinoid antagonist SR 141716

Life Sci.

SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset

Behav. Pharmacol.

Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats

Br. J. Pharmacol.

Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland

Neuroendocrinology

Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens

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

Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin

J. Neurosci.

Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets

J. Physiol.

A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding

J. Neurosci.

Review
Endocannabinoids and the control of energy balance