Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity

Abstract

Endogenous cannabinoids acting at CB 1 receptors stimulate appetite, and CB 1 antagonists show promise in the treatment of obesity. CB 1 -/-mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB 1 in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB 1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB 1 . High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB 1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB 1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB 1 ligands. We conclude that anandamide acting at hepatic CB 1 contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation. IntroductionMaintenance of energy homeostasis and body weight involves the coordinated regulation of appetitive behavior and peripheral energy metabolism (1), as illustrated by the ability of the appetitereducing hormone leptin to regulate fat metabolism in the liver (2). Endocannabinoids are novel lipid mediators that modulate appetitive behavior through the activation of CB 1 (3-11). Sites in the hypothalamus (4, 10, 12), limbic forebrain (11-13), and peripheral sensory nerve terminals (7) have been implicated in mediating the orexigenic effect of endocannabinoids, which is potentiated by hunger or in hyperphagia associated with obesity (4-6, 9) and antagonized by CB 1 blockade. Indeed, CB 1 antagonists show promise in the treatment of obesity (14). A number of recent observations suggest that reduction of food intake alone cannot fully account for the antiobesity effects of CB 1 antagonists. In a mouse model of diet-induced obesity, chronic treatment with the CB 1 antagonist SR141716 caused a transient reduction in food intake and a more prolonged reduction in body weight (15). Mice lacking CB 1 are resistant to diet-induced obesity even though their total caloric intake is similar to that of wild-type littermates, which become obese on the same diet (16). CB 1 -/-mice display a moderately lean phenotype throughout adulthood but only a temporary hypophagia in the first few weeks of life (17). These observations suggest that endocannabinoids and CB 1 also regulate peripheral energy metabolism. Indeed, adipocytes have been found to express

Influence of Cannabis Use on Severity of Hepatitis C Disease

“…Antagonism of the CB1 receptor has been associated with reduced expression of the TGFβ1, a cytokine central to fibrosis production, and decreased stellate cell proliferation and increased apoptosis, all of which would be predicted to reduce fibrosis (9). Additionally, CB1 receptor antagonism has been associated with increased levels of adiponectin (26), an adipokine with antifibrotic properties in animal models (27). Thus, there are several potential mechanisms by which enhanced CB1 receptor expression or activity may lead to increased fibrosis.…”

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

“…As low levels of CB1R mRNA can be detected by PCR in adipocytes and liver, it has also been hypothesized that direct actions of rimonabant on adipocytes 4 or hepatocytes 41,42 may contribute to the observed physiological effects. It is impossible to show by conventional in vivo studies whether the physiological effects of CB1R inverse agonists may include a component of the peripheral site of action, because of the intact communication between the brain and peripheral tissues.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…Many of the biological actions of the ECS are mediated through G‐protein‐coupled cannabinoid type 1 (CB1R) and type 2 (CB2R) receptors which can be activated by several endogenous ligands, including anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG). Importantly, ECS dysregulation has been linked to abdominal obesity and other risk factors for type 2 diabetes (Engeli et al ., 2005; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). For example, genetic and diet‐induced obese animal models display elevated endocannabinoid levels in the hypothalamus and peripheral tissues (Di Marzo et al ., 2001; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006).…”

“…Importantly, ECS dysregulation has been linked to abdominal obesity and other risk factors for type 2 diabetes (Engeli et al ., 2005; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). For example, genetic and diet‐induced obese animal models display elevated endocannabinoid levels in the hypothalamus and peripheral tissues (Di Marzo et al ., 2001; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). Furthermore, increased circulating levels of AEA and 2‐AG, as well as elevated levels of 2‐AG within visceral adipose tissue, have been reported in obese and/or hyperglycaemic type 2 diabetic patients (Bluher et al ., 2006; Matias et al ., 2006).…”

“…Furthermore, increased circulating levels of AEA and 2‐AG, as well as elevated levels of 2‐AG within visceral adipose tissue, have been reported in obese and/or hyperglycaemic type 2 diabetic patients (Bluher et al ., 2006; Matias et al ., 2006). In accord with this, hyperactivation of CB1R‐induced signalling has been implicated in numerous metabolic abnormalities including hyperphagia, insulin resistance, glucose intolerance and impaired lipid homeostasis (Engeli et al ., 2005; Jbilo et al ., 2005; Osei‐Hyiaman et al ., 2005). Conversely, genetic or pharmacological CB1R blockade improves metabolic status, for example by promoting reductions in body weight and fat mass, as well as enhancing insulin sensitivity and glucose tolerance.…”