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Endogenous cannabinoids acting at CB1 receptors stimulate appetite, and CB1 antagonists show promise in the treatment of obesity. CB1−/− 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 CB1 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 CB1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB1. High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB1 ligands. We conclude that anandamide acting at hepatic CB1 contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.
Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115: 1298-1305. (Reprinted with permission from the American Society for Clinical Investigation.), , , , , , et al.
Robert F. Schwabe M.D.*, * Department of Medicine, Columbia University College of Physicians & Surgeons, New York, NY
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Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of abnormal liver test results in the adult population in the United States and has been estimated to affect 10% to 24% of the population.1 The primary cause of hepatic steatosis is thought to be insulin resistance, which causes increased peripheral lipolysis and delivery of free fatty acids to the liver.2 Accordingly, NAFLD is most prevalent among obese patients (66%), patients with diabetes (50%) and severely obese patients with diabetes (100%).1 In a subset of these patients hepatic steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and carries an adverse prognosis. Additionally, NAFLD is an adverse modifier of outcome in large cohorts of patients with underlying liver disease including chronic hepatitis C virus infection.3
In recent years a variety of mediators and pathways have been identified which are linked to the development of hepatic and systemic insulin resistance and fatty liver. Among these are the adipokines leptin and adiponectin, the cytokine tumor necrosis factor α (TNFα), the proinflammatory kinases c-Jun N-terminal kinase, and IκB kinase beta, as well as the transcription factor PPARγ.2, 4–6 Despite our expanding knowledge of molecular events that contribute to hepatic inflammation and insulin resistance associated with adiposity, there is still a fundamental gap in our understanding of the regulation of food intake and hepatic lipogenesis during the early stages.
The appetite-stimulating effects of Cannabis sativa ingredients have been known since ancient times.7 In the past decade two G-protein–coupled receptors that bind cannabinoids, CB1 and CB2, have been cloned.8, 9 CB1 is mainly expressed in the central nervous system,8, 10 whereas CB2 is preferentially expressed on cells of the immune system.9 Several endogenous lipid mediators, including N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol, that act as agonists for CB1 and CB2 have been discovered. Together, these components constitute an endogenous cannabinoid system, termed the “endocannabinoid system.”10 The endocannabinoid system plays a role in a variety of physiological processes, including nociception and sleep regulation and exerts an important function in the regulation of food intake.10 The stimulatory effects of Δ-9-tetrahydrocannibol, the main active compound of Cannabis sativa, on food intake have led to studies investigating its effect in AIDS wasting syndrome and cancer, where it showed moderate efficacy. Vice versa, disruption of CB1 signaling by the CB1 receptor antagonist SR141716 (Rimonabant) or by genetic inactivation of CB1 reduces food intake after periods of food deprivation.11 Accordingly, CB1-deficient mice retain a lean phenotype throughout their life and are resistant to diet-induced obesity.12 One main target of endocannabinoids is the hypothalamus, which expresses high levels of CB1 and upregulates food intake after CB1 stimulation. However, it has been suggested that endocannabinoids additionally act through peripheral targets that regulate lipogenesis.12
Based on the fact that the liver plays a major role in de novo lipogenesis, Osei-Hyaiman et al. investigated the role of hepatic CB1 receptors in diet-induced obesity and showed compelling evidence that the liver is a major target of a peripheral lipogenic endocannabinoid pathway.13 One of the most remarkable findings of this study is that CB1-deficient mice are completely resistant to the development of diet-induced hepatic steatosis. Whereas wild-type mice showed remarkable hepatic steatosis after 3 and 14 weeks of high-fat diet, CB1-deficient mice displayed virtually no hepatic steatosis. In addition, CB1-deficient mice showed no significant increase in body weight or levels of triglycerides, insulin, and leptin, as well as no significant decrease of adiponectin. The development of hepatic steatosis in wild-type mice was not due to higher food intake, which further strengthens the authors' hypothesis that endocannabinoids regulate peripheral lipogenesis. In comparison to CB1-deficient mice, wild-type mice showed an approximate 3-fold induction of hepatic fatty acid synthesis. Wild-type mice on high-fat diet displayed more than 3-fold upregulated hepatic levels of anandamide, whereas hepatic anandamide levels were slightly less induced in CB1-deficient mice. These elevations were not caused by an increased synthesis of anandamide, but by a decrease in anandamide degradation by the enzyme fatty acid amide hydrolase (FAAH). CB1 receptor expression was low in mice on normal diet with only weak staining of pericentral hepatocytes, but increased in mice after high-fat diet. To provide further evidence for the role of hepatic CB1 receptors, the authors stimulated mice with HU210, a specific CB1 agonist. HU210 upregulated the hepatic expression of genes that are known to be key regulators of fat metabolism in the liver, including the transcription factor SREBP-1c and its targets, acetyl coenzyme-A carboxylase (ACC1) and fatty acid synthase (FAS), and increased hepatic fatty synthesis 2-fold. Finally, the authors demonstrated that CB1 stimulation also regulates the expression of lipogenic genes such as SREBP-1c and FAS in the hypothalamus, where these pathways are believed to regulate appetite control. Thus, the authors provide evidence for the existence of a peripheral and a central endocannabinoid pathway to regulate lipogenesis and food intake, respectively.
There are several important lessons to be learned from this study. (1) Food intake and lipogenesis can be regulated through different mechanisms by the same mediators: Food intake is regulated by CB1 expressed in the hypothalamus, whereas lipogenesis is regulated by CB1 receptors in the periphery, predominantly in the liver. (2) Adiposity and hepatic steatosis do not necessarily correlate with food intake but depend on the activation of lipogenic pathways. (3) The hepatic lipogenic pathway is induced by activation of the hepatic endocannabinoid system in response to high-fat diet; i.e., by an upregulation of CB1 expression and an increase in anandamide levels mediated through an inhibition of the anandamide-degrading enzyme FAAH (Fig. 1). This study adds tremendously to our knowledge about the role of endocannabinoids in the liver. Previous studies have shown that endocannabinoids regulate blood pressure in advanced liver cirrhosis,14, 15 that CB2 reduces hepatic fibrosis,16 and that anandamide induces selective cell death in hepatic stellate cells.17 Based on the results of the study by Osei-Hyaiman et al., the hepatic endocannabinoid system may represent a target for the treatment of NAFLD. The CB1 antagonist Rimonabant is expected to be approved for the treatment of obesity shortly and may thus provide a second pharmacological treatment option for NAFLD in addition to the thiazolidinedione class of PPARγ agonist. These novel pharmacological treatments may help to prevent sequelae of NAFLD such as hepatic fibrosis and hepatocellular carcinoma, and reduce the necessity for bariatric surgery. Of further interest is the fact that CB1 is part of a reward system in alcoholism and that blocking CB1 reduces alcohol craving.18 Therefore, blocking CB1 might also be a promising treatment option for patients with alcoholic fatty liver disease. However, the role of the endocannabinoid system in the normal and injured liver requires further study to judge potential adverse effects of blocking CB1.
Figure 1. Endocannabinoids regulate hepatic lipogenesis. High-fat diet induces CB1 receptor expression in hepatocytes and increases hepatic levels of the anandamide (AEA) by reducing the activity of the AEA-degrading enzyme fatty acid amide hydrolase (FAAH). These changes in CB1 expression and AEA levels induce the expression of the lipogenic transcription factor SREBP-1c and induce lipogenesis in hepatocytes. These changes are accompanied by an increase in insulin and leptin and a decrease in adiponectin.
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