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

Abstract

Diet-induced obesity is associated with fatty liver, insulin resistance, leptin resistance, and changes in plasma lipid profile. Endocannabinoids have been implicated in the development of these associated phenotypes, because mice deficient for the cannabinoid receptor CB 1 (CB1 -/-) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effects, however, remain unknown. We therefore investigated the relative role of hepatic versus extrahepatic CB 1 receptors in the metabolic consequences of a high-fat diet, using liver-specific CB 1 knockout (LCB1 -/-) mice. LCB1 -/-mice fed a high-fat diet developed a similar degree of obesity as that of wild-type mice, but, similar to CB1 -/-mice, had less steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a high-fat diet. CB 1 agonistinduced increase in de novo hepatic lipogenesis and decrease in the activity of carnitine palmitoyltransferase-1 and total energy expenditure were absent in both CB1 -/-and LCB1 -/-mice. We conclude that endocannabinoid activation of hepatic CB 1 receptors contributes to the diet-induced steatosis and associated hormonal and metabolic changes, but not to the increase in adiposity, observed with high-fat diet feeding. Theses studies suggest that peripheral CB 1 receptors could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order to minimize the neuropsychiatric side effects of nonselective CB 1 blockade during treatment of obesity-associated conditions.

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

“…52 This model provides the potential to evaluate CB1R inverse agonist in the presence or in the absence of liver CB1R. With regard to diet-induced obesity (DIO), the liver CB1R KO mice show the same phenotype of DIO as the WT mice, whereas the global KO mice are resistant to DIO.…”

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

“…Jbilo et al 18 found that treatment with this CB 1 -receptor antagonist increases gene expression of enzymes involved in lipolysis and b-oxidation in white and brown adipose tissue. Herling et al 19 and Osei-Hyiaman et al 19,20 independently reinforced these results by showing increased rates of lipid oxidation (by indirect calorimetry) following bolus administration of rimonabant, particularly during the post-ingestive phase. Finally, CB 1 -receptor antagonist in obese patients consistently improved plasma lipid profiles.…”

“…12,13,21 With respect to the liver, Osei-Hyiaman et al 11 observed that feeding a high-fat (HF) diet increases hepatic levels of anandamide and CB 1 -receptor density, and showed that pharmacological activation of CB 1 -receptors by HU210 in mice increases hepatic gene expression of Srebp-1c (srebf1), Acc1 (Acaca) and Fasn, all indicative of increased lipogenesis. While CB 1 -receptor-null mice have reduced hepatic lipogenesis, 20 which was suggested to explain their lean phenotype, data on the effects of chronic rimonabant-treatment on markers of hepatic lipogenesis are currently lacking. Taken together, these data indicate that CB 1 -receptor antagonism is a useful tool against disturbances in lipid fluxes known to be underlying, or at least associated with, the 'metabolic syndrome'.…”

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

“…Crucially, we demonstrate increased CB1R gene expression in aged skeletal muscle and liver, indicative of enhanced endocannabinoid/CB1R tone in response to aging. Notably, our findings are consistent with previous work reporting high fat diet‐induced increases in CB1R tissue expression in younger animals, together with the amelioration of dyslipidaemia and lipogenesis, as well as improved insulin sensitivity in mice deficient for CB1R (Osei‐Hyiaman et al ., 2008). Indeed, it is possible that the improvements in insulin sensitivity that are conveyed by rimonabant in aged mice may be due, at least in part, to reductions in adiposity.…”

“…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. Indeed, these beneficial responses may be mediated through central appetite suppression and/or through direct modulation of peripheral energy metabolism (Bensaid et al ., 2003; Ravinet Trillou et al ., 2003, 2004; Jbilo et al ., 2005; Pagotto et al ., 2006; Osei‐Hyiaman et al ., 2008; Jourdan et al ., 2010). …”