Hepatic Cannabinoid Receptor-1 Mediates Diet-Induced Insulin Resistance via Inhibition of Insulin Signaling and Clearance in Mice

Abstract

BACKGROUND & AIMS Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB1) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB1 in insulin resistance and inhibition of insulin signaling pathways. METHODS Wild-type mice and mice with disruption of CB1 (CB1−/− mice) or with hepatocyte-specific deletion or transgenic overexpression of CB1 were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB1 in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression. RESULTS The HFD induced hepatic insulin resistance in wild-type mice, but not in CB1−/− mice or mice with hepatocyte-specific deletion of CB1. CB1−/− mice that overexpressed CB1 specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB1, the HFD or CB1 activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB1 activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB1 was up-regulated in samples from patients with nonalcoholic fatty liver disease. CONCLUSIONS Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB1-mediated inhibition of insulin signaling and clearance.

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

“…Moreover, CB1R inhibition did not significantly alter phosphorylation of IRS‐1 at Ser307 (Fig. 5B), a site whose phosphorylation in response to CB1R activation has been associated with suppressed IRS‐1/PKB dependent signalling (Liu et al ., 2012). Indeed, this is consistent with our previous work demonstrating the ability of rimonabant to enhance insulin sensitivity in rat L6 myotubes, an in vitro skeletal muscle model, without altering upstream IRS‐1/PI3K signalling (Lipina et al ., 2010).…”

“…Indeed, this is consistent with our previous work demonstrating the ability of rimonabant to enhance insulin sensitivity in rat L6 myotubes, an in vitro skeletal muscle model, without altering upstream IRS‐1/PI3K signalling (Lipina et al ., 2010). Therefore, we next focussed on alternative pathways involving the potential modulation of PHLPP1 and PP2A (protein phosphatase 2A), two key negative regulators which act to dephosphorylate and inactivate PKB/Akt (Resjo et al ., 2002; Liu et al ., 2012). Rimonabant treatment did not alter levels of PHLPP1 protein in aged gastrocnemius muscle (Fig.…”

Sistema endocanabinoide y desarrollo de esteatosis hepática

“…Datos de la literatura indican que hay una correlación positiva entre las concentraciones de 2-AG en sangre arterial y venosa hepática y el contenido de lípidos en hígado 33 . Adicionalmente, un estudio reciente demostró un robusto aumento de RCB 1 hepáticos en individuos con hígado graso no alcohólico 34 . El impacto del SEC sobre la esteatosis hepática se ha investigado más acuciosamente en pacientes con hepatitis C, en los cuales la prevalencia de esteatosis es de 30-70%, ya sea como consecuencia de perturbaciones metabólicas asociadas o bien por los efectos esteatogénicos propios del genotipo 3 del virus de la hepatitis C. En un estudio prospectivo en pacientes con hepatitis C no tratados, el uso diario de Cannabis durante 6 meses se reconoció como un predictor independiente de esteatosis severa 35 .…”

“…Finalmente, es importante considerar que el SEC hepático no sólo participa en la fisiología y fisiopatología del hígado, sino que también está implicado en otros efectos sistémicos asociados al síndrome metabólico, como es el caso de la dislipidemia y resistencia a insulina y leptina 20,34 .…”

Acute Activation of Cannabinoid Receptors by Anandamide Reduces Gastrointestinal Motility and Improves Postprandial Glycemia in Mice

“…However, even if the CB1R-dependent stimulation of food intake may be the main initial cause of various metabolic deregulations associated with obesity, several data collected from animal and human studies using the specific CB1R antagonist SR141716 (rimonabant) suggested that peripheral ECS might also directly regulate energy metabolism (6)(7)(8). It was recently reported that activation of peripheral CB1R signaling in key tissues relevant to insulin action is associated with alteration of glucose homeostasis and contributes to diet-induced insulin resistance in mice (9)(10)(11). Nevertheless, very little information is available concerning the impact of peripheral ECS activation on intestinal glucose absorption that is however the major determinant of how quickly glucose appears in the circulation during the fed state.…”