Abstract

Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gene for the secreted glycoprotein lipocalin 2 (lcn2), which has been implicated in obesity and insulin resistance, was among those most responsive to alterations in CB1 signaling. The expression pattern of IDFP mice segregated from DMSO mice in hierarchal cluster analysis and AM251 pre-administration reduced (>50%) the majority (303 of 533) of the IDFP induced alterations. Pathway analysis revealed that IDFP altered expression of genes involved in lipid, fatty acid and steroid metabolism, the acute phase response, and amino acid metabolism in a CB1-dependent manner. PCR confirmed array results of key target genes in multiple independent experiments. Overall, we show that acute IDFP treatment induces hepatic TG accumulation and insulin resistance, at least in part through the CB1 receptor, and identify novel cannabinoid responsive genes.

Highlights

  • Obesity elicits a cluster of interrelated disorders, termed the ‘‘metabolic syndrome’’, that increase the risk of cardiovascular disease [1]

  • 1.1 isopropyl dodecylfluorophosphonate (IDFP) produces cannabinoid type 1 receptor (CB1)-dependent hepatic steatosis To test the effects of elevated ECs on hepatic lipid levels, mice were treated with IDFP or vehicle control (DMSO)

  • The data presented here establish that IDFP induces hepatic steatosis and insulin resistance partially through CB1 signaling

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Summary

Introduction

Obesity elicits a cluster of interrelated disorders, termed the ‘‘metabolic syndrome’’, that increase the risk of cardiovascular disease [1]. Pharmacological or genetic ablation of CB1 in diet-induced and genetic mouse models of obesity results in a transient hypophagic response, followed by prolonged effects on weight loss, adiposity, and normalization of metabolic parameters [13,14,15,16,17,18]. These effects suggest that reduced food intake does not fully explain the improvement in adiposity-related measures with CB1 inactivation. Together these observations raise the possibility that aberrant EC signaling mediates development of the metabolic syndrome, both by influencing body weight and directly regulating metabolic processes

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