Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes
نویسندگان
چکیده
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.
منابع مشابه
Association between lipid accumulation and the cannabinoid system in Huh7 cells expressing HCV genes.
Evidence from clinical and laboratory studies has accumulated indicating that the activation of the cannabinoid system is crucial for steatosis, especially in non-alcoholic fatty liver disease. However, the association between hepatitis C virus (HCV) infection and the cannabinoid system has not been well investigated and it is unclear whether steatosis in chronic hepatitis C develops via activa...
متن کاملCannabinoid receptor signaling regulates liver development and metabolism.
Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but ...
متن کاملOveractive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins.
The endocannabinoid (EC) system regulates food intake and energy metabolism. Cannabinoid receptor type 1 (CB1) antagonists show promise in the treatment of obesity and its metabolic consequences. Although the reduction in adiposity resulting from therapy with CB1 antagonists may not account fully for the concomitant improvements in dyslipidemia, direct effects of overactive EC signaling on plas...
متن کاملHepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.
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 CB1 (CB1-/-) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effec...
متن کاملEndocannabinoids in the Pathogenesis and Treatment of Liver Fibrosis
Abbreviations: Anandamide (AEA), 2-Arachidonoyl-glycerol (2-AG), Hepatic stellate cell (HSC), Fatty acid amide hydrolase (FAAH), Cannabinoid receptor (CB), Transient receptor potential vanilloid 1 (TRPV1). Abstract Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure and high incidence of hepa...
متن کامل