1. “De-liver-ance” From CB1: A Way to Counteract Insulin Resistance?
Vincenzo Di Marzo 
Gastroenterology 
Volume 142, Issue 5, Pages (May 2012)
DOI: /j.gastro
Copyright © 2012 AGA Institute Terms and Conditions

2. Figure 1
CB1 receptors and insulin resistance (IR). Several peripheral organs provide the substrates through which HFD-induced endocannabinoid overactivity at CB1 receptors causes insulin resistance and glucose intolerance via synergistic mechanisms. Enhanced CB1-mediated inhibition of norepinephrine release from autonomic fibers innervating brown adipose tissue reduces thermogenesis and energy expenditure.8 This contributes to fat accumulation in the white adipose tissue and to adipocyte hypertrophy and inflammation (with reduced adiponectin, and increased interleukin [IL]-6, monocyte chemotactic protein [MCP]-1, and tumor necrosis factor [TNF]-α release), in a way partly exacerbated by adipocyte CB1 receptor overactivation.1,15,19 This phenotype of white, particularly visceral, adipose depots, and the subsequently enhanced free fatty acid release, concur to reducing insulin sensitivity and glucose uptake in the skeletal muscle and inducing triglyceride accumulation in the liver, in a manner that might be worsened by myotube and hepatocyte CB1 receptor overactivation, respectively.2,4,18 Hepatocyte CB1 activation induces hepatic IR either directly or via hepatic triglyceride accumulation or impaired insulin clearance.4,6 Hepatic IR results in increased production of glucose,6 which is in part taken up by adipocytes (where CB1 stimulation enhances glucose transporter-4 activity20) and converted into triglycerides, thus creating a vicious circle, which is reinforced by enhanced triglyceride efflux from the liver, also partly adsorbed by adipocytes. CB1 overactivation in pancreatic β-cells might also contribute to hyperinsulinemia.3,16,17 This model explains why selective knockout of CB1 receptors from either noradrenergic neurons,8 hepatocytes,4,6 or adipocytes12 is sufficient to nearly abolish HFD-induced glucose intolerance and hyperinsulinemia in mice. Conversely, overexpressing CB1 receptors in hepatocytes of CB1−/− mice causes glucose intolerance per se,6 possibly because of the lack of the CB1-mediated, glucose buffering effect of adipocytes.20 Blue arrows, peripheral sites of CB1 action and overactivity; black arrows, effects that are more or less strong depending on arrow thickness; grey boxed area, effects in hepatocytes; white boxed area, effects in white adipocytes.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2012 AGA Institute Terms and Conditions