Cannabinoid receptor 1 (CB1) agonist arachidonyl-2'-chloroethylamide (ACEA) induces Egr1 in murine 3T3-L1 and human adipocytes
Zehr, Bradley Preston
MetadataShow full item record
Obesity and type 2 diabetes mellitus are parallel global pandemics fueled by worldwide trends toward longer lifespan, Western high-fat diet, and sedentary lifestyle. Lipotoxicity – lipid overflow from adipose tissue to liver, muscle, and pancreas resulting from chronically elevated plasma free fatty acid levels – is now known to be the underlying cause of insulin resistance and T2DM. Control of lipolysis in adipose tissue is central to the regulation of plasma free fatty acid. Adipose triglyceride lipase (ATGL), the rate-limiting lipolytic enzyme in adipose tissue, is downregulated in the insulin-stimulated state, and this antilipolytic signal is defective in obesity and T2DM and may contribute to lipotoxicity. The antilipolytic insulin signal is mediated by mammalian target of rapamycin complex 1 (mTORC1), but how activated mTORC1 decreased ATGL expression remained elusive. The Kandror Lab recently identified transcription factor early growth responsive gene 1 (Egr1) as the missing link between insulin-activated mTORC1 and decreased ATGL expression. mTORC1 induces Egr1, which directly binds the ATGL promoter and decreases its expression. Intriguingly, Egr1 has also been implicated in a new model of the pathogenesis of insulin resistance in the pre-diabetic hyperinsulinemic state. Several groups have demonstrated that chronic hyperinsulinism causes an imbalance between PI3K/Akt signaling and MAPK signaling, and this defect is mediated by high levels of Egr1 in obesity. Additionally, the endocannabinoid system (ECS) is known to be hyperactive in obesity and diabetes, and antagonism of cannabinoid receptor 1 (CB1) by pharmaceutical rimonabant was effective at decreasing weight and improving insulin resistance in overweight and obese patients. Previous research demonstrated induction of Egr1 by CB1 stimulation in neurons, however the same effect has not been demonstrated in adipocytes. We stimulated murine 3T3-L1 and human adipocytes with 2 uM arachidonyl-2'-chloroethylamide (ACEA), a synthetic analogue of major endocannabinoid anandamide and a specific CB1 agonist. Egr1 mRNA was significantly increased in ACEA-stimulated murine and human adipocytes relative to controls after 4 hours, as analyzed by quantitative polymerase chain reaction. This finding potentially implicates hyperactive ECS during obesity in the pathogenesis of insulin resistance, and it further validates CB1 as a rich diabetes drug target.
Thesis (M.A.)--Boston University