Abstract
We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.
Highlights
Obesity and type 2 diabetes (T2D) are recognized as major health problems of epidemic proportions worldwide
The gene corresponding to the endocannabinoid synthesizing enzyme diacylglycerol lipase (DAGL)-ALPHA was upregulated in T2D subjects compared with control subjects (p < 0.05, Fig. 1d), while DAGL-BETA was downregulated (p < 0.05, Fig. 1e)
The gene expression levels of the 2AG-degrading enzyme MGL had a trend to be reduced in T2D subjects compared with control subjects (p = 0.094, Fig. 1g) while the gene expression levels of the AEAdegrading enzyme, fatty acid amide hydrolase (FAAH), were lower in T2D subjects compared with control subjects (p < 0.05) (Fig. 1h)
Summary
Obesity and type 2 diabetes (T2D) are recognized as major health problems of epidemic proportions worldwide. From a public health perspective it is of interest to identify and explore mechanisms and potential treatment concepts that are common for insulin resistance and obesity because of their shared association with the onset of T2D. Glucocorticoids are steroid hormones whose synthetic analogs are used clinically for the treatment of autoimmune or inflammatory conditions [2]. Due to their immunosuppressive properties they are used in transplant patients to prevent graft rejection. In a previous microarray study [4], using a model of insulin resistance by incubating human adipose tissue with the synthetic glucocorticoid dexamethasone, cannabinoid receptor type 1 (CNR1) was identified as one of the genes with the greatest increase in expression in subcutaneous and omental adipose tissue (SAT and OAT, respectively). The highest expression levels of CNR1 are observed in different brain regions, but it is present at lower levels in most other cells/tissue types, including adipose tissue [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
