Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance

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.

Characterization of the endocannabinoid system in subcutaneous adipose tissue in periparturient dairy cows and its association to metabolic profiles

“…Here, we found a tendency for increased AT mRNA expression of CNR1 in HWL compared with LWL cows at 4 d PP. Overactivation of the eCB/CB1 receptor system has been documented both centrally and peripherally during obesity and IR[ 26 , 49 , 50 ]. In humans, subcutaneous AT CNR1 expression levels were 2-fold higher in type 2 diabetic subjects compared with controls[ 49 ], suggesting a potential role of the peripheral eCB system in promoting AT dysfunction and inflammation.…”

“…Overactivation of the eCB/CB1 receptor system has been documented both centrally and peripherally during obesity and IR[ 26 , 49 , 50 ]. In humans, subcutaneous AT CNR1 expression levels were 2-fold higher in type 2 diabetic subjects compared with controls[ 49 ], suggesting a potential role of the peripheral eCB system in promoting AT dysfunction and inflammation. Conversely, and as mentioned previously, all the biological actions reported for CB1 receptor activation in AT in vitro minimize lipolysis[ 14 ], which apparently is in contrast with the tendency for increased expression of AT CNR1 in HWL cows, which exhibited increased lipolysis compared with LWL cows, although we did not examine receptor activation—only gene expression.…”

Changes in adipose tissue lipolysis gene expression and insulin sensitivity after weight loss

“…It is postulated that a decreased lipase expression and an impaired AT lipolysis may contribute to the development and maintenance of obesity (16,19). However, this explanation is rather unlikely, as HSLdeficient animals are resistant to diet-induced obesity (42), and humans with HSL null mutation display an impaired lipolysis and metabolic disturbances; however, their BMI is usually within the range of overweight and not obese (24). 9:2…”

“…Null mutation in HSL gene leads to impaired AT lipolysis, dyslipidemia, hepatic steatosis, insulin resistance and diabetes (23). Decreased AT expression of MGLL, PLIN1, CIDEA and G0S2 in different conditions associated with insulin resistance was observed (5,24,25,26). The differences in human studies may come from different characteristics of the study groups and different clinical situations.…”

Proof-of-concept for CRISPR/Cas9 gene editing in human preadipocytes: Deletion of FKBP5 and PPARG and effects on adipocyte differentiation and metabolism

“…www.nature.com/scientificreports www.nature.com/scientificreports/ To understand the role of FKBP51 to modify glucocorticoid action in adipocytes, we asked whether the loss of FKBP51 alters the transcriptional activity of the glucocorticoid receptor and thereby its action. We addressed this question by measuring the expression levels of several previously reported glucocorticoid target genes in differentiated adipocytes 6,23 . However, we observed that only CNR1 gene expression was differentially expressed following dexamethasone exposure in wild type vs FKBP51 knockout cultures, respectively.…”