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Cannabinoid type 1 receptor mediates depot-specific effects on differentiation, inflammation and oxidative metabolism in inguinal and epididymal white adipocytes.

Wagner IV, Perwitz N, Drenckhan M, Lehnert H, Klein J - Nutr Diabetes (2011)

Bottom Line: Uncoupling protein-1 as well as PGC-1α expression was significantly elevated.In conclusion, we found depot-specific effects on differentiation, apoptosis, inflammation and oxidative metabolism in CB1-receptor knockout cells.Thus, CB1-receptor-mediated pathways differentially target adipose tissue depots to a dual effect that minimizes cardiometabolic risk, on the one hand, by diminishing visceral fat, and that enhances thermogenesis in subcutaneous adipocytes, on the other.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University of Luebeck, Luebeck, Germany.

ABSTRACT

Objective: The endocannabinoid system is a major component in the control of energy metabolism. Cannabinoid 1 (CB1)-receptor blockade induces weight loss and reduces the risk to develop the metabolic syndrome with its associated cardiovascular complications. These effects are mediated by central and peripheral pathways. Interestingly, weight loss is mainly achieved by a reduction of visceral fat mass. We analyzed fat depot-specific differences on adipocyte differentiation, inflammation and oxidative metabolism in CB1-receptor knockout cells.

Materials and methods: We used newly generated epididymal/inguinal adipose cell lines from CB1-receptor knockout mice. Differences in differentiation were measured by fat-specific Oil Red O staining and quantitative analysis of key differentiation markers. Induction of apoptosis was evaluated by cell death detection and investigation of p53 phosphorylation. Inflammation markers were quantified by real-time PCR. For analyzing the process of transdifferentiation we measured oxygen consumption and mitochondrial biogenesis.

Results: Differentiation was reduced in visceral adipocytes from CB1-receptor knockout mice as compared with wild-type controls. Moreover, we found an induction of apoptosis in these cells. In contrast, subcutaneous adipocytes from CB1-receptor knockout mice showed an accelerated differentiation and a reduced rate of apoptosis. Inflammation was increased in visceral fat cells, as analyzed by the expression pattern of interleukin-6, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α, whereas in subcutaneous adipocytes these markers were decreased. Furthermore, subcutaneous CB1-receptor knockout cells were more sensitive toward a conversion into a brown fat phenotype. Uncoupling protein-1 as well as PGC-1α expression was significantly elevated. This was accompanied by an increase in mitochondrial biogenesis and oxygen consumption.

Conclusion: In conclusion, we found depot-specific effects on differentiation, apoptosis, inflammation and oxidative metabolism in CB1-receptor knockout cells. Thus, CB1-receptor-mediated pathways differentially target adipose tissue depots to a dual effect that minimizes cardiometabolic risk, on the one hand, by diminishing visceral fat, and that enhances thermogenesis in subcutaneous adipocytes, on the other.

No MeSH data available.


Related in: MedlinePlus

(a, b) PGC-1α expression is increased in inguinal (ING) knockout (KO) cells. Expression is illustrated at days 0 and 6 during the differentiation process. (a) Compares PGC-1α expression of epididymal wild-type (WT) cells and epididymal (EPI) CB1-receptor KO cells, (b) shows PGC-1α expression of ING WT cells compared with ING CB1-receptor KO cells. All data normalized using 36B4 as a housekeeping gene. Six independent experiments are shown as mean±s.e.m., *P<0.05, **P<0.01 comparing WT control cells to CB1-receptor KO cells.
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fig7: (a, b) PGC-1α expression is increased in inguinal (ING) knockout (KO) cells. Expression is illustrated at days 0 and 6 during the differentiation process. (a) Compares PGC-1α expression of epididymal wild-type (WT) cells and epididymal (EPI) CB1-receptor KO cells, (b) shows PGC-1α expression of ING WT cells compared with ING CB1-receptor KO cells. All data normalized using 36B4 as a housekeeping gene. Six independent experiments are shown as mean±s.e.m., *P<0.05, **P<0.01 comparing WT control cells to CB1-receptor KO cells.

Mentions: In epididymal cells, the expression of PGC-1α, a transcriptional activator of PPARγ on the UCP-1 promoter, was slightly but not significant reduced by 23% in preadipocytes (because of high standard deviation results were not significant), but was significantly decreased by 64% in mature cells when compared with controls. In contrast, inguinal preadipocytes showed a highly significant increase of PGC-1α expression by 152% in preadipocytes and a significant enhancement of 315% in mature cells (Figure 7). In line with these results, the expression of UCP-1 did not differ significantly in epididymal preadipocytes, whereas the mature cells showed a significantly decreased expression by 57% of this brown fat cell marker. There was an increased basal expression of UCP-1 in inguinal CB1-receptor knockout cells by 252% at day 0 and 243% at day 6 compared with inguinal control cells (Figure 8).


Cannabinoid type 1 receptor mediates depot-specific effects on differentiation, inflammation and oxidative metabolism in inguinal and epididymal white adipocytes.

Wagner IV, Perwitz N, Drenckhan M, Lehnert H, Klein J - Nutr Diabetes (2011)

(a, b) PGC-1α expression is increased in inguinal (ING) knockout (KO) cells. Expression is illustrated at days 0 and 6 during the differentiation process. (a) Compares PGC-1α expression of epididymal wild-type (WT) cells and epididymal (EPI) CB1-receptor KO cells, (b) shows PGC-1α expression of ING WT cells compared with ING CB1-receptor KO cells. All data normalized using 36B4 as a housekeeping gene. Six independent experiments are shown as mean±s.e.m., *P<0.05, **P<0.01 comparing WT control cells to CB1-receptor KO cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3303536&req=5

fig7: (a, b) PGC-1α expression is increased in inguinal (ING) knockout (KO) cells. Expression is illustrated at days 0 and 6 during the differentiation process. (a) Compares PGC-1α expression of epididymal wild-type (WT) cells and epididymal (EPI) CB1-receptor KO cells, (b) shows PGC-1α expression of ING WT cells compared with ING CB1-receptor KO cells. All data normalized using 36B4 as a housekeeping gene. Six independent experiments are shown as mean±s.e.m., *P<0.05, **P<0.01 comparing WT control cells to CB1-receptor KO cells.
Mentions: In epididymal cells, the expression of PGC-1α, a transcriptional activator of PPARγ on the UCP-1 promoter, was slightly but not significant reduced by 23% in preadipocytes (because of high standard deviation results were not significant), but was significantly decreased by 64% in mature cells when compared with controls. In contrast, inguinal preadipocytes showed a highly significant increase of PGC-1α expression by 152% in preadipocytes and a significant enhancement of 315% in mature cells (Figure 7). In line with these results, the expression of UCP-1 did not differ significantly in epididymal preadipocytes, whereas the mature cells showed a significantly decreased expression by 57% of this brown fat cell marker. There was an increased basal expression of UCP-1 in inguinal CB1-receptor knockout cells by 252% at day 0 and 243% at day 6 compared with inguinal control cells (Figure 8).

Bottom Line: Uncoupling protein-1 as well as PGC-1α expression was significantly elevated.In conclusion, we found depot-specific effects on differentiation, apoptosis, inflammation and oxidative metabolism in CB1-receptor knockout cells.Thus, CB1-receptor-mediated pathways differentially target adipose tissue depots to a dual effect that minimizes cardiometabolic risk, on the one hand, by diminishing visceral fat, and that enhances thermogenesis in subcutaneous adipocytes, on the other.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University of Luebeck, Luebeck, Germany.

ABSTRACT

Objective: The endocannabinoid system is a major component in the control of energy metabolism. Cannabinoid 1 (CB1)-receptor blockade induces weight loss and reduces the risk to develop the metabolic syndrome with its associated cardiovascular complications. These effects are mediated by central and peripheral pathways. Interestingly, weight loss is mainly achieved by a reduction of visceral fat mass. We analyzed fat depot-specific differences on adipocyte differentiation, inflammation and oxidative metabolism in CB1-receptor knockout cells.

Materials and methods: We used newly generated epididymal/inguinal adipose cell lines from CB1-receptor knockout mice. Differences in differentiation were measured by fat-specific Oil Red O staining and quantitative analysis of key differentiation markers. Induction of apoptosis was evaluated by cell death detection and investigation of p53 phosphorylation. Inflammation markers were quantified by real-time PCR. For analyzing the process of transdifferentiation we measured oxygen consumption and mitochondrial biogenesis.

Results: Differentiation was reduced in visceral adipocytes from CB1-receptor knockout mice as compared with wild-type controls. Moreover, we found an induction of apoptosis in these cells. In contrast, subcutaneous adipocytes from CB1-receptor knockout mice showed an accelerated differentiation and a reduced rate of apoptosis. Inflammation was increased in visceral fat cells, as analyzed by the expression pattern of interleukin-6, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α, whereas in subcutaneous adipocytes these markers were decreased. Furthermore, subcutaneous CB1-receptor knockout cells were more sensitive toward a conversion into a brown fat phenotype. Uncoupling protein-1 as well as PGC-1α expression was significantly elevated. This was accompanied by an increase in mitochondrial biogenesis and oxygen consumption.

Conclusion: In conclusion, we found depot-specific effects on differentiation, apoptosis, inflammation and oxidative metabolism in CB1-receptor knockout cells. Thus, CB1-receptor-mediated pathways differentially target adipose tissue depots to a dual effect that minimizes cardiometabolic risk, on the one hand, by diminishing visceral fat, and that enhances thermogenesis in subcutaneous adipocytes, on the other.

No MeSH data available.


Related in: MedlinePlus