Abstract
De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in the expression of lipogenic enzymes.
Highlights
Over the last two decades many studies have shown that the health risks related with obesity are associated with the enlarged fat depots that closely surround the viscera [1]
In the present study we evaluated the role of CB1-mediated activity in perirenal fat -a part of the retroperitoneal depot white adipose tissue- of lean and diet-induced obese animals focusing on the study of: i) expression of CB1; ii) expression of the transcription factors Lxr, Srebf-1 and carbohydrate-responsiveelement-binding protein (ChREBP), iii) expression of their lipogenic target gene enzymes Acaca, Fasn and Scd1, and iv) the CB1mediated signalling machinery involved in the expression and activity of lipogenic factors
We examined the Cnr1 gene expression in perirenal adipose tissue (PrAT) from rats fed a high-carbohydrate diet (HCHD) and high-fat diet (HFD) as compared with rats fed a regular chow diet and the effect of the AM251
Summary
Over the last two decades many studies have shown that the health risks related with obesity are associated with the enlarged fat depots that closely surround the viscera [1]. An increase in de novo lipogenesis appears to be an important contributor to enlarged fat mass [5]. The roles of the transcription factors liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsiveelement-binding protein (ChREBP) are well established in the regulation of lipogenic gene expression [6]. The transcription factors LXR, SREBP and ChREBP play an important role in the regulation of the expression of the genes encoding for these three enzymes FAS, ACC and SCD1 (Fasn, Acaca, Scd1), leading to triglyceride storage in hepatocytes and adipocytes [5]. An increase in mRNA levels of Srebf-1, Fasn and Acaca, and de novo lipogenesis has been described in the liver and adipose tissue of animals and humans with high fat diet-induced obesity or after a carbohydrate overfeeding [7,8]. Lower adipose tissue levels of Srebf-1, Fasn and Acaca mRNA were reported in obese compared to lean subjects [9,10]
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