CB1 Blockade Potentiates Down-Regulation of Lipogenic Gene Expression in Perirenal Adipose Tissue in High Carbohydrate Diet-Induced Obesity

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.

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

“…In contrast, PC females with higher perigonadal adiposity but not perirenal adiposity, exhibited greater gene expression of Cnr1 in PAT, when compared to CC females. These results are in agreement to previous reports after chronic exposure to high-carbohydrate diets [86]. Curiously, this increment was not accompanied by other alterations in fatty acid metabolism genes and leptinemia, which suggests an isolated effect.…”

The Endocannabinoid System – Back to the Scene of Cardiometabolic Risk Factors Control?

“…In the adipose tissue, activation of CB1 receptors increase lipoprotein lipase (LPL), an enzyme required for fatty acid uptake and storage, in a dose dependent manner [ 31 ] which, together with increased activity of fatty acid synthase (FAS) and inhibition of monophosphate-activated protein kinase (AMPK), results in increased lipogenesis and decreased lipolysis and fatty acid oxidation [ 32 ] . The demonstration that CB1 blockade potentiates downregulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity corroborates these fi ndings [ 33 ] . In the liver, CB1 receptors upregulate the lipogenic transcription factor sterol regulatory element binding transcription factor 1 (SREBF1), thus enhancing the expression of acetyl-Coenzyme A carboxylase-α (ACC1) and FAS, resulting in increased lipogenesis [ 34 ] .…”

Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status

“…Second, studies in mice, rats, and humans revealed downregulation of de novo lipogenesis in adipose tissue in obesity [35–37] , which has been suggested as an adaptive process to limit an ongoing increase of fat mass [37] . Cellular ATP demand for lipogenic enzyme activity, and the resulting requirement for mitochondrial OXPHOS activity for this process, would therefore be reduced.…”