CB1 blockade potentiates down-regulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity

PLoS One. 2014 Feb 25;9(2):e90016. doi: 10.1371/journal.pone.0090016. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / drug effects*
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Animals
  • Body Weight / drug effects
  • Diet, High-Fat / adverse effects
  • Dietary Carbohydrates / adverse effects*
  • Down-Regulation / drug effects*
  • Kidney / pathology
  • Lipogenesis / drug effects
  • Lipogenesis / genetics*
  • Male
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology*
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Time Factors
  • Transcription Factors / metabolism

Substances

  • Dietary Carbohydrates
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Transcription Factors
  • AM 251

Grant support

This work was supported by Grants: from the Spanish Institute of Health “Carlos III (PI061109; CP12/03109; CIBERobn EU-ERDF-CB06/03/1008); from the Andalusian Ministry of Health (PI0552); from Andalusian Ministry of Economy, Innovation, Science and Employment EU-ERDF (CTS-8221 and CTS-433); from Spanish Ministry of Science and Innovation (SAF2010-20521); from European Union’s 7th Framework Programme (Health- F2-2008-223713, REPROBESITY). Elena Baixeras is a tenured investigator through the I3SNS Program of the Spanish National Health System of Spanish Ministry of Science and Innovation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.