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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online July 11, 2005 as doi:10.1096/fj.04-3177fje. |
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,1
* Oncology Research Department, Sanofi-Synthelabo Recherche, Montpellier, France;
Central Nervous System Research Department, Sanofi-Synthelabo Recherche, Toulouse, France;
Central Nervous System Research Department, Sanofi-Synthelabo Recherche, Montpellier, France; and
Sanofi-Synthelabo Recherche, Paris, France
2 Correspondence: Sanofi-Synthelabo Recherche, 371 rue du Professeur Joseph Blayac, Montpellier 34184, France. E-mail: pierre.casellas{at}sanofi-aventis.com
SPECIFIC AIMS
The aim of the present study was to unravel the molecular events involved in the reduction of adipose mass by the selective central cannabinoid CB1 receptor antagonist, SR141716. We used a transcriptional approach and characterized gene modulations in adipose tissues of SR141716-treated diet-induced obese mice, a mouse model that closely resembles human obesity. Thereby, we identified the metabolic pathways mediating the sustained long term anti-obesity effect of this molecule.
PRINCIPAL FINDINGS
1. SR141716 reversed the obese adipocyte phenotype
C57BL/6J mice were fed either a standard (STD) or a high fat diet (HFD) for 12 wk and then were treated with SR141716 at 10 mg/kg/day p.o. for 40 days. The treatment resulted in a remarkable reduction of body weight by –18% in HFD mice treated with SR141716 compared with vehicle-treated HFD mice. Lumbar white fat (WAT) and brown fat (BAT) adipose tissue appeared to be the primary peripheral targets of the drug effect since their weight were both reduced by more than 50% following treatment. White adipocytes in vehicle-treated HFD mice were large and exhibited heterogeneous sizes while adipocytes in SR141716-treated animals were significantly smaller than those in vehicle-treated animals (Fig. 1
). The number of nuclei was elevated in SR141716-treated HFD WAT compared with STD WAT. This would reflect the prior obese status of these mice with adipocyte hyperplasia, suggesting that the body weight change induced by the drug was not the result of adipocyte apoptosis but rather of a dramatic depletion of the adipocyte’s fat content.
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2. SR141716 reversed gene expression patterns induced by the high fat regimen
The analysis of the transcriptional profiles in WAT and BAT following a high fat diet, referred to as "HFD signatures," revealed a substantial alteration in gene expression levels (Fig. 2
A, B). Remarkably, most gene modulations induced by SR141716 in obese mice were in the opposite direction of those found in the HFD signatures, see "SR141716 signatures in HFD mice" (Fig. 2A, B
). Almost no effect of SR141716 was observed in STD mice. We also determined the CB1 KO signature in HFD mice, which was obtained by comparing gene expression in CB1 KO HFD mice and CB1 WT HFD mice. The SR141716 signature in HFD mice and the CB1 KO signature in HFD mice showed very similar patterns, supporting that SR141716-induced gene modulations resulted from a CB1-mediated process (Fig. 2A, B
).
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3. The molecule exerted its sustained anti-obesity effect mainly through the regulation of lipolysis and energy balance
The functional analysis of the SR141716 signature in HFD revealed that the long term weight loss induced by the drug was accompanied by specific gene modulations in WAT and BAT. In WAT, one can distinguish two groups: 1) gene modulations that would contribute to reducing fat storage revealed that the molecule enhanced lipolysis through the induction of enzymes of the ß-oxidation and TCA cycle, increased energy expenditure mainly through futile cycling (calcium and substrate) and a tight regulation of glucose homeostasis; 2) gene modulations that were thought to occur as a consequence of the reduction in adipose mass, including genes that encode specific adipocyte proteins or control cell morphology or inflammatory responses. Consistent with the changes observed in WAT, we observed that SR141716 affected the expression of genes involved in energy storage and expenditure, genes encoding specific adipocyte secreted proteins, and also genes involved in the regulation of mitochondrial functions in BAT.
CONCLUSIONS AND SIGNIFICANCE
The results presented here shed some light on the mechanisms involved in the long-term anti-obesity effect of SR141716 and showed that the molecule reversed the phenotype of obese adipocytes. We revealed remarkable differences at both macroscopic and genomic levels by comparing treated obese mice and nontreated obese animals. The analysis of gene expression patterns at the end of the treatment indicated that the modifications of body weight and fat storage were accompanied with changes in gene expression profiles in WAT and BAT. These changes revealed that treatment with SR141716 induced coordinated events that jointly led to the normalization of transcriptional events involved in obesity. Moreover, they allowed us to outline the possible mechanisms through which the molecule could exert its sustained anti-obesity effect. Supporting the view that SR141716 would act through the CB1 receptor and target upstream pathways along the cascade regulating energy expenditure, our data strongly indicate that the endocannabinoid system has a major role in the regulation of energy metabolism.
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FOOTNOTES
1 These authors contributed equally to this work. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/1096/fj.04-3177fje;
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