Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats

Abstract

SUMMARYWe have modelled elaidyl-sulfamide (ES), a sulfamoyl analogue of oleoylethanolamide (OEA). ES is a lipid mediator of satiety that works through the peroxisome proliferator-activated receptor alpha (PPARα). We have characterised the pharmacological profile of ES (0.3–3 mg/kg body weight) by means of in silico molecular docking to the PPARα receptor, in vitro transcription through PPARα, and in vitro and in vivo administration to obese rats. ES interacts with the binding site of PPARα in a similar way as OEA does, is capable of activating PPARα and also reduces feeding in a dose-dependent manner when administered to food-deprived rats. When ES was given to obese male rats for 7 days, it reduced feeding and weight gain, lowered plasma cholesterol and reduced the plasmatic activity of transaminases, indicating a clear improvement of hepatic function. This pharmacological profile is associated with the modulation of both cholesterol and lipid metabolism regulatory genes, including the sterol response element-binding proteins SREBF1 and SREBF2, and their regulatory proteins INSIG1 and INSIG2, in liver and white adipose tissues. ES treatment induced the expression of thermogenic regulatory genes, including the uncoupling proteins UCP1, UCP2 and UCP3 in brown adipose tissue and UCP3 in white adipose tissue. However, its chronic administration resulted in hyperglycaemia and insulin resistance, which represent a constraint for its potential clinical development.

Non-targeted human plasma metabolomics reveals the changes in oleoylethanolamide, a lipid-derived signaling molecule, by acute exposure of electric field

“…In the present study, OEA binding to PPAR-α was stabilized through the formation of hydrogen bouds with Ser280, Tyr314, and Phe273, whereas a previous study reported hydrogen bounding with Ser280 and His440 [26]. This apparent discrepancy may have resulted from differences in model systems; e.g., 1i7g (crystal structure of the ligand binding domain from human PPAR-α in complex with the agonist AZ242) versus 1k7l (crystal structure of the human PPAR-α ligand binding domain bound with GW409544 and a co-activator peptide) [26].…”

“…This apparent discrepancy may have resulted from differences in model systems; e.g., 1i7g (crystal structure of the ligand binding domain from human PPAR-α in complex with the agonist AZ242) versus 1k7l (crystal structure of the human PPAR-α ligand binding domain bound with GW409544 and a co-activator peptide) [26].…”

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

“…We performed real-time qPCR (TaqMan, Life Technologies) as described previously [48]. Tissue portions (100–300 mg) of the liver, PAT and the whole hypothalamus were homogenized.…”

The Endocannabinoid-Like Derivative Oleoylethanolamide at the Gut–Brain Interface: A “Lipid Way” to Control Energy Intake and Body Weight

“…Furthermore, in rats OEA regulates several hepatic enzymes including liver fatty acid binding protein (responsible for uptake and intracellular trafficking of fatty acids) [113] and the thermogenic uncoupling protein-1 [114]. Also, subchronic administration of a recently synthesized analog of OEA that binds PPARα receptors, elaidyl-sulfamide, was found to lower plasma cholesterol and improve the hepatic function of obese rats [115]. Clearly, these…”