title: Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat.
abstract: β-adrenergic receptor activation promotes brown adipose tissue (BAT) β-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-α (PPARα) in white adipose tissue (WAT). Here we explore whether PPARα activation potentiates the effect of β3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, β-oxidation, and lipid and cholesterol metabolism in epididymal (e)WAT was monitored. CL316243 (1 mg/kg) and OEA (5 mg/kg) co-administration over 6 days enhanced the reduction of both food intake and body weight gain, increased the energy expenditure and reduced the respiratory quotient (VCO2/VO2). This negative energy balance agreed with decreased fat mass and increased BAT weight and temperature, as well as with lowered plasma levels of triglycerides, cholesterol, nonessential fatty acids (NEFAs), and the adipokines leptin and TNF-α. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPARα and UCP1, reduced p38-MAPK phosphorylation, and promoted brown-like features in the white adipocytes: the mitochondrial (Cox4i1, Cox4i2) and BAT (Fgf21, Prdm16) genes were overexpressed in eWAT. The enhancement of the fatty-acid β-oxidation factors Cpt1b and Acox1 in eWAT was accompanied by an upregulation of de novo lipogenesis and reduced expression of the unsaturated-fatty-acid-synthesis enzyme gene, Scd1. We propose that the combination of β-adrenergic and PPARα receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.
authors.affiliation: Laboratorio de Medicina Regenerativa, Hospital Carlos Haya-IBIMA (Pabellón de Gobierno), Avenida, Carlos Haya 82, 29010 Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.forename: Sergio
authors.initials: S
authors.lastname: Arrabal
authors.forename: Ana
authors.initials: A
authors.lastname: Crespillo
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
authors.forename: Elena
authors.initials: E
authors.lastname: Baixeras
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Pavón
authors.forename: Manuel
authors.initials: M
authors.lastname: Cifuentes
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.forename: Joan
authors.initials: J
authors.lastname: Ballesteros
authors.forename: Carlos
authors.initials: C
authors.lastname: Dieguez
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
mesh_terms: D052437:Adipocytes, Brown / Q000502:physiology*; D052438:Adipocytes, White / Q000502:physiology*; D054392:Adipokines / Q000378:metabolism; D058667:Adrenergic beta-3 Receptor Agonists / Q000737:chemistry; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D004149:Dioxoles / Q000737:chemistry; D004435:Eating; D063388:Endocannabinoids; D004822:Epididymis / Q000378:metabolism*; D006706:Homeostasis; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000628:therapy; D009829:Oleic Acids / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D047493:PPAR alpha / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013696:Temperature; D022722:Thermogenesis
chemical_list: D054392:Adipokines; D058667:Adrenergic beta-3 Receptor Agonists; D004149:Dioxoles; D063388:Endocannabinoids; D008055:Lipids; D009829:Oleic Acids; D047493:PPAR alpha; D011943:Receptors, Adrenergic, beta; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C488250:oleoylethanolamide; D002784:Cholesterol; D010100:Oxygen
keywords: Adipocyte; Peroxisome proliferator-activated receptor alpha; Thermogenesis; β-oxidation; β3-adrenergic receptor