Oleoylethanolamide enhances β-adrenergic-mediated thermogenesis and white-to-brown adipocyte phenotype in epididymal white adipose tissue in rat.

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.

Journal Article; Research Support, Non-U.S. Gov't;

This work was supported by the seventh Framework Programme of European Union (grant number HEALTH-F2-2008-223713, REPROBESITY; and 245009, NEUROFAST). The following grants from the Spanish Ministry of Science and Innovation also supported our work: SAF2010-20521, MINECO co-funded by the FEDER Program of EU (R.N.: RyC-2008-02219 and BFU2012-35255; C.D.: BFU2011-29102), Xunta de Galicia (R.N.: EM 2012/039 and 2012-CP069), National Institute of Health ‘Carlos III’ Red de Trastornos Adictivos EU-ERDF (RD06/0001/0000 and RD06/0001/0014), and CIBER-OBN EU-ERDF (CB06/03/1008). Finally, we are supported by the EU-ERDF grants (CTS-433, CTS-8221 and PI45403) from the Andalusian Ministry of Economy, Innovation and Science. J.S. is recipient of a ‘Miguel Servet’ research contract from the National Institute of Health ‘Carlos III’ (CP12/03109).