Journal
DISEASE MODELS & MECHANISMS
Volume 7, Issue 1, Pages 129-141Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.013110
Keywords
Peroxisome proliferator-activated receptor alpha; beta 3-adrenergic receptor; Thermogenesis; beta-oxidation; Adipocyte
Categories
Funding
- European Union [HEALTH-F2-2008-223713, 245009]
- Spanish Ministry of Science and Innovation [SAF2010-20521]
- FEDER Program of EU [RyC-2008-02219, BFU2012-35255, BFU2011-29102]
- Xunta de Galicia [EM 2012/039, 2012-CP069]
- National Institute of Health 'Carlos III' Red de Trastornos Adictivos EU-ERDF [RD06/0001/0000, RD06/0001/0014]
- CIBER-OBN EU-ERDF [CB06/03/1008]
- EU-ERDF from the Andalusian Ministry of Economy, Innovation and Science [CTS-433, CTS-8221, PI45403]
- National Institute of Health 'Carlos III' [CP12/03109]
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beta-adrenergic receptor activation promotes brown adipose tissue (BAT) beta-oxidation and thermogenesis by burning fatty acids during uncoupling respiration. Oleoylethanolamide (OEA) can inhibit feeding and stimulate lipolysis by activating peroxisome proliferator-activating receptor-alpha (PPAR alpha) in white adipose tissue (WAT). Here we explore whether PPAR alpha activation potentiates the effect of beta 3-adrenergic stimulation on energy balance mediated by the respective agonists OEA and CL316243. The effect of this pharmacological association on feeding, thermogenesis, beta-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-alpha. Regarding eWAT, CL316243 and OEA treatment elevated levels of the thermogenic factors PPAR alpha 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 beta-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 beta-adrenergic and PPAR alpha receptor agonists promotes therapeutic adipocyte remodelling in eWAT, and therefore has a potential clinical utility in the treatment of obesity.
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