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.
Highlights
Despite initial expectations, data obtained over the last two decades have shown an almost complete failure of traditional pharmacological-based monotherapies for the treatment of obesity
CL316243 and OEA increased the expression of peroxisome proliferator-activated receptor (PPAR) and uncoupling protein-1 (UCP1) in epididymal WAT (eWAT) and brown adipose tissue (BAT), and reduced p38 mitogen-activated protein kinase (MAPK) phosphorylation in eWAT To obtain information about the regulators mediating CL+OEAinduced negative energy balance and BAT temperature, first we examined the morphology of the white and brown adipocytes, and we analyzed the expression of thermogenic markers such as peroxisome proliferator-activating receptor-α (PPARα) and UCP1 in eWAT and BAT
A combinatorial therapy based on the association of β3-adrenergic receptor stimulation with the natural PPARα receptor ligand OEA was developed on the basis of potential convergent effects of OEA with the adrenergic mechanisms in the adipose tissue
Summary
Data obtained over the last two decades have shown an almost complete failure of traditional pharmacological-based monotherapies for the treatment of obesity. The inhibition of mitogen-activated protein kinase (MAPK) potentiates the effect of β3-adrenergic activation on UCP1-mediated energy dissipation in BAT of fatty acids released from WAT (Inokuma et al, 2006; Klein et al, 2000). In this regard, the stimulation of the transcription factor
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