Cooperative role of the glucagon-like peptide-1 receptor and 3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats

AimTo explore the cooperation of GLP-1 receptor and 3-adrenergic receptor (3-AR)-mediated signalling in the control of fat mass/feeding behaviour by studying the effects of a combined therapy composed of the GLP-1R agonist liraglutide and the 3-AR agonist CL316243. MethodsThe study included the analysis of key mechanisms regulating lipid/cholesterol metabolism, and thermogenesis in brown (BAT) and epididymal white (eWAT) adipose tissues, abdominal muscle and liver of male rats. ResultsCL316243 (1mgkg(-1)) and liraglutide (100gkg(-1)) co-administration over 6days potentiated an overall negative energy balance (reduction in food intake, body weight gain, fat/non-fat mass ratio, liver fat content, and circulating levels of non-essential fatty acids, triglycerides, very low-density lipoprotein-cholesterol and leptin). These effects were accompanied by increased plasma levels of insulin and IL6. We also observed increased gene expression of uncoupling proteins regulating thermogenesis in BAT/eWAT (Ucp1) and muscle (Ucp2/3). Expression of transcription factor and enzymes involved either in de novo lipogenesis (Chrebp, Acaca, Fasn, Scd1, Insig1, Srebp1) or in fatty acid -oxidation (Cpt1b) was enhanced in eWAT and/or muscle but decreased in BAT. Ppar and Ppar, essentials in lipid flux/storage, were decreased in BAT/eWAT but increased in the muscle and liver. Cholesterol synthesis regulators (Insig2, Srebp2, Hmgcr) were particularly over-expressed in muscle. These GLP-1R/3-AR-induced metabolic effects were associated with the downregulation of cAMP-dependent signalling pathways (PKA/AKT/AMPK). ConclusionCombined activation of GLP-1 and 3-ARs potentiate changes in peripheral pathways regulating lipid/cholesterol metabolism in a tissue-specific manner that favours a switch in energy availability/expenditure and may be useful for obesity treatment.