Cooperative role of the glucagon-like peptide-1 receptor and β3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats.
AIM
To explore the cooperation of GLP-1 receptor and β3-adrenergic receptor (β3-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 β3-AR agonist CL316243.


METHODS
The 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.


RESULTS
CL316243 (1 mg kg-1 ) and liraglutide (100 μg kg-1 ) co-administration over 6 days 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 β-oxidation (Cpt1b) was enhanced in eWAT and/or muscle but decreased in BAT. Pparα and Pparγ, 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/β3-AR-induced metabolic effects were associated with the downregulation of cAMP-dependent signalling pathways (PKA/AKT/AMPK).


CONCLUSION
Combined activation of GLP-1 and β3-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.
['Decara|J|J|', 'Rivera|P|P|', 'Arrabal|S|S|', 'Vargas|A|A|', 'Serrano|A|A|', 'Pavón|F J|FJ|', 'Dieguez|C|C|', 'Nogueiras|R|R|', 'Rodríguez de Fonseca|F|F|', 'Suárez|J|J|']
D055372:AMP-Activated Protein Kinases D000273:Adipose Tissue D058667:Adrenergic beta-3 Receptor Agonists D000818:Animals D001823:Body Composition D017868:Cyclic AMP-Dependent Protein Kinases D015536:Down-Regulation D004734:Energy Metabolism D005247:Feeding Behavior D000067757:Glucagon-Like Peptide-1 Receptor D050356:Lipid Metabolism D000069450:Liraglutide D008297:Male D018482:Muscle, Skeletal D051057:Proto-Oncogene Proteins c-akt D051381:Rats D022702:Receptors, Adrenergic, beta-3 D015398:Signal Transduction
glucagon-like peptide-1 adipose tissue muscle β3-adrenergic receptor thermogenesis lipid metabolism