J Decara1, P Rivera2, S Arrabal1, A Vargas1, A Serrano1, F J Pavón1, C Dieguez3,4, R Nogueiras3,4, F Rodríguez de Fonseca1, J Suárez1,5. 1. Instituto de Investigación Biomédica de Málaga (IBIMA), UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, Málaga, Spain. 2. Department of Endocrinology, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain. 3. Department of Physiology, School of Medicine-CIMUS, University of Santiago De Compostela-Instituto De Investigación Sanitaria, Santiago De Compostela, Spain. 4. CIBER OBN, Instituto de Salud Carlos III, Madrid, Spain. 5. Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, IBIMA, Universidad de Málaga, Málaga, Spain.
Abstract
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.
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.
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