Efeitos do Mirabegron, um agonista β3 adrenérgico seletivo, nas respostas cardiometabólicas de camundongos obesos
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2018-04-12
Autores
Valgas da Silva, Carmem Peres
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Universidade Estadual Paulista (Unesp)
Resumo
O sistema nervoso simpático desempenha importante papel no sistema cardiovascular e no metabolismo, sendo que os receptores adrenérgicos do subtipo β3 (β3 –AR) estão amplamente distribuídos em diferentes células, encontrando-se especialmente no tecido cardíaco, musculatura lisa e tecido adiposo. Esses receptores estão relacionados a diversas ações fisiológicas, como relaxamento da musculatura lisa vascular e não vascular, lipólise do tecido adiposo branco e termogênese do tecido adiposo marrom. Por outro lado, a importância dos β3 –AR no tecido adiposo perivascular (PVAT) e regulação do tono vascular não é conhecida. O mirabegron (YM-178) é um agonista β₃-AR seletivo, atualmente desenvolvido por Astellas Pharma Inc., e aprovado desde 2012 pelos EUA, para tratamento de bexiga hiperativa, considerando a ação dos receptores β₃-AR no relaxamento do músculo liso. Contudo não existe nenhum estudo envolvendo o mirabegron nos parâmetros cardiometabólicos plasmáticos e no metabolismo do tecido adiposo e em modelos de obesidade. Objetivos: Analisar os efeitos do tratamento de Mirabegron (Mira), um agonista β₃-AR seletivo, por duas semanas em parâmetros cardiometabólicos e reatividade vascular na presença ou ausência de PVAT de camundongos obesos. Métodos: Camundongos C57BL/6J foram divididos em grupos controle veículo (CTR), controle tratado com Mira (CTR+MIRA), obeso alimentado com dieta hiperlipídica (HFD 12 semanas) tratado com veículo (OB) e obeso tratado com Mira (OB+MIRA). Mira foi administrado por duas semanas (10mg/kg) na forma de gavagem. Curvas concentração-resposta à acetilcolina (ACh 100pM a 30 μM) e serotonina (5HT 1nM a 30μM) foram realizadas em anéis de aorta PVAT+, PVAT-. Foram medidos a temperatura corporal e gasto energético; bem como pressão arterial, frequência cardíaca e tolerçancia ao esforço, além de análises bioquímicas de perfil lipídico, glicemia de jejum, insulina sérica, Glicerol, AGL, TBARS, leptina e TNF-α. Foram calculados o índice HOMA e o índice aterogênico. A histologia hepática e dos depósitos de tecido adiposo foi realizada pela coloração de hematoxilina e eosina. Resultados: O tratamento com Mira (OB+ mira) por duas semanas aumentou o gasto energético (17%) sem alterar a temperatura corporal, redução do peso corporal (7%), gordura epididmal (25%), colesterol total (17%), LDL-C (55%), índice aterogênico (45%), TBARS (20%), TNF-α (48%), Glicerol e AGL (40%), insulina (67%), e índice HOMA (65%) quando comparados ao grupo OB. Os níveis elevados de leptina (1000%) no grupo OB não foram alterados pelo Mira. Como esperado os depósitos de lipídios hepáticos, do TAM e PVAT foram aumentado com a dieta HFD e Mira reverteu parcialmente essa alteração, observados na histologia. Observamos modificação nas gotículas lipídicas tecido adiposo inguinal dos grupos CTR+MIRA e OB+MIRA. Anéis com PVAT+ apresentaram aumento na resposta máxima (Emax) à 5HT (%KCl) em anéis de aorta de OB+MIRA (109±10) comparado aos outros grupos (CTR: 69±9; CTR+MIRA: 77±11; OB: 65±9). Conclusão: Em camundongos obesos, o tratamento com Mira por duas semanas resultou em modificação dos tecidos adiposos marrom e inguinal, aumento do gasto energético, melhora de importantes parâmetros bioquímicos como o perfil lipídico e glicêmico, além de reduzir o marcador de estresse oxidativo TBARS, sem contudo alterar a tolerância ao esforço, pressão arterial e frequência cardíaca. Entretanto, em anéis de aorta PVAT+, o tratamento com Mira resultou em aumento da Emax para 5-HT.
Sympathetic nervous system plays an important role in the cardiovascular system and metabolism. In particular, the β3 subtype adrenergic receptors (β3-AR) are widely distributed in different cells, especially in cardiac tissue, smooth muscle and adipose tissue. These receptors are related to several physiological actions, such as vascular and non-vascular smooth muscle relaxation, lipolysis and thermogenesis. In addition, β3-AR participates in the increasing of the number of mitochondria at specific sites of white adipose tissue, called browning of white adipose tissue. Finally, it is not known whether these receptor subtypes may play a role in regulation of the perivascular adipose tissue (PVAT) vasomotricity. Despite these important actions involving these receptor population, studies involving selective β3-AR agonists on obesity state are scarce. Mirabegron (YM-178) is a selective β₃-AR agonist, currently developed by Astellas Pharma Inc. and approved since 2012 by the USA for overactive bladder treatment, considering the action of β₃-AR receptors on smooth muscle relaxation. Intrestingly, there is no study involving the effects of mirabegron on cardiometabolic parameters, adipose tissue metabolism in obesity models. Objectives: To examine the effects of Mirabegron (Mira) treatment, for two weeks on cardiometabolic parameters and vascular reactivity in the presence or in the absence of PVAT in obese mice. Methods: C57BL / 6J mice were divided into vehicle control (CTR), Mira treated (CTR + MIRA), obese mice fed with hyperlipid diet (HFD 12 weeks) treated with vehicle (OB) and obese treated with Mira (OB + MIRA). Mira was given for two weeks (10mg / kg) as a gavage. Concentration-response curves to Acetylcholine (ACh 100pM at 30μM) and serotonin (5HT 1nM at 30μM) were obtained in PVAT + aorta rings, PVAT-. Body temperature and energy expenditure were measured as well as biochemical parameters: lipid profile, fasting glycemia, serum insulin, glycerol, FFA, TBARS, leptin and TNF-α. HOMA index and atherogenic index were calculated. Hepatic and adipose tissue histology was performed by staining hematoxylin and eosin. Results: Treatment with Mira for two weeks increased energy expenditure (17%), without alteration in body temperature. Reduction is body weight (7%), epididymal fat (25%), total cholesterol (17%), LDL-C (55%), atherogenic index (45%), TBARS %), TNF-α (48%), Glycerol and AGL (40%), insulin (67%) and HOMA index (65%) was seen in OB + MIRA when compared with OB group. The increase in leptin levels (1000%) in OB group was not modified by Mira. In contrast, the increased lipid deposits in hepatic, TAM and PVAT, observed in histology, was partially reversed by Mira. We observed changes in lipid droplets in the inguinal adipose tissue of CTR+MIRA and OB+MIRA groups. Rings with PVAT + showed an increase in the Emax to 5HT (% KCl) in aortic rings of OB + MIRA (109 ± 10) compared with the other groups (CTR: 69 ± 9; 65 ± 9; CTR+MIRA: 77±11; OB: 65±9). Conclusion: In obese mice, treatment with Mira for two weeks resulted in modification of brown and inguinal adipose tissues, an increase in energy expenditure, improvement of biochemical parameters such as lipid profile and glycemia, without any modification in the tolerance to exercise effort, blood pressure and heart rate. On the other hand, in PVAT + aortic rings, Mira treatment resulted in increased in Emax to 5HT.
Sympathetic nervous system plays an important role in the cardiovascular system and metabolism. In particular, the β3 subtype adrenergic receptors (β3-AR) are widely distributed in different cells, especially in cardiac tissue, smooth muscle and adipose tissue. These receptors are related to several physiological actions, such as vascular and non-vascular smooth muscle relaxation, lipolysis and thermogenesis. In addition, β3-AR participates in the increasing of the number of mitochondria at specific sites of white adipose tissue, called browning of white adipose tissue. Finally, it is not known whether these receptor subtypes may play a role in regulation of the perivascular adipose tissue (PVAT) vasomotricity. Despite these important actions involving these receptor population, studies involving selective β3-AR agonists on obesity state are scarce. Mirabegron (YM-178) is a selective β₃-AR agonist, currently developed by Astellas Pharma Inc. and approved since 2012 by the USA for overactive bladder treatment, considering the action of β₃-AR receptors on smooth muscle relaxation. Intrestingly, there is no study involving the effects of mirabegron on cardiometabolic parameters, adipose tissue metabolism in obesity models. Objectives: To examine the effects of Mirabegron (Mira) treatment, for two weeks on cardiometabolic parameters and vascular reactivity in the presence or in the absence of PVAT in obese mice. Methods: C57BL / 6J mice were divided into vehicle control (CTR), Mira treated (CTR + MIRA), obese mice fed with hyperlipid diet (HFD 12 weeks) treated with vehicle (OB) and obese treated with Mira (OB + MIRA). Mira was given for two weeks (10mg / kg) as a gavage. Concentration-response curves to Acetylcholine (ACh 100pM at 30μM) and serotonin (5HT 1nM at 30μM) were obtained in PVAT + aorta rings, PVAT-. Body temperature and energy expenditure were measured as well as biochemical parameters: lipid profile, fasting glycemia, serum insulin, glycerol, FFA, TBARS, leptin and TNF-α. HOMA index and atherogenic index were calculated. Hepatic and adipose tissue histology was performed by staining hematoxylin and eosin. Results: Treatment with Mira for two weeks increased energy expenditure (17%), without alteration in body temperature. Reduction is body weight (7%), epididymal fat (25%), total cholesterol (17%), LDL-C (55%), atherogenic index (45%), TBARS %), TNF-α (48%), Glycerol and AGL (40%), insulin (67%) and HOMA index (65%) was seen in OB + MIRA when compared with OB group. The increase in leptin levels (1000%) in OB group was not modified by Mira. In contrast, the increased lipid deposits in hepatic, TAM and PVAT, observed in histology, was partially reversed by Mira. We observed changes in lipid droplets in the inguinal adipose tissue of CTR+MIRA and OB+MIRA groups. Rings with PVAT + showed an increase in the Emax to 5HT (% KCl) in aortic rings of OB + MIRA (109 ± 10) compared with the other groups (CTR: 69 ± 9; 65 ± 9; CTR+MIRA: 77±11; OB: 65±9). Conclusion: In obese mice, treatment with Mira for two weeks resulted in modification of brown and inguinal adipose tissues, an increase in energy expenditure, improvement of biochemical parameters such as lipid profile and glycemia, without any modification in the tolerance to exercise effort, blood pressure and heart rate. On the other hand, in PVAT + aortic rings, Mira treatment resulted in increased in Emax to 5HT.
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Palavras-chave
Mirabegron, Obesidade, Metabolismo, PVAT, Termogenese, β₃-AR, Obesity, Metabolism, Thermogenesis