RESUMO
According to several population-based studies, betel nut chewing is associated with metabolic syndrome and diabetes in British South Asians and Taiwanese. However, the underlying molecular mechanism is not yet clear. Arecoline is an alkaloid-type natural product found in betel nuts. Our aim was to clarify the influence of betel nut extract and arecoline on lipid accumulation and insulin signaling in adipocytes. We found that betel nut extract and arecoline blocked lipid storage in 3T3-L1 adipocytes. The possible mechanism may function by inhibiting the expression of the insulin receptor, glucose transporter-4, fatty acid synthase, and the lipid droplet proteins perilipin and adipophilin. In addition, betel nut extract and arecoline increased the basal level of IRS-1 serine(307) phosphorylation and decreased insulin-stimulated IRS-1 tyrosine, Akt, and PI3 kinase phosphorylation. In conclusion, betel nut extract and arecoline have diabetogenic potential on adipocytes that may result in insulin resistance and diabetes at least in part via the obstruction of insulin signaling and the blockage of lipid storage.
Assuntos
Adipócitos/efeitos dos fármacos , Areca/efeitos adversos , Arecolina/efeitos adversos , Diabetes Mellitus Tipo 2/metabolismo , Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Areca/química , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Diabetes Mellitus Tipo 2/patologia , Ácido Graxo Sintases/antagonistas & inibidores , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 4/antagonistas & inibidores , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Proteínas Substratos do Receptor de Insulina/antagonistas & inibidores , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Perilipina-1 , Perilipina-2 , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
PURPOSE: Angiotensin II (Ang II), the physiologically-active product of the renin-angiotensin system (RAS), has recently been found to be an adipokine secreted by adipocytes. Although Ang II is known to exert its effects via angiotensin II receptor type 1 (AT1R) or type 2 (AT2R), the roles of the two receptors in the adipose tissue are unclear. Apelin, another adipokine, has been found able to restore glucose tolerance in obese and insulin-resistant mice. Because they are both involved in metabolic disorders, there may be an interaction between the two adipokines. METHODS: To observe the expression of RAS and apelin, 3T3-L1 adipocytes were harvested after 1, 2, 4, and 6 days of differentiation. The RAS blockers captopril (10(-4) M), perindopril (10(-3) M), losartan (10(-4) M), or PD123319 (10(-4) M) were added at day 2 of differentiation and harvested at day 4 and 6, when apelin expression was measured. Expressions of mRNAs were detected by real-time PCR. Production of Ang II and apelin was measured from culture media by ELISA. Cellular lipid droplets were detected by oil-red staining. RESULTS: Our study showed that the mRNA expressions of AGT, renin, ACE1, and AT2R were up-regulated while AT1R mRNA was down-regulated during adipogenesis. Apelin expression increased during adipogenesis, and this increase was further augmented by blocking RAS. RAS blockers also prevented excessive lipid accumulation and the generation of ROS (reactive oxygen species) in differentiating adipocytes. CONCLUSIONS: Our study suggests that RAS blockers achieve their beneficial effects by their enhancement of adipocyte secretion of apelin.