Department of Cardio-Diabetes Medicine, The University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Eur J Pharmacol. 2012 Oct 5;692(1-3):84-90. doi: 10.1016/j.ejphar.2012.07.026. Epub 2012 Jul 20.
Telmisartan exerts anti-metabolic effects beyond its angiotensin receptor blockade activities, but the mechanisms have hitherto remained elusive. We sought to elucidate the peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent and PPAR-γ-independent mechanisms underlying the anti-metabolic effects of telmisartan in white adipose tissue. Nine-week-old male C57BL/6 mice were fed with a 60% high-fat diet for 6 weeks, with 1mg/kg telmisartan or vehicle administrated orally during the last 3 weeks. 3T3-L1 adipocytes were cultured with telmisartan either with 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective irreversible antagonist of PPAR-γ, or compound C, an ATP-competitive inhibitor of AMPK. Western blotting and semiquantitative RT-PCR analysis were used to assess adiponectin, Sirt1, and AMPK levels. Lipid accumulation was assessed by Oil red O staining. The activation of transcription factor PPAR-γ2 was evaluated by using a luciferase reporter assay for mPPAR-γ2 expression plasmid vector. Treatment with telmisartan increased serum adiponectin levels in high-fat diet-fed mice concomitantly with an upregulation of adiponectin mRNA in visceral adipose tissue. In vitro telmisartan treatment dose-dependently increased adiponectin mRNA in 3T3-L1 cells; the increase was inhibited by compound C, but not by GW9662. Telmisartan increased expression of Sirt1 mRNA and Sirt1 protein as well as the phosphorylation of AMPK in 3T3-L1 cells. Telmisartan can increase adiponectin production in white adipose tissue partly via a PPAR-γ2-independent mechanism. Precise understanding of this molecular mechanism will require further investigation.
替米沙坦除了阻断血管紧张素受体外，还具有抗代谢作用，但迄今为止，其作用机制仍不清楚。我们试图阐明替米沙坦在白色脂肪组织中产生抗代谢作用的过氧化物酶体增殖物激活受体-γ（PPAR-γ）依赖性和非依赖性机制。9 周龄雄性 C57BL/6 小鼠用 60%高脂肪饮食喂养 6 周，在最后 3 周给予 1mg/kg替米沙坦或载体口服。用替米沙坦或 2-氯-5-硝基-N- 苯甲酰胺（GW9662），一种 PPAR-γ 的选择性不可逆拮抗剂，或化合物 C，一种 AMPK 的 ATP 竞争性抑制剂，培养 3T3-L1 脂肪细胞。用 Western blot 和半定量 RT-PCR 分析评估脂联素、Sirt1 和 AMPK 水平。用油红 O 染色评估脂质积累。通过使用 mPPAR-γ2 表达质粒载体的荧光素酶报告基因测定评估转录因子 PPAR-γ2 的激活。替米沙坦治疗可增加高脂肪饮食喂养小鼠的血清脂联素水平，并同时上调内脏脂肪组织的脂联素 mRNA。替米沙坦体外处理可剂量依赖性地增加 3T3-L1 细胞的脂联素 mRNA；该增加被化合物 C 抑制，但不被 GW9662 抑制。替米沙坦增加了 3T3-L1 细胞中 Sirt1 mRNA 和 Sirt1 蛋白的表达以及 AMPK 的磷酸化。替米沙坦可通过一种非 PPAR-γ2 依赖的机制增加白色脂肪组织中的脂联素产生。进一步研究需要更精确地了解这种分子机制。
