Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation.
Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation.
复制标题
DOI：
10.1186/s12974-017-0869-7
复制
发表时间：
2017-04-26
影响因子：
9.3
通讯作者：
Velloso LA
中科院分区：
文献类型：
--
作者：
Dragano NRV;Solon C;Ramalho AF;de Moura RF;Razolli DS;Christiansen E;Azevedo C;Ulven T;Velloso LA
摄入大量膳食脂肪是导致肥胖和代谢紊乱的最重要的环境因素之一。GPR120和GPR40是多不饱和脂肪酸受体，发挥许多有益于代谢和炎症性疾病的全身作用。在这里，我们评估下丘脑GPR120和GPR40作为肥胖治疗靶点的表达和潜在作用。雄性瑞士猪（6周龄）饲喂高脂肪饲粮（HFD， 60%卡路里来自脂肪）4周。接下来，对小鼠进行立体定向手术，将留置套管置入右侧脑室。脑室灌管小鼠每天2次，连续6天，分别给予2.0 μL生理盐水或GPR40和GPR120激动剂GW9508、TUG1197或TUG905 （2.0 μL, 1.0 mM）。在治疗期间测量食物摄入量和体重。实验结束时，采集下丘脑进行实时PCR分析。我们发现这两种受体都在下丘脑中表达；GPR120主要存在于小胶质细胞中，而GPR40在神经元中表达。在脑室内治疗后，GW9508（一种针对这两种受体的非特异性激动剂）降低了能量效率和下丘脑炎症基因的表达。使用基于慢病毒的方法降低GPR120下丘脑表达导致GW9508抗炎作用的丧失和能量效率的提高。分别使用GPR120和gpr40特异性激动剂TUG1197和TUG905在脑室内治疗的效果比GW9508产生的效果更轻。GPR120和GPR40在下丘脑中协同作用，降低能量效率并调节与肥胖相关的炎症。下丘脑中两种受体的联合激活比单独激活任一受体产生更好的代谢结果。本文的在线版本（doi:10.1186/s12974-017-0869-7）包含补充材料，可供授权用户使用。
The consumption of large amounts of dietary fats is one of the most important environmental factors contributing to the development of obesity and metabolic disorders. GPR120 and GPR40 are polyunsaturated fatty acid receptors that exert a number of systemic effects that are beneficial for metabolic and inflammatory diseases. Here, we evaluate the expression and potential role of hypothalamic GPR120 and GPR40 as targets for the treatment of obesity. Male Swiss (6-weeks old), were fed with a high fat diet (HFD, 60% of kcal from fat) for 4 weeks. Next, mice underwent stereotaxic surgery to place an indwelling cannula into the right lateral ventricle. intracerebroventricular (icv)-cannulated mice were treated twice a day for 6 days with 2.0 μL saline or GPR40 and GPR120 agonists: GW9508, TUG1197, or TUG905 (2.0 μL, 1.0 mM). Food intake and body mass were measured during the treatment period. At the end of the experiment, the hypothalamus was collected for real-time PCR analysis. We show that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular treatment, GW9508, a non-specific agonist for both receptors, reduced energy efficiency and the expression of inflammatory genes in the hypothalamus. Reducing GPR120 hypothalamic expression using a lentivirus-based approach resulted in the loss of the anti-inflammatory effect of GW9508 and increased energy efficiency. Intracerebroventricular treatment with the GPR120- and GPR40-specific agonists TUG1197 and TUG905, respectively, resulted in milder effects than those produced by GW9508. GPR120 and GPR40 act in concert in the hypothalamus to reduce energy efficiency and regulate the inflammation associated with obesity. The combined activation of both receptors in the hypothalamus results in better metabolic outcomes than the isolated activation of either receptor alone. The online version of this article (doi:10.1186/s12974-017-0869-7) contains supplementary material, which is available to authorized users.