Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity
Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity
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DOI：
10.2337/db14-0346
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发表时间：
2015-04-01
期刊：
影响因子：
7.7
通讯作者：
Cervera, Ana M.
中科院分区：
文献类型：
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作者：
McCreath, Kenneth J.;Espada, Sandra;Cervera, Ana M.
许多代谢物通过g蛋白偶联受体具有信号特性。琥珀酸盐是一种克雷布斯循环中间体，在能量代谢失调后增加，并可与其同源受体琥珀酸受体1 （Sucnr1，或GPR91）结合，激活下游信号通路。我们发现，Sucnr1在小鼠的白色脂肪组织（WAT）室中高度表达，并调节脂肪量和葡萄糖稳态。生成Sucnr1（-/-）小鼠，在基础应激和营养应激（高脂饮食[HFD]）条件下监测体重增加。在鼠粮中，Sucnr1（-/-）小鼠的能量消耗增加，瘦，WAT室更小，葡萄糖缓冲能力得到改善。脂解测量显示，Sucnr1（-/-）小鼠从琥珀酸诱导的脂解抑制中释放出来，证明了Sucnr1在脂肪组织中的功能。删除Sucnr1也可以保护小鼠在HFD上不肥胖，但仅在初始阶段；在后期，hfd喂养的Sucnr1（-/-）小鼠体重与野生型（WT）小鼠几乎相当，但WAT含量更高。此外，这些小鼠逐渐变得高血糖，无法分泌胰岛素，尽管胰腺结构与WT小鼠相似。这些发现表明，Sucnr1是膳食能量的传感器，并提出了一种有趣的可能性，即调节Sucnr1的方案可能在肥胖的情况下具有治疗效用。
A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1(-/-) mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1(-/-) mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1(-/-) mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1(-/-) mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity.