Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions
Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions
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DOI：
10.1073/pnas.1912573116
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发表时间：
2019-11-19
影响因子：
11.1
通讯作者：
Kimura, Ikuo
中科院分区：
文献类型：
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作者：
Miyamoto, Junki;Ohue-Kitano, Ryuji;Kimura, Ikuo
酮体包括β-羟基丁酸和乙酰乙酸，是能源短缺时期重要的替代能源。β-羟基丁酸也通过特异性G蛋白偶联受体（GPCR）作为信号分子;然而，乙酰乙酸的特异性相关GPCR和生理功能仍然未知。在这里，我们确定乙酰乙酸作为内源性激动剂短链脂肪酸（SCFA）受体GPR 43的配体筛选在异源表达系统。在生酮条件下，如饥饿和低碳水化合物饮食，血浆乙酰乙酸水平显著增加，而血浆和盲肠SCFA水平显著降低，沿着肠道微生物群组成的改变。此外，Gpr 43缺陷小鼠在禁食和正常热量生酮饮食喂养期间显示体重减轻和血浆脂蛋白脂酶活性抑制。此外，Gpr 43缺陷小鼠在间歇性禁食后表现出最小的体重下降。这些观察结果提供了深入了解酮体在营养变化下的能量代谢中的作用，并可能有助于通过饮食和食物开发预防医学。
Ketone bodies, including beta-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. beta-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.