Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, 183-8509 Tokyo, Japan.
Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Chiyoda-ku, 100-0004 Tokyo, Japan.
Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23813-23821. doi: 10.1073/pnas.1912573116. Epub 2019 Nov 4.
Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-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, -deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, -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.
酮体，包括β-羟丁酸和乙酰乙酸，是能量短缺时的重要替代能源。β-羟丁酸还通过特定的 G 蛋白偶联受体 (GPCR) 发挥信号分子作用；然而，乙酰乙酸的特定相关 GPCR 和生理功能仍不清楚。在这里，我们通过在异源表达系统中的配体筛选，将乙酰乙酸鉴定为短链脂肪酸 (SCFA) 受体 GPR43 的内源性激动剂。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升高，而血浆和盲肠 SCFA 水平急剧下降，同时肠道微生物群组成发生改变。此外，-缺陷小鼠在禁食和等热量生酮饮食喂养期间体重减轻减少，血浆脂蛋白脂肪酶活性受到抑制。此外，-缺陷小鼠在间歇性禁食后体重下降最小。这些观察结果提供了对营养变化下酮体在能量代谢中的作用的深入了解，并可能通过饮食和食物为预防医学的发展做出贡献。
