Nonogaki Katsunori, Kaji Takao
Laboratory of Diabetes and Nutrition, Tohoku University New Industry Creation Hatcher Center, Japan.
Heliyon. 2020 Dec 19;6(12):e05774. doi: 10.1016/j.heliyon.2020.e05774. eCollection 2020 Dec.
Plasma fibroblast growth factor 21 (FGF21) levels and hepatic FGF21, serotonin 2a receptor (htr2a), and stromal cell-derived factor 2 like 1 (Sdf2l1) expression are increased in insulin-resistant C57BL6J mice fed a high-fat diet. Here we show that plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression were decreased in 6-week-old db/db mice compared with C57BL6J mice, whereas they were increased in 6-week-old KKA mice compared with KK mice. Expression of hepatic htr2b was increased in db/db mice and KKA mice compared with controls. Treatment with the selective htr2b antagonist SB204741 suppressed the hyperglycemia in either db/db mice or KKA mice. Treatment with SB20471 reversed the decreases in plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression in db/db mice, whereas it suppressed the increases in plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression in KKA mice. Moreover, treatment with SB204741 increased plasma FGF21 levels and expression of hepatic FGF21, htr2a, and Sdf2l1 in C57BL6J mice, whereas it decreased plasma FGF21 levels and hepatic FGF21 expression in KK mice. These findings suggest that pharmacologic inhibition of htr2b ameliorates the hyperglycemia and altered expression of hepatic FGF21, Sdf2l1 and htr2a in obese and diabetic db/db and KKA mice.
在喂食高脂饮食的胰岛素抵抗C57BL6J小鼠中，血浆成纤维细胞生长因子21（FGF21）水平以及肝脏FGF21、5-羟色胺2a受体（htr2a）和基质细胞衍生因子2样1（Sdf2l1）的表达均升高。在此我们发现，与C57BL6J小鼠相比，6周龄的db/db小鼠血浆FGF21水平以及肝脏FGF21、Sdf2l1和htr2a的表达降低，而与KK小鼠相比，6周龄的KKA小鼠中这些指标则升高。与对照组相比，db/db小鼠和KKA小鼠肝脏htr2b的表达增加。用选择性htr2b拮抗剂SB204741治疗可抑制db/db小鼠或KKA小鼠的高血糖。用SB20471治疗可逆转db/db小鼠血浆FGF21水平以及肝脏FGF21、Sdf2l1和htr2a表达的降低，而在KKA小鼠中则抑制血浆FGF21水平以及肝脏FGF21、Sdf2l1和htr2a表达的升高。此外，用SB204741治疗可增加C57BL6J小鼠血浆FGF21水平以及肝脏FGF21、htr2a和Sdf2l1的表达，而在KK小鼠中则降低血浆FGF21水平以及肝脏FGF21的表达。这些发现表明，药理学上抑制htr2b可改善肥胖和糖尿病db/db及KKA小鼠的高血糖以及肝脏FGF21、Sdf2l1和htr2a表达的改变。
