The Key Laboratory of Laboratory Medical Diagnostics in the Ministry of Education and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China; Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Metabolism. 2020 Feb;103:154029. doi: 10.1016/j.metabol.2019.154029. Epub 2019 Nov 23.
Secreted frizzled-related protein 5 (Sfrp5) has been shown to be associated with energy homeostasis and insulin resistance in mouse models of obesity and diabetes. However, its central role in glucose and lipid metabolism is unknown.
HFD-fed rats received ICV infusions of vehicle or Sfrp5 during a pancreatic euglycemic clamp procedure. To delineate the pathway(s) by which ICV Sfrp5 modulates HGP and VLDL-TG secretion, we inhibited the hypothalamic K channel using glibenclamide, the DVC NMDA receptor with MK801, and selectively transected the hepatic branch of the vagal nerve while centrally infusing Sfrp5.
ICV Sfrp5 in HFD-fed rats significantly increased the glucose infusion required to maintain euglycemia due to HGP inhibition during the clamp procedure; moreover, hepatic PEPCK and G6Pase expression was decreased, and InsR and Akt phosphorylation was increased in the liver. ICV Sfrp5 also decreased circulating triglyceride levels via inhibiting hepatic VLDL-TG secretion. These changes were accompanied by the inhibition of enzymes related to lipogenesis in the liver. ICV Sfrp5 significantly increased insulin-stimulated phosphorylation of InsR and Akt in the hypothalamus of HFD-fed rats, and insulin-stimulated immunodetectable PIP3 levels were higher in Sfrp5 group than in control group both in vitro and vivo. The glucose- and lipid-lowering effects of ICV Sfrp5 were eliminated by NMDA receptor or DVC K channel inhibition or HVAG.
The present study demonstrates that central Sfrp5 signaling activates a previously unappreciated InsR-Akt-PI3k-K channel pathway in the hypothalamus and brain-hepatic vagus neurocircuitry to decrease HGP and VLDL-TG secretion.
已有研究表明，分泌型卷曲相关蛋白 5（Sfrp5）与肥胖和糖尿病小鼠模型中的能量平衡和胰岛素抵抗有关。然而，其在葡萄糖和脂质代谢中的核心作用尚不清楚。
高脂饮食喂养的大鼠在胰腺正常血糖钳夹过程中接受脑室注射载体或 Sfrp5。为了描绘脑室注射 Sfrp5 调节肝葡萄糖生成（HGP）和 VLDL-TG 分泌的途径，我们使用格列本脲抑制下丘脑 K 通道，使用 MK801 抑制背侧脑室 NMDA 受体，并在中枢注射 Sfrp5 的同时选择性地横断迷走神经的肝支。
在高脂饮食喂养的大鼠中，脑室注射 Sfrp5 显著增加了维持钳夹过程中血糖所需的葡萄糖输注量，这是由于 HGP 抑制所致；此外，肝脏中 PEPCK 和 G6Pase 的表达减少，InsR 和 Akt 的磷酸化增加。脑室注射 Sfrp5 还通过抑制肝脏 VLDL-TG 分泌来降低循环甘油三酯水平。这些变化伴随着肝脏中与脂肪生成相关的酶的抑制。脑室注射 Sfrp5 还显著增加了高脂饮食喂养大鼠下丘脑胰岛素刺激的 InsR 和 Akt 磷酸化，并且体外和体内 Sfrp5 组的胰岛素刺激免疫可检测到的 PIP3 水平均高于对照组。NMDA 受体或 DVC K 通道抑制或 HVAG 消除了脑室注射 Sfrp5 的降血糖和降血脂作用。
本研究表明，中枢 Sfrp5 信号通过激活下丘脑和脑-肝迷走神经回路中以前未被认识的 InsR-Akt-PI3k-K 通道途径，降低 HGP 和 VLDL-TG 分泌。
