OBJECTIVE 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. METHODS 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 KATP channel using glibenclamide, the DVC NMDA receptor with MK801, and selectively transected the hepatic branch of the vagal nerve while centrally infusing Sfrp5. RESULTS 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 KATP channel inhibition or HVAG. CONCLUSIONS The present study demonstrates that central Sfrp5 signaling activates a previously unappreciated InsR-Akt-PI3k-KATP channel pathway in the hypothalamus and brain-hepatic vagus neurocircuitry to decrease HGP and VLDL-TG secretion.

中文翻译：

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Central Sfrp5调节肝葡萄糖通量和VLDL-甘油三酸酯分泌。

目的在肥胖和糖尿病的小鼠模型中，分泌型卷曲相关蛋白5（Sfrp5）与能量稳态和胰岛素抵抗有关。然而，其在葡萄糖和脂质代谢中的中心作用尚不清楚。方法HFD喂养的大鼠在胰高血糖钳夹过程中接受了媒介物或Sfrp5的ICV输注。为了描述ICV Sfrp5调节HGP和VLDL-TG分泌的途径，我们使用格列本脲，MVC801的DVC NMDA受体抑制了下丘脑KATP通道，并选择性地横穿迷走神经的肝分支，同时向中央注入Sfrp5。结果在HFD喂养的大鼠中，ICV Sfrp5显着增加了在钳夹过程中由于HGP的抑制而需要维持正常血糖所需的葡萄糖输注。此外，肝PEPCK和G6Pase表达降低，肝脏中InsR和Akt的磷酸化增加。ICV Sfrp5还通过抑制肝VLDL-TG分泌而降低循环甘油三酯水平。这些变化伴随着与肝脏脂肪生成有关的酶的抑制。ICV Sfrp5显着增加了由HFD喂养的大鼠下丘脑的胰岛素刺激的InsR和Akt磷酸化，在体外和体内，Sfrp5组的胰岛素刺激的免疫可检测PIP3水平均高于对照组。NMDA受体或DVC KATP通道抑制或HVAG消除了ICV Sfrp5的降糖和降脂作用。