Sepa-Kishi Diane M, Katsnelson Glen, Bikopoulos George, Iqbal Ayesha, Ceddia Rolando B
Muscle Health Research Center, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
Physiol Rep. 2018 Mar;6(5). doi: 10.14814/phy2.13592.
This study investigated the molecular and metabolic responses of the liver to cold-induced thermogenesis. To accomplish that, male Wistar rats were exposed to cold (4°C) for 7 days. Livers were then extracted and used for the determination of glucose and fatty acid oxidation, glycogen content, the expression and content of proteins involved in insulin signaling, as well as in the regulation of gluconeogenesis and de novo lipid synthesis. Despite being hyperphagic, cold-acclimated rats displayed normoglycemia with reduced insulinemia, which suggests improved whole-body insulin sensitivity. However, liver protein kinase B (AKT) and glycogen synthase kinase 3 (GSK3) phosphorylations were markedly reduced along with the expressions of the insulin receptor (IR) and its substrates IRS1 and IRS2, whereas glycogen synthase (GS) phosphorylation increased. Thus, major signaling steps of the glycogen synthesis pathway in the liver were inhibited. Furthermore, glucagonemia and hepatic glucose and fatty acid oxidation were increased, whereas liver glycogen content was reduced by cold acclimation. This was accompanied by significantly elevated expressions of the gluconeogenic transcription regulators CRTC2, PGC-1α, and FoxO1, as well as of major gluconeogenic enzymes (G6Pase, FBP1, and PEPCK). Conversely, phosphorylation and contents of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) content were markedly downregulated in livers of cold-acclimated rats. In conclusion, cold acclimation suppressed hepatic glycogen synthesis and promoted profound metabolic changes in the liver so the organ could sustain its ability to regulate whole-body glucose and lipid metabolism under conditions of high-energy demand in thermogenic tissues.
本研究调查了肝脏对冷诱导产热的分子和代谢反应。为此，将雄性Wistar大鼠暴露于4°C的寒冷环境中7天。然后提取肝脏，用于测定葡萄糖和脂肪酸氧化、糖原含量、参与胰岛素信号传导以及糖异生和从头脂质合成调节的蛋白质的表达和含量。尽管冷适应大鼠食量增加，但表现出正常血糖且胰岛素血症降低，这表明全身胰岛素敏感性提高。然而，肝脏蛋白激酶B（AKT）和糖原合酶激酶3（GSK3）的磷酸化以及胰岛素受体（IR）及其底物IRS1和IRS2的表达显著降低，而糖原合酶（GS）的磷酸化增加。因此，肝脏中糖原合成途径的主要信号步骤受到抑制。此外，冷适应使胰高血糖素血症以及肝脏葡萄糖和脂肪酸氧化增加，而肝脏糖原含量降低。这伴随着糖异生转录调节因子CRTC2、PGC-1α和FoxO1以及主要糖异生酶（葡萄糖-6-磷酸酶、果糖-1,6-二磷酸酶和磷酸烯醇式丙酮酸羧激酶）的表达显著升高。相反，冷适应大鼠肝脏中AMP活化蛋白激酶（AMPK）和乙酰辅酶A羧化酶（ACC）的磷酸化及含量以及脂肪酸合酶（FAS）含量显著下调。总之，冷适应抑制了肝脏糖原合成并促进了肝脏深刻的代谢变化，以便该器官在产热组织高能量需求的条件下能够维持其调节全身葡萄糖和脂质代谢的能力。
