Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
PLoS One. 2013 Apr 23;8(4):e62669. doi: 10.1371/journal.pone.0062669. Print 2013.
Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability.
METHODOLOGY/PRINCIPAL FINDINGS: In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation.
CONCLUSION/SIGNIFICANCE: Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.
下丘脑 AMPK 作为细胞能量传感器，可以调节摄食、葡萄糖稳态和脂肪酸生物合成。已知向下丘脑内注射脂肪酸会抑制肝脏葡萄糖生成，主要通过激活下丘脑 ATP 敏感性钾 (K(ATP)) 通道。由于所有涉及的模型似乎都涉及丙二酰辅酶 A 生物合成，我们假设乙酰辅酶 A 羧化酶可以独立于营养物质的可用性来调节代偿性反应。
方法/主要发现：在这项研究中，我们通过免疫印迹、实时 PCR、ELISA 和生化测量表明，脑室注射反义寡核苷酸降低了下丘脑乙酰辅酶 A 羧化酶的表达，增加了食物摄入和 NPY mRNA 的表达，并减少了 CART、CRH 和 TRH mRNA 的表达。此外，与禁食大鼠一样，在反义寡核苷酸处理的大鼠中，血清胰高血糖素和酮体增加，而血清胰岛素和肝糖原水平降低。下丘脑乙酰辅酶 A 羧化酶的减少也增加了肝脏中 PEPCK 的表达、AMPK 的磷酸化和葡萄糖的产生。有趣的是，这些效应的观察没有改变下丘脑 AMPK 的磷酸化。
结论/意义：下丘脑 ACC 抑制可以激活肝脏的代偿性反应，而不依赖于下丘脑 AMPK 的激活。
