Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Department of Physiology, Monash University, Clayton, Victoria, Australia.
Endocrinology. 2018 Nov 1;159(11):3605-3614. doi: 10.1210/en.2018-00536.
Metabolic feedback from the periphery to the brain results from a dynamic physiologic fluctuation of nutrients and hormones, including glucose and fatty acids, ghrelin, leptin, and insulin. The specific interactions between humoral factors and how they influence feeding is largely unknown. We hypothesized that acute glucose availability may alter how the brain responds to ghrelin, a hormonal signal of energy availability. Acute glucose administration suppressed a range of ghrelin-induced behaviors as well as gene expression changes in hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons after ghrelin administration. Knockdown of the energy-sensing molecule AMP-activated protein kinase (AMPK) in AgRP neurons resulted in loss of the glucose effect, and mice responded as though pretreated with saline. Conversely, 2-deoxyglucose (2-DG), which decreases glucose availability, potentiated ghrelin-induced feeding and increased hypothalamic NPY mRNA levels. AMPK knockdown did not alter the additive effect of 2-DG and ghrelin on feeding. Our findings support the idea that computation of energy status is dynamic, is informed by multiple signals, and responds to acute fluctuations in metabolic state. These observations are broadly relevant to the investigation of neuroendocrine control of feeding and highlight the underappreciated complexity of control within these systems.
外周向大脑的代谢反馈源于营养物质和激素（包括葡萄糖和脂肪酸、胃饥饿素、瘦素和胰岛素）的动态生理波动。体液因素之间的具体相互作用以及它们如何影响进食在很大程度上尚不清楚。我们假设急性葡萄糖供应可能会改变大脑对胃饥饿素的反应，胃饥饿素是能量供应的激素信号。急性葡萄糖给药可抑制一系列胃饥饿素诱导的行为以及下丘脑神经肽 Y（NPY）和刺鼠相关肽（AgRP）神经元中胃饥饿素给药后的基因表达变化。在 AgRP 神经元中敲低能量感应分子 AMP 激活的蛋白激酶（AMPK）会导致葡萄糖作用丧失，而小鼠的反应就像是预先用盐水处理过的一样。相反，2-脱氧葡萄糖（2-DG）可降低葡萄糖的可用性，增强胃饥饿素诱导的进食并增加下丘脑 NPY mRNA 水平。AMPK 敲低不会改变 2-DG 和胃饥饿素对进食的相加作用。我们的研究结果支持这样一种观点，即能量状态的计算是动态的，受到多种信号的影响，并对代谢状态的急性波动做出反应。这些观察结果与神经内分泌对进食的控制的广泛研究有关，并突出了这些系统中控制的被低估的复杂性。
