Department of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
J Neurosci. 2011 Apr 20;31(16):6019-27. doi: 10.1523/JNEUROSCI.6498-10.2011.
Nutrient excess in obesity and diabetes is emerging as a common putative cause for multiple deleterious effects across diverse cell types, responsible for a variety of metabolic dysfunctions. The hypothalamus is acknowledged as an important regulator of whole-body energy homeostasis, through both detection of nutrient availability and coordination of effectors that determine nutrient intake and utilization, thus preventing cellular and whole-body nutrient excess. However, the mechanisms underlying hypothalamic nutrient detection and its impact on peripheral nutrient utilization remain poorly understood. Recent data suggest a role for thioredoxin-interacting protein (TXNIP) as a molecular nutrient sensor important in the regulation of energy metabolism, but the role of hypothalamic TXNIP in the regulation of energy balance has not been evaluated. Here we show in mice that TXNIP is expressed in nutrient-sensing neurons of the mediobasal hypothalamus, responds to hormonal and nutrient signals, and regulates adipose tissue metabolism, fuel partitioning, and glucose homeostasis. Hypothalamic expression of TXNIP is induced by acute nutrient excess and in mouse models of obesity and diabetes, and downregulation of mediobasal hypothalamic TXNIP expression prevents diet-induced obesity and insulin resistance. Thus, mediobasal hypothalamic TXNIP plays a critical role in nutrient sensing and the regulation of fuel utilization.
肥胖和糖尿病中的营养过剩正成为多种细胞类型中多种有害影响的常见假定原因，导致各种代谢功能障碍。下丘脑被认为是全身能量稳态的重要调节剂，通过检测营养物质的可用性和协调决定营养物质摄入和利用的效应器，从而防止细胞和全身营养过剩。然而，下丘脑营养物质检测的机制及其对周围营养物质利用的影响仍知之甚少。最近的数据表明，硫氧还蛋白相互作用蛋白 (TXNIP) 作为一种重要的分子营养传感器，在调节能量代谢中发挥作用，但下丘脑 TXNIP 在调节能量平衡中的作用尚未得到评估。在这里，我们在小鼠中表明，TXNIP 表达在中脑基底部下丘脑的营养感应神经元中，对激素和营养信号作出反应，并调节脂肪组织代谢、燃料分配和葡萄糖稳态。急性营养过剩和肥胖及糖尿病小鼠模型中诱导下丘脑 TXNIP 表达，而下丘脑 TXNIP 的下调可预防饮食诱导的肥胖和胰岛素抵抗。因此，中脑基底部下丘脑 TXNIP 在营养感应和燃料利用的调节中发挥关键作用。
