Fruhwürth Stefanie, Vogel Heike, Schürmann Annette, Williams Kevin Jon
Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
Front Endocrinol (Lausanne). 2018 Mar 26;9:89. doi: 10.3389/fendo.2018.00089. eCollection 2018.
Obesity has become a worldwide health problem, but we still do not understand the molecular mechanisms that contribute to overeating and low expenditure of energy. Leptin has emerged as a major regulator of energy balance through its actions in the hypothalamus. Importantly, obese people exhibit high circulating levels of leptin, yet the hypothalamus no longer responds normally to this hormone to suppress appetite or to increase energy expenditure. Several well-known hypotheses have been proposed to explain impaired central responsiveness to the effects of leptin in obesity, including defective transit across the blood-brain barrier at the arcuate nucleus, hypothalamic endoplasmic reticulum stress, maladaptive sterile inflammation in the hypothalamus, and overexpression of molecules that may inhibit leptin signaling. We also discuss a new explanation that is based on our group's recent discovery of a signaling pathway that we named "NSAPP" after its five main protein components. The NSAPP pathway consists of an oxide transport chain that causes a transient, targeted burst in intracellular hydrogen peroxide (HO) to inactivate redox-sensitive members of the protein tyrosine phosphatase gene family. The NSAPP oxide transport chain is required for full activation of canonical leptin signaling in neurons but fails to function normally in states of overnutrition. Remarkably, leptin and insulin both require the NSAPP oxide transport chain, suggesting that a defect in this pathway could explain simultaneous resistance to the appetite-suppressing effects of both hormones in obesity.
肥胖已成为一个全球性的健康问题，但我们仍不了解导致暴饮暴食和能量消耗低的分子机制。瘦素已成为能量平衡的主要调节因子，通过其在下丘脑的作用发挥作用。重要的是，肥胖者的循环瘦素水平较高，但下丘脑不再对这种激素产生正常反应以抑制食欲或增加能量消耗。已经提出了几种著名的假说来解释肥胖症中下丘脑对瘦素作用的反应受损，包括在弓状核处穿过血脑屏障的缺陷、下丘脑内质网应激、下丘脑的适应性无菌炎症以及可能抑制瘦素信号传导的分子的过表达。我们还讨论了一种新的解释，它基于我们小组最近发现的一条信号通路，我们根据其五个主要蛋白质成分将其命名为“NSAPP”。NSAPP 通路由一个氧化物转运链组成，该转运链会导致细胞内过氧化氢（HO）短暂、有针对性地爆发，从而使蛋白质酪氨酸磷酸酶基因家族的氧化还原敏感成员失活。NSAPP 氧化物转运链是神经元中经典瘦素信号完全激活所必需的，但在营养过剩状态下不能正常发挥作用。值得注意的是，瘦素和胰岛素都需要 NSAPP 氧化物转运链，这表明该通路的缺陷可以解释肥胖症中对这两种激素抑制食欲作用的同时抵抗。
