DEP-1 is a novel brain insulin receptor phosphatase and disallows the development of futile cycles

A healthy metabolism relies on the precise regulation of anabolic and catabolic pathways. Insulin and AMPK serve as key regulators of anabolism and catabolism, respectively. While insulin deficiency markedly impairs anabolism, insulin resistance in obesity leads to metabolic dysfunction especially via altered brain insulin receptor activity. Density-enhanced phosphatase-1 (DEP-1), a ubiquitously expressed receptor-like tyrosine phosphatase, has been described as an insulin receptor phosphatase in peripheral tissues. Strikingly, diet-induced obese mice exhibit elevated DEP-1 expression in the brain. This study uncovers DEP-1's role in brain insulin signaling and its impact on ana- and catabolic pathways. Neurons lacking DEP-1 exhibit heightened insulin receptor phosphorylation and downstream signaling upon acute insulin stimulation. Surprisingly, this is accompanied by simultaneous activation of the AMPK cascade due to increased phospholipase C gamma 1 signaling. These opposing pathways in male DEP-1 forebrain/hippocampus-specific knockout mice result in heightened lipolysis in white adipose tissue, and enhanced fat oxidation in brown adipose tissue due to elevated sympathetic activation and enhanced beta-adrenergic receptor expression.

健康的代谢状态依赖于合成代谢通路（anabolic pathways）与分解代谢通路（catabolic pathways）的精准调控。胰岛素（Insulin）与腺苷酸活化蛋白激酶（AMPK）分别为合成代谢与分解代谢的核心调控因子。胰岛素缺乏会显著削弱合成代谢功能，而肥胖状态下的胰岛素抵抗则会引发代谢紊乱，尤其当脑内胰岛素受体活性发生改变时。密度增强磷酸酶1（Density-enhanced phosphatase-1，DEP-1）是一种广泛表达的受体样酪氨酸磷酸酶，既往研究已证实其在外周组织中可作为胰岛素受体磷酸酶发挥功能。值得注意的是，饮食诱导肥胖小鼠的脑内DEP-1表达水平显著升高。本研究揭示了DEP-1在脑胰岛素信号通路中的作用，及其对合成与分解代谢通路的影响。缺失DEP-1的神经元在急性胰岛素刺激下，胰岛素受体磷酸化水平及下游信号通路均显著增强。令人意外的是，这一现象同时伴随磷脂酶Cγ1（phospholipase C gamma 1）信号通路的激活，进而引发AMPK级联反应的活化。在雄性小鼠前脑/海马特异性敲除DEP-1的模型中，上述两条相互拮抗的通路最终导致：白色脂肪组织（white adipose tissue）的脂肪分解增强，同时由于交感激活程度升高、β肾上腺素能受体（beta-adrenergic receptor）表达增加，棕色脂肪组织（brown adipose tissue）的脂肪氧化功能也得到提升。