Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America.
PLoS One. 2011;6(9):e25169. doi: 10.1371/journal.pone.0025169. Epub 2011 Sep 28.
The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.
METHODOLOGY/PRINCIPAL FINDINGS: We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.
CONCLUSIONS/SIGNIFICANCE: Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food lifestyle" creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.
肥胖症的患病率在全球范围内急剧上升。肥胖症流行迫切需要新的概念和治疗靶点，以协调解决“食物滥用”障碍。我们证明了一种中枢激酶（Akt）的损伤与高脂肪（HF）饮食暴露引起的胰岛素信号转导之间存在分子联系，这种激酶参与进食的高级电路的调节。富含多巴胺（DA）的脑结构，如纹状体，为进食提供动机刺激。在这些中枢电路中，DA 功能障碍被认为是肥胖发病机制的原因。我们确定了代谢失调与促进体重增加的适应不良行为之间的机制联系。胰岛素是一种外周激素，也在中枢神经系统中发挥作用，以调节基于稳态和奖励的 HF 进食。它通过控制 DA 清除的关键元素，即 DA 转运体（DAT），来调节 DA 稳态。在 HF 喂养期间，黑质纹状体神经元迅速发展出胰岛素信号转导缺陷，导致 HF 卡路里摄入量增加。
方法/主要发现：我们表明，高脂肪食物的摄入会损害纹状体中胰岛素激活信号激酶 Akt 的激活。反过来，HF 诱导的 Akt 损伤会降低 DAT 细胞表面表达和功能，从而降低 DA 稳态和安非他命（AMPH）诱导的 DA 外排。此外，HF 介导的 Akt 信号转导失调会损害与 DA 相关的行为，如（AMPH）诱导的运动和增加的热量摄入。我们使用重组病毒载体表达技术恢复黑质纹状体 Akt 磷酸化。我们观察到 HF 喂养大鼠中 DAT 表达的恢复，这与 AMPH 诱导的运动反应的恢复和 HF 饮食诱导的多食症的正常化有关。
结论/意义：大脑胰岛素作用的获得性破坏可能会增加“食物滥用”障碍和肥胖症的风险或成为其基础。因此，这种分子模型解释了即使是短期暴露于“快餐生活方式”如何导致进食紊乱的循环，这种紊乱会导致 DA 信号转导的病理变化，从而导致体重增加和肥胖。
