Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room Y6-220C, Dallas, Texas 75390-9077, USA.
Endocrinology. 2011 Jan;152(1):11-8. doi: 10.1210/en.2010-0778. Epub 2010 Nov 10.
Changes in physical activities and feeding habits have transformed the historically rare disease of obesity into a modern metabolic pandemic. Obesity occurs when energy intake exceeds energy expenditure over time. This energy imbalance significantly increases the risk for cardiovascular disease and type 2 diabetes mellitus and as such represents an enormous socioeconomic burden and health threat. To combat obesity, a better understanding of the molecular mechanisms and neurocircuitries underlying normal body weight homeostasis is required. In the 1940s, pioneering lesion experiments unveiled the importance of medial and lateral hypothalamic structures. In the 1980s and 1990s, several neuropeptides and peripheral hormones critical for appropriate feeding behavior, energy expenditure, and hence body weight homeostasis were identified. In the 2000s, results from metabolic analyses of genetically engineered mice bearing mutations only in selected neuronal groups greatly advanced our knowledge of the peripheral/brain feedback-loop modalities by which central neurons control energy balance. In this review, we will summarize these recent progresses with particular emphasis on the biochemical identities of hypothalamic neurons and molecular components underlying normal appetite, energy expenditure, and body weight homeostasis. We will also parse which of those neurons and molecules are critical components of homeostatic adaptive pathways against obesity induced by hypercaloric feeding.
身体活动和饮食习惯的改变将肥胖这一历史罕见的疾病转变为现代代谢性流行病。当能量摄入超过一段时间的能量消耗时，就会发生肥胖。这种能量失衡显著增加了心血管疾病和 2 型糖尿病的风险，因此代表了巨大的社会经济负担和健康威胁。为了对抗肥胖，我们需要更好地了解正常体重平衡的分子机制和神经回路。20 世纪 40 年代，开创性的损伤实验揭示了内侧和外侧下丘脑结构的重要性。在 20 世纪 80 年代和 90 年代，确定了几种对适当的喂养行为、能量消耗以及因此体重平衡至关重要的神经肽和外周激素。在 21 世纪，仅对特定神经元群发生突变的基因工程小鼠的代谢分析结果极大地提高了我们对中枢神经元控制能量平衡的外周/大脑反馈回路模式的认识。在这篇综述中，我们将重点介绍这些最近的进展，特别强调下丘脑神经元的生化特征和正常食欲、能量消耗和体重平衡的分子成分。我们还将分析哪些神经元和分子是对抗高热量喂养引起的肥胖的体内平衡适应性途径的关键组成部分。
