Wilding J P H
Clinical Sciences Centre, University Hospital Aintree, Longmoor lane, Liverpool L9 7AL, Liverpool, UK.
Diabet Med. 2002 Aug;19(8):619-27. doi: 10.1046/j.1464-5491.2002.00790.x.
Obesity is important in the aetiology of type 2 diabetes, and presents a major barrier to its successful prevention and management. Obesity develops when energy intake exceeds energy expenditure over time. A complex system has evolved to maintain energy homeostasis, but this is biased towards weight gain. Meal size is controlled by a series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin whereas others may initiate meals, such as the recently discovered hormone, ghrelin. Other hormones such as insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act at several central nervous system (CNS) sites but the pathways converge on the hypothalamus, which contains a large number of peptide and other neurotransmitters that influence food intake. As energy deficit is most likely to compromise survival, it is not surprising that the most powerful of these pathways are those that increase food intake and decrease energy expenditure when stores are depleted. When energy stores are low, production of leptin from adipose tissue, and thus circulating leptin concentrations fall, leading to increased production of hypothalamic neurotransmitters that strongly increase food intake, such as neuropeptide Y (NPY), galanin and agouti-related protein (AGRP) and decreased levels of alpha-melanocyte-stimulating hormone (alpha-MSH), cocaine and amphetamine-regulated transcript (CART) and neurotensin that reduce food intake and increase energy expenditure. The finding that mutations in leptin and POMC lead to severe early onset obesity in humans has highlighted the importance of these peptides in humans. This new understanding may eventually lead to new treatments for obesity that will be of particular benefit in the prevention and treatment of type 2 diabetes.
肥胖在2型糖尿病的病因中起着重要作用，并且是其成功预防和管理的主要障碍。当能量摄入长期超过能量消耗时，肥胖就会产生。一个复杂的系统已经进化出来以维持能量平衡，但这个系统倾向于体重增加。进餐量由一系列来自胃肠道的短期激素和神经信号控制，如胆囊收缩素，而其他信号可能引发进餐，如最近发现的激素胃饥饿素。其他激素如胰岛素和瘦素，以及循环中的营养物质，表明长期能量储备。所有这些信号都作用于几个中枢神经系统（CNS）部位，但这些途径都汇聚在下丘脑，下丘脑含有大量影响食物摄入的肽和其他神经递质。由于能量不足最有可能危及生存，所以当能量储备耗尽时，这些途径中最强大的是那些增加食物摄入和减少能量消耗的途径，这并不奇怪。当能量储备较低时，脂肪组织中瘦素的产生减少，因此循环中的瘦素浓度下降，导致下丘脑神经递质的产生增加，这些神经递质会强烈增加食物摄入，如神经肽Y（NPY）、甘丙肽和刺鼠相关蛋白（AGRP），同时减少α-黑素细胞刺激素（α-MSH）、可卡因和苯丙胺调节转录物（CART）以及神经降压素的水平，这些物质会减少食物摄入并增加能量消耗。瘦素和促黑素细胞皮质激素原（POMC）的突变会导致人类严重的早发性肥胖，这一发现凸显了这些肽在人类中的重要性。这种新的认识最终可能会带来肥胖的新治疗方法，这对2型糖尿病的预防和治疗将特别有益。
