Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland; Drug Research Doctoral Program, University of Turku, Turku, Finland; Turku Center for Disease Modeling, University of Turku, Turku, Finland.
Acta Physiol (Oxf). 2015 Apr;213(4):902-19. doi: 10.1111/apha.12436. Epub 2014 Dec 26.
Neuropeptide Y (NPY) co-localized with noradrenaline in central and sympathetic nervous systems seems to play a role in the control of energy metabolism. In this study, the aim was to elucidate the effects and pathophysiological mechanisms of increased NPY in catecholaminergic neurones on accumulation of body adiposity.
Transgenic mice overexpressing NPY under the dopamine-beta-hydroxylase promoter (OE-NPY(DβH) ) and wild-type control mice were followed for body weight gain and body fat content. Food intake, energy expenditure, physical activity, body temperature, serum lipid content and markers of glucose homoeostasis were monitored. Thermogenic and lipolytic responses in adipose tissues, and urine catecholamine and tissue catecholamine synthesizing enzyme levels were analysed as indices of sympathetic tone.
Homozygous OE-NPY(DβH) mice showed significant obesity accompanied with impaired glucose tolerance and insulin resistance. Increased adiposity was explained by neither increased food intake or fat absorption nor by decreased total energy expenditure or physical activity. Adipocyte hypertrophy and decreased circulating lipid levels suggested decreased lipolysis and increased lipid uptake. Brown adipose tissue thermogenic capacity was decreased and brown adipocytes filled with lipids. Enhanced response to adrenergic stimuli, downregulation of catecholamine synthesizing enzyme expressions in the brainstem and lower adrenaline excretion supported the notion of low basal catecholaminergic activity.
Increased NPY in catecholaminergic neurones induces obesity that seems to be a result of preferential fat storage. These results support the role of NPY as a direct effector in peripheral tissues and an inhibitor of sympathetic activity in the pathogenesis of obesity.
神经肽 Y（NPY）与去甲肾上腺素在中枢和交感神经系统中共同存在，似乎在控制能量代谢中发挥作用。本研究旨在阐明儿茶酚胺能神经元中 NPY 增加对体脂积累的影响和病理生理机制。
在多巴胺-β-羟化酶启动子（OE-NPY(DβH)）的控制下过表达 NPY 的转基因小鼠（OE-NPY(DβH)）和野生型对照小鼠被跟踪观察体重增加和体脂肪含量。监测食物摄入量、能量消耗、体力活动、体温、血清脂质含量和葡萄糖稳态标志物。分析脂肪组织的产热和脂肪分解反应，以及尿儿茶酚胺和组织儿茶酚胺合成酶水平，作为交感神经张力的指标。
杂合子 OE-NPY(DβH) 小鼠表现出明显的肥胖，伴有糖耐量受损和胰岛素抵抗。增加的肥胖既不是由于食物摄入量或脂肪吸收增加，也不是由于总能量消耗或体力活动减少引起的。脂肪细胞肥大和循环脂质水平降低表明脂肪分解减少和脂质摄取增加。棕色脂肪组织的产热能力降低，棕色脂肪细胞充满脂质。增强对肾上腺素能刺激的反应、脑干部位儿茶酚胺合成酶表达的下调以及肾上腺素排泄减少支持了基础儿茶酚胺能活性低的观点。
儿茶酚胺能神经元中 NPY 的增加会导致肥胖，这似乎是脂肪优先储存的结果。这些结果支持 NPY 作为外周组织中直接效应物和肥胖发病机制中交感神经活动抑制剂的作用。
