Boey D, Lin S, Karl T, Baldock P, Lee N, Enriquez R, Couzens M, Slack K, Dallmann R, Sainsbury A, Herzog H
Neurobiology Research Programme, Garvan Institute of Medical Research, St Vincent's Hospital, 384 Victoria Street, Darlinghust, Sydney, NSW 2010, Australia.
Diabetologia. 2006 Jun;49(6):1360-70. doi: 10.1007/s00125-006-0237-0. Epub 2006 Apr 21.
AIMS/HYPOTHESIS: Obese people exhibit reduced circulating peptide YY (PYY) levels, but it is unclear whether this is a consequence or cause of obesity. We therefore investigated the effect of Pyy ablation on energy homeostasis.
Body composition, i.p. glucose tolerance, food intake and hypothalamic neuropeptide expression were determined in Pyy knock-out and wild-type mice on a normal or high-fat diet.
Pyy knock-out significantly increased bodyweight and increased fat mass by 50% in aged females on a normal diet. Male chow-fed Pyy (-/-) mice were resistant to obesity but became significantly fatter and glucose-intolerant compared with wild-types when fed a high-fat diet. Pyy knock-out animals exhibited significantly elevated fasting or glucose-stimulated serum insulin concentrations vs wild-types, with no increase in basal or fasting-induced food intake. Pyy knock-out decreased or had no effect on neuropeptide Y expression in the arcuate nucleus of the hypothalamus, and significantly increased proopiomelanocortin expression in this region. Male but not female knock-outs exhibited significantly increased growth hormone-releasing hormone expression in the ventromedial hypothalamus and significantly elevated serum IGF-I and testosterone levels. This sex difference in activation of the hypothalamo-pituitary somatotrophic axis by Pyy ablation may contribute to the resistance of chow-fed male knock-outs to late-onset obesity.
CONCLUSIONS/INTERPRETATION: PYY signalling is important in the regulation of energy balance and glucose homeostasis, possibly via regulation of insulin release. Therefore reduced PYY levels may predispose to the development of obesity, particularly with ageing or under conditions of high-fat feeding.
目的/假设：肥胖人群循环肽YY（PYY）水平降低，但尚不清楚这是肥胖的结果还是原因。因此，我们研究了PYY缺失对能量平衡的影响。
对正常饮食或高脂饮食的PYY基因敲除小鼠和野生型小鼠进行身体成分、腹腔葡萄糖耐量、食物摄入量及下丘脑神经肽表达的测定。
在正常饮食的老年雌性小鼠中，PYY基因敲除显著增加体重，脂肪量增加50%。雄性普通饮食的PYY（-/-）小鼠对肥胖具有抗性，但在高脂饮食时比野生型小鼠明显更胖且出现葡萄糖不耐受。与野生型相比，PYY基因敲除动物的空腹或葡萄糖刺激的血清胰岛素浓度显著升高，基础或空腹诱导的食物摄入量未增加。PYY基因敲除使下丘脑弓状核中的神经肽Y表达降低或无影响，并显著增加该区域的阿黑皮素原表达。雄性而非雌性敲除小鼠在下丘脑腹内侧核中生长激素释放激素表达显著增加，血清IGF-I和睾酮水平显著升高。PYY缺失对下丘脑-垂体生长激素轴的激活存在性别差异，这可能导致普通饮食的雄性敲除小鼠对晚发性肥胖具有抗性。
结论/解读：PYY信号传导在能量平衡和葡萄糖稳态的调节中很重要，可能是通过调节胰岛素释放实现的。因此，PYY水平降低可能易导致肥胖的发生，尤其是在衰老或高脂喂养条件下。
