Oregon National Primate Research Center, Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA.
Endocrinology. 2010 Apr;151(4):1598-610. doi: 10.1210/en.2009-1295. Epub 2010 Mar 1.
Childhood obesity increases the risk of adult obesity and diabetes, suggesting that early overnutrition permanently programs altered energy and glucose homeostasis. In the present studies, we used a mouse model to investigate whether early overnutrition increases susceptibility to obesity and insulin resistance in response to a high-fat diet (HFD). Litters from Swiss Webster dams were culled to three [chronic postnatal overnutrition (CPO)] or 10 (control) pups and then weaned onto standard chow at postnatal day (P) 23. At 6 wk of age, a subset of mice was placed on HFD, and glucose and insulin tolerance were examined at 16-17 wk of age. Leptin sensitivity was determined by hypothalamic phosphorylated signal transducer and activator of transcription-3 immunoreactivity at P16 and adulthood after ip leptin. CPO mice exhibited accelerated body weight gain and hyperleptinemia during the preweaning period but only a slightly heavier body weight and normal glucose tolerance in adulthood on standard chow diet. Importantly, CPO mice exhibited significant leptin resistance in the arcuate nucleus, demonstrated by reduced activation of phospho-signal transducer and activator of transcription-3, as early as P16 and throughout life, despite normalized leptin levels. In response to HFD, CPO but not control mice displayed insulin resistance in response to an insulin tolerance test. In conclusion, CPO mice exhibited early and persistent leptin resistance in the arcuate nucleus and, in response to HFD, rapid development of obesity and insulin resistance. These studies suggest that early overnutrition can permanently alter energy homeostasis and significantly increase susceptibility to obesity and insulin resistance.
儿童肥胖会增加成年后肥胖和糖尿病的风险，这表明早期的营养过剩会永久性地改变能量和葡萄糖稳态。在本研究中，我们使用小鼠模型来研究早期营养过剩是否会增加对高脂肪饮食（HFD）的肥胖和胰岛素抵抗易感性。瑞士 Webster 母鼠的幼崽被淘汰至 3 只（慢性产后营养过剩（CPO））或 10 只（对照组），然后在出生后第 23 天（P）断奶到标准饲料。在 6 周龄时，一部分小鼠被置于 HFD 下，在 16-17 周龄时检查葡萄糖和胰岛素耐量。在 P16 和成年后通过腹腔注射瘦素测定下丘脑磷酸化信号转导子和转录激活因子 3 免疫反应性来确定瘦素敏感性。CPO 小鼠在断奶前表现出体重增加和高瘦素血症加速，但在标准饲料成年时体重仅略重且葡萄糖耐量正常。重要的是，CPO 小鼠在弓状核中表现出明显的瘦素抵抗，这表现为磷酸化信号转导子和转录激活因子 3 的活性降低，早在 P16 时就出现，并且终生存在，尽管瘦素水平正常。在 HFD 反应中，CPO 而不是对照组小鼠在胰岛素耐量试验中表现出胰岛素抵抗。总之，CPO 小鼠在弓状核中表现出早期和持续的瘦素抵抗，并且对 HFD 迅速发展为肥胖和胰岛素抵抗。这些研究表明，早期营养过剩会永久性地改变能量稳态，并显著增加肥胖和胰岛素抵抗的易感性。
