Gorski Judith N, Dunn-Meynell Ambrose A, Levin Barry E
Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry, Newark, NJ, USA.
Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1782-91. doi: 10.1152/ajpregu.00749.2006. Epub 2007 Jan 11.
In rats selectively bred to develop diet-induced obesity (DIO) or to be diet-resistant (DR), DIO maternal obesity selectively enhances the development of obesity and insulin resistance in their adult offspring. We postulated that the interaction between genetic predisposition and factors in the maternal environment alter the development of hypothalamic peptide systems involved in energy homeostasis regulation. Maternal obesity in the current studies led to increased body and fat pad weights and higher leptin and insulin levels in postnatal day 16 offspring of both DIO and DR dams. However, by 6 wk of age, most of these intergroup differences disappeared and offspring of obese DIO dams had unexpected increases in arcuate nucleus leptin receptor mRNA, peripheral insulin sensitivity, diet- and leptin-induced brown adipose temperature increase and 24-h anorectic response compared with offspring of lean DIO, but not lean DR dams. On the other hand, while offspring of obese DIO dams did have the highest ventromedial nucleus melanocortin-4 receptor expression, their anorectic and brown adipose thermogenic responses to the melanocortin agonist, Melanotan II (MTII), did not differ from those of offspring of lean DR or DIO dams. Thus, during their rapid growth phase, juvenile offspring of obese DIO dams have alterations in their hypothalamic systems regulating energy homeostasis, which ameliorates their genetic and perinatally determined predisposition toward leptin resistance. Because they later go onto become more obese, it is possible that interventions during this time period might prevent the subsequent development of obesity.
在经选择性培育以发生饮食诱导性肥胖（DIO）或对饮食具有抗性（DR）的大鼠中，DIO 母鼠肥胖选择性地增强其成年后代肥胖和胰岛素抵抗的发展。我们推测，遗传易感性与母鼠环境中的因素之间的相互作用会改变参与能量稳态调节的下丘脑肽系统的发育。在当前研究中，母鼠肥胖导致 DIO 和 DR 母鼠产后第 16 天的后代体重和脂肪垫重量增加，瘦素和胰岛素水平升高。然而，到 6 周龄时，这些组间差异大多消失，与瘦的 DIO 母鼠（而非瘦的 DR 母鼠）的后代相比，肥胖 DIO 母鼠的后代弓状核瘦素受体 mRNA、外周胰岛素敏感性、饮食和瘦素诱导的棕色脂肪温度升高以及 24 小时厌食反应出现意外增加。另一方面，虽然肥胖 DIO 母鼠的后代腹内侧核黑皮质素-4 受体表达最高，但其对黑皮质素激动剂 Melanotan II（MTII）的厌食和棕色脂肪产热反应与瘦的 DR 或 DIO 母鼠的后代并无差异。因此，在其快速生长阶段，肥胖 DIO 母鼠的幼年后代下丘脑调节能量稳态的系统发生改变，这改善了它们对瘦素抵抗的遗传和围产期决定的易感性。由于它们后来会变得更肥胖，在此时间段进行干预有可能预防随后肥胖的发生。
