Augustine Rachael A, Grattan David R
Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, Dunedin, New Zealand.
Endocrinology. 2008 Mar;149(3):1049-55. doi: 10.1210/en.2007-1018. Epub 2007 Dec 6.
Pregnancy in rats is associated with hyperphagia, increased fat deposition, and elevated plasma leptin concentrations. Elevated leptin would be expected to inhibit food intake, but hypothalamic leptin resistance develops around midpregnancy, allowing hyperphagia to be maintained and excess energy to be stored as fat in preparation for future metabolic demands of lactation. To investigate the hormonal mechanisms inducing leptin resistance during pregnancy, the anorectic response to leptin was examined during pseudopregnancy. Pseudopregnant rats have identical hormonal profiles to early pregnancy, but no placenta formation, allowing differentiation of maternal and placental hormone effects on appetite. To investigate the effect of leptin on food intake, d-9 pseudopregnant rats were injected with leptin (4 microg) via an intracerebroventricular (icv) cannula, and then food intake was measured 24 h later. Pseudopregnant rats were hyperphagic but had normal anorectic responses to leptin. We therefore hypothesized that a longer exposure time to high concentrations of progesterone might be required to mimic the leptin resistance that occurs on d 14 of pregnancy. Pseudopregnant rats were given progesterone to prolong pseudopregnancy beyond the time that leptin resistance develops during pregnancy. However, rats remained responsive to icv leptin. To model the placental lactogen secretion that occurs during pregnancy, pseudopregnant rats were given progesterone and chronic icv ovine prolactin infusion. Central icv injection of leptin had no effect on food intake in pseudopregnant rats receiving chronic ovine prolactin. These results suggest that chronically high lactogen levels, secreted by the placenta during the second half of pregnancy, induce central leptin resistance.
大鼠怀孕与摄食过量、脂肪沉积增加以及血浆瘦素浓度升高有关。瘦素水平升高本应抑制食物摄入，但在怀孕中期左右会出现下丘脑瘦素抵抗，从而使摄食过量得以维持，多余能量以脂肪形式储存，为未来哺乳的代谢需求做准备。为了研究怀孕期间诱导瘦素抵抗的激素机制，在假孕期间检测了对瘦素的厌食反应。假孕大鼠的激素谱与怀孕早期相同，但没有胎盘形成，这样可以区分母体和胎盘激素对食欲的影响。为了研究瘦素对食物摄入的影响，给怀孕第9天的假孕大鼠通过脑室内（icv）套管注射瘦素（4微克），然后在24小时后测量食物摄入量。假孕大鼠摄食过量，但对瘦素具有正常的厌食反应。因此，我们推测可能需要更长时间暴露于高浓度孕酮才能模拟怀孕第14天出现的瘦素抵抗。给假孕大鼠注射孕酮以延长假孕时间，使其超过怀孕期间出现瘦素抵抗的时间。然而，大鼠对脑室内注射瘦素仍有反应。为了模拟怀孕期间发生的胎盘催乳素分泌，给假孕大鼠注射孕酮并进行慢性脑室内注射羊催乳素。在接受慢性羊催乳素注射的假孕大鼠中，脑室内注射瘦素对食物摄入没有影响。这些结果表明，怀孕后半期胎盘分泌的长期高催乳素水平会诱导中枢性瘦素抵抗。
