Role of food intake and cortisol on leptin in humans.

描述(由申请人提供)： 脂肪细胞激素瘦素在控制能量平衡方面起着关键作用。我们和其他人证明了糖皮质激素(GC)和食物摄入量(或胰岛素)对瘦素和肥胖者瘦素的协同作用。早晨进食会增加胰岛素，中午皮质醇会激增，晚上瘦素会增加。在禁食期间，胰岛素和皮质醇都不会在中午达到峰值，瘦素在晚上也不会上升。单独使用胰岛素并不能产生夜间因进餐而导致的血清瘦素升高。我们假设，进食时皮质醇水平的升高可能是餐后胰岛素对夜间瘦素产生影响的原因。因此，我们预计，服用皮质醇生产阻滞剂美替拉奉应该会减弱瘦素对食物摄入量的反应。因此，通过人工模拟中午皮质醇的激增，给服用甲替拉奉的受试者注射氢化可的松，将恢复瘦素对饮食的反应。这项机械实验将在瘦身的受试者中进行。肥胖，尤其是腹型肥胖，与下丘脑-垂体-肾上腺(HPA)轴的紊乱有关。血浆皮质醇对应激源(如午餐)的反应增强。瘦素对糖皮质激素的反应也升高。因此，我们还将调查上半身肥胖(UBO)患者进食时皮质醇分泌和瘦素夜间升高之间的关系是否受到干扰。UBO有很高的发生代谢并发症的风险，并且代表了肥胖者中HPA轴异常最典型的一个亚组。我们假设，与肥胖个体的随机子集相比，UBO将对皮质醇操作表现出更健壮和同质的反应。综上所述，这些实验应该提供有关营养/激素对血清瘦素影响的基本机制的信息，以及关于这些机制如何在肥胖中改变的初步数据。最终，这些结果将有助于更好地理解肥胖受试者瘦素失调的机制。

DESCRIPTION (provided by applicant): The adipocyte hormone leptin plays a key role in the control of energy balance. We and others have demonstrated a synergistic effect of administered glucocorticoids (GC) and food intake (or insulin) on leptin in lean and obese subjects. Morning food intake produces an increase in insulin, a midday spike of cortisol and an increase of leptin at night. During fasting, neither insulin or cortisol peak in midday, and leptin does not rise at night. Administration of insulin alone cannot produce the meal-entrained nocturnal rise in serum leptin. We hypothesize that the spike of cortisol occurring with feeding is permissive for post-prandial insulin effects on nighttime leptin. Thus we anticipate that administration of metyrapone, a blocker of cortisol production, should blunt the leptin response to food intake. Accordingly, the administration of hydrocortisone to subjects receiving metyrapone, by artificially simulating the midday surge of cortisol, will restore the leptin response to the meal. This mechanistic experiment will be conducted in lean subjects. Obesity, particularly abdominal obesity, is associated with perturbations of the hypothalamic-pituitary-adrenal (HPA) axis. The response of plasma cortisol to stressors, such as a lunch meal, is increased. The leptin response to the administration of GC is also elevated. Thus, we will also investigate whether the relationship between the meal-entrained cortisol secretion and leptin night rise is perturbed in upper body obese (UBO). UBO have a high risk of developing metabolic complications, and represent a subgroup of obese with the most well-characterized abnormalities of the HPA axis. We hypothesize that UBO will exhibit a more robust and homogenous response to cortisol manipulations than a random subset of obese individuals. Taken together, these experiments should provide information on basic mechanisms of nutritional/hormonal effects on serum leptin, as well as preliminary data on how these mechanisms may be altered in obesity. Ultimately, these results would lead to a better understanding of the mechanisms of leptin dysregulation in obese subjects