Giovambattista A, Chisari A N, Gaillard R C, Spinedi E
Neuroendocrine Unit, Multidisciplinary Institute on Cell Biology (CIC-CONICET), La Plata, Argentina.
Neuroendocrinology. 2000 Dec;72(6):341-9. doi: 10.1159/000054603.
The mutation of the ob gene is known to induce a phenotype of obesity accompanied by symptoms including enhanced production of glucocorticoid. Chronic administration to ob/ob mice of leptin, the ob gene product, reverses hypercorticosteronemia. This establishes a clear relation between adipocyte and hypothalamo-pituitary-adrenal (HPA) axis functions. In the present study we investigated the acute modulatory effects of food intake-stimulated leptin secretion on HPA axis activity and hypothalamic leptin receptor (Ob-Rb) expression in 24-hour fasting, adult female, BALB/c mice after insulin-induced hypoglycemia. Our results indicate that: (1) food supply for 45 min to 24-hour fasting mice increased plasma glucose levels and reversed both hypercorticosteronemia and hypoleptinemia; (2) the insulin-induced hypoglycemia produced a marked HPA axis activation in animals with no access to food but this response was fully prevented by food intake and the consecutive increase in plasma leptin levels; (3) the inhibitory effect of leptin on the HPA axis response to insulin-induced hypoglycemia was corroborated by i.p. administration of murine leptin, and (4) fasting-induced hypothalamic Ob-Rb overexpression is not modulated by insulin itself but by leptin, since increase in leptin levels by food intake or by administration of exogenous leptin completely reversed this Ob-Rb overexpression. These results confirm the inhibitory effect of leptin on the HPA axis response to various stress stimuli. They clearly demonstrate that acute food intake in 24-hour fasting mice: (a) rapidly reduced fasting-induced hypercorticosteronemia by enhancing both spontaneous and insulin-elicited endogenous leptin secretion; (b) fully prevented HPA axis response to insulin administration, by rapidly increasing endogenous leptin secretion and probably also by diminishing the extent and the duration of insulin-induced hypoglycemia, and (c) abolished hypothalamic Ob-Rb overexpression induced by fasting itself combined with insulin treatment. The present data strongly suggests an inhibitory effect of endogenous leptin on insulin-induced HPA axis response, an interaction relevant to the physiological adaptation to starvation and caloric excess, and further supports the pivotal role played by the hypothalamus in restoring homeostasis in different allostatic states.
已知ob基因的突变会诱发肥胖表型，并伴有包括糖皮质激素分泌增加在内的症状。向ob/ob小鼠长期施用ob基因产物瘦素可逆转高皮质酮血症。这确立了脂肪细胞与下丘脑 - 垂体 - 肾上腺（HPA）轴功能之间的明确关系。在本研究中，我们调查了胰岛素诱导低血糖后，24小时禁食的成年雌性BALB/c小鼠中食物摄入刺激的瘦素分泌对HPA轴活性和下丘脑瘦素受体（Ob-Rb）表达的急性调节作用。我们的结果表明：（1）给禁食24小时的小鼠提供45分钟食物，可提高血糖水平，并逆转高皮质酮血症和低瘦素血症；（2）胰岛素诱导的低血糖在无食物供应的动物中引起显著HPA轴激活，但这种反应可通过食物摄入和随后血浆瘦素水平的升高而完全预防；（3）腹腔注射小鼠瘦素证实了瘦素对HPA轴对胰岛素诱导低血糖反应的抑制作用；（4）禁食诱导的下丘脑Ob-Rb过表达不是由胰岛素本身调节，而是由瘦素调节，因为通过食物摄入或施用外源性瘦素使瘦素水平升高可完全逆转这种Ob-Rb过表达。这些结果证实了瘦素对HPA轴对各种应激刺激反应的抑制作用。它们清楚地表明，24小时禁食小鼠的急性食物摄入：（a）通过增强自发和胰岛素诱导的内源性瘦素分泌，迅速降低禁食诱导的高皮质酮血症；（b）通过迅速增加内源性瘦素分泌，可能还通过减少胰岛素诱导低血糖的程度和持续时间，完全预防HPA轴对胰岛素给药的反应；（c）消除了禁食本身与胰岛素治疗联合诱导的下丘脑Ob-Rb过表达。目前的数据强烈表明内源性瘦素对胰岛素诱导的HPA轴反应具有抑制作用，这种相互作用与对饥饿和热量过剩的生理适应相关，并进一步支持下丘脑在恢复不同应激状态下的内环境稳态中所起的关键作用。
