Stengel Andreas, Goebel Miriam, Wang Lixin, Rivier Jean, Kobelt Peter, Mönnikes Hubert, Lambrecht Nils W G, Taché Yvette
Center for Neurovisceral Sciences and Women's Health CURE, Building 115, Room 117, Veterans Administration Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073, USA.
Endocrinology. 2009 Nov;150(11):4911-9. doi: 10.1210/en.2009-0578. Epub 2009 Oct 1.
Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 microg/rat, icv) decreased 2-3 h and 3-6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 microg/rat) had no effect. The corticotropin-releasing factor (CRF)(1)/CRF(2) antagonist astressin-B or the CRF(2) antagonist astressin(2)-B abolished icv nesfatin-1's anorexigenic action, whereas an astressin(2)-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv astressin(2)-B. Nesfatin-1 into the 4v (0.05 microg/rat) or ic (0.5 microg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic astressin(2)-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF(2)-receptor-dependent pathways after forebrain injection and CRF(2)-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.
Nesfatin-1由核结合蛋白2衍生而来，在下丘脑中表达，一项研究报道其可减少大鼠的食物摄入量（FI）。为了明确nesfatin-1的中枢性厌食作用以及胃排空（GE）是否改变，我们将nesfatin-1注射到长期插管大鼠的侧脑室（脑室内，icv）或第四脑室（4v），或在短时间麻醉下注射到小脑延髓池（脑池内，ic），并与腹腔注射进行比较。Nesfatin-1（0.05微克/大鼠，icv）分别使暗期2 - 3小时和3 - 6小时的FI降低87%和45%，而腹腔给药（2微克/大鼠）则无作用。促肾上腺皮质激素释放因子（CRF）(1)/CRF(2)拮抗剂阿斯特辛 - B或CRF(2)拮抗剂阿斯特辛(2)-B可消除icv nesfatin-1的厌食作用，而缺乏CRF受体结合亲和力的阿斯特辛(2)-B类似物则无此作用。Icv nesfatin-1可使GE剂量依赖性降低26%和43%，而icv阿斯特辛(2)-B对此无影响。注射到4v（0.05微克/大鼠）或ic（0.5微克/大鼠）的nesfatin-1在1小时时使累积暗期FI分别降低29%和60%，在3至5小时之间分别降低41%和37%。这种作用既不受ic阿斯特辛(2)-B的影响，也与GE的变化无关。胆囊收缩素（腹腔注射）可诱导下丘脑室旁核中43%的nesfatin-1神经元和孤束核中24%的nesfatin-1神经元表达Fos。这些数据表明，nesfatin-1在前脑注射后通过CRF(2)受体依赖性途径、在后脑注射后通过CRF(2)受体非依赖性途径在中枢发挥作用以减少暗期FI。胆囊收缩素在调节食物摄入的部位激活nesfatin-1神经元，这可能提示其在肠道肽饱腹感效应中发挥作用。
