Obesity and Metabolic Health Theme, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen AB21 9SB, United Kingdom.
Endocrinology. 2012 Jul;153(7):3147-57. doi: 10.1210/en.2012-1134. Epub 2012 May 16.
Obesity disrupts homeostatic energy balance circuits leading to insulin resistance. Here we examined in vivo peripheral and central insulin sensitivity, and whether central insensitivity in terms of the voluntary food intake (VFI) response occurs within the hypothalamus or at blood-brain transfer level, during obesity and after subsequent weight loss. Sheep with intracerebroventricular (i.c.v.) cannulae were fed complete diet for 40 wk ad libitum (obese group) or at control level (controls). Thereafter, obese sheep were food restricted (slimmers) and controls fed ad libitum (fatteners) for 16 wk. Dual-energy x-ray absorptiometry (DEXA) measured total body fat, insulin analyses in blood and cerebrospinal fluid (CSF) assessed blood-brain transfer, i.v. glucose tolerance test (GTT) and insulin tolerance test (ITT) measured peripheral insulin sensitivity, and VFI responses to icv insulin assessed intrahypothalamic sensitivity. Insulinemia was higher in obese than controls; plasma insulin correlated with DEXA body fat and CSF insulin. Insulinemia was higher in fatteners than slimmers but ratio of CSF to plasma insulin correlated only in fatteners. Plasma glucose baseline and area under the curve were higher during GTT and ITT in obese than controls and during ITT in fatteners than slimmers. GTT and ITT glucose area under the curve correlated with DEXA body fat. VFI decreased after i.c.v. insulin, with response magnitude correlating negatively with DEXA body fat. Overall, insulin resistance developed first in the periphery and then within the brain, thereafter correlating with adiposity; central resistance in terms of VFI response resulted from intrahypothalamic insensitivity rather than impaired blood-brain transfer; modest weight loss improved peripheral but not central insulin sensitivity and induced central hypoinsulinemia.
肥胖破坏了体内平衡能量平衡电路，导致胰岛素抵抗。在这里，我们研究了肥胖症和随后的体重减轻过程中体内和中枢胰岛素敏感性，以及在自愿食物摄入量（VFI）反应方面，中枢敏感性是否发生在下丘脑或在血脑转移水平。用脑室（i.c.v.）套管的绵羊通过自由摄取全饮食喂养 40 周（肥胖组）或控制水平（对照组）。此后，肥胖绵羊被限制食物（减肥者），而对照组则继续自由摄取食物（增肥者）16 周。双能 X 射线吸收法（DEXA）测量全身脂肪，血液和脑脊液（CSF）中的胰岛素分析评估血脑转移，静脉内葡萄糖耐量试验（GTT）和胰岛素耐量试验（ITT）测量外周胰岛素敏感性，以及向脑室注射胰岛素评估下丘脑内敏感性的 VFI 反应。肥胖组的胰岛素血症高于对照组；血浆胰岛素与 DEXA 体脂肪和 CSF 胰岛素相关。增肥组的胰岛素血症高于减肥者，但 CSF 与血浆胰岛素的比值仅在增肥者中相关。GTT 和 ITT 的血糖基线和曲线下面积在肥胖组中高于对照组，在增肥组中高于减肥者。GTT 和 ITT 的血糖曲线下面积与 DEXA 体脂肪相关。脑室注射胰岛素后 VFI 下降，响应幅度与 DEXA 体脂肪呈负相关。总体而言，胰岛素抵抗首先在周围发生，然后在大脑内发生，此后与肥胖相关；VFI 反应方面的中枢抵抗是由于下丘脑内敏感性降低而不是血脑转移受损引起的；适度的体重减轻改善了外周胰岛素敏感性，但没有改善中枢胰岛素敏感性，并引起中枢性低胰岛素血症。
