Obesity and Metabolic Health Division, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, Scotland, UK.
Int J Obes (Lond). 2010 Jun;34(6):980-8. doi: 10.1038/ijo.2010.28. Epub 2010 Feb 9.
Hypothalamic resistance to the anorexigenic actions of the peripheral adipostat hormone leptin is characteristic of obesity. Here, we use an obese animal model of similar body weight to that of the human to test in vivo whether leptin resistance is due to decreased blood-brain leptin transport or intra-hypothalamic insensitivity, and whether sensitivity to leptin is restored by weight loss. For 40 weeks, adult sheep surgically prepared with intra-cerebroventricular (ICV) cannulae were given a complete natural diet ad libitum ('Obese' group) or in restricted quantities ('Lean' group), and then the dietary amounts were reversed for 16 weeks until mean group body weights converged ('Slimmers' and 'Fatteners', respectively).
ICV leptin injection (0.5 mg) at 8-week intervals acutely decreased voluntary food intake by approximately 35% in the 'Obese' group on each occasion and in 'Slimmers' and 'Fatteners' at the end, providing no evidence of intra-hypothalamic insensitivity. The ratio between endogenous leptin concentrations in ventricular cerebrospinal fluid (CSF) and peripheral blood decreased with increasing leptinaemia in 'Obese' sheep, indicating decreased efficiency of blood-brain leptin transport, whereas leptin concentrations remained low and the CSF:blood ratio remained high in 'Lean' sheep. Compared with 'Fatteners' of similar body weight, 'Slimmers' were hypoleptinaemic, but their CSF:blood leptin concentration ratio remained low. Thus, the obesity-induced impairment of leptin blood-brain transport was sustained despite an approximately 15% weight loss.
These results support the hypothesis that central resistance to leptin in obesity with associated peripheral hyperleptinaemia is attributable to decreased efficiency of leptin transport into the brain and not to intra-hypothalamic leptin insensitivity. However, leptin transport efficiency is not restored after weight loss by caloric restriction despite the prevailing hypoleptinaemia.
外周脂肪激素瘦素对下丘脑的厌食作用产生抵抗是肥胖的特征。在这里，我们使用一种与人类体重相似的肥胖动物模型来体内检测瘦素抵抗是否是由于血脑瘦素转运减少或下丘脑内不敏感引起的，以及体重减轻是否会恢复对瘦素的敏感性。在 40 周的时间里，通过手术在羊的脑室内（ICV）放置导管，让它们自由地摄入完整的天然饮食（“肥胖”组）或限制饮食（“瘦”组），然后将饮食量颠倒 16 周，直到平均体重组趋于一致（分别为“减肥者”和“增肥者”）。
每隔 8 周，通过 ICV 注射（0.5mg）瘦素，每次都能使“肥胖”组的自愿性食物摄入量急性减少约 35%，而在最后一次和“减肥者”及“增肥者”中则没有下丘脑内不敏感的证据。脑室脑脊液（CSF）和外周血中内源性瘦素浓度的比值随着“肥胖”羊中瘦素血症的增加而降低，表明血脑瘦素转运效率降低，而“瘦”羊中的瘦素浓度仍然较低，CSF:血液比值仍然较高。与体重相似的“增肥者”相比，“减肥者”的瘦素水平较低，但他们的 CSF:血液瘦素浓度比值仍然较低。因此，尽管体重减轻了约 15%，但肥胖引起的瘦素血脑转运受损仍持续存在。
这些结果支持了这样一种假设，即肥胖症中与外周性高瘦素血症相关的瘦素对大脑的抵抗是由于瘦素向大脑的转运效率降低所致，而不是由于下丘脑内瘦素不敏感所致。然而，尽管存在普遍的低瘦素血症，通过热量限制减肥后，瘦素转运效率并没有恢复。
