Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts.
Section of Endocrinology, VA Boston Healthcare System, Boston, Massachusetts.
Diabetes Obes Metab. 2019 Nov;21(11):2459-2464. doi: 10.1111/dom.13827. Epub 2019 Aug 8.
GLP-1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer-term administration at the highest dose approved for obesity (liraglutide 3.0 mg).
A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo-controlled, double-blind, cross-over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center.
While using liraglutide, patients lost more weight (placebo-subtracted -2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons).
In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter-regulatory increase in reward-related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.
GLP-1 类似物作为通过中枢神经系统（CNS）作用降低体重的有效药物，最近已成为研究热点。然而，在肥胖症最高批准剂量（利拉鲁肽 3.0mg）下长期给药后，它们在人类大脑中的 CNS 作用尚未得到研究。
共有 20 名肥胖患者参加了一项随机、安慰剂对照、双盲、交叉试验，在经过 5 周的剂量递增后，他们分别接受安慰剂和利拉鲁肽（3.0mg）治疗。在 Beth Israel Deaconess Medical Center 的临床研究中心检查了对食物线索的神经认知和神经影像学（fMRI）反应。
使用利拉鲁肽时，患者体重减轻更多（安慰剂减去 -2.7%；P<.001），空腹血糖降低（P<.001），胆固醇水平改善。在非对照分析中，与安慰剂相比，利拉鲁肽并未改变对食物图像的大脑激活。当控制 BMI/体重时，利拉鲁肽增加了右眶额皮质（OFC）对食物线索的激活（P<.016，经多重比较校正）。
与先前的研究相反，我们首次证明，在肥胖症最高批准剂量下，长时间给予利拉鲁肽治疗不会改变对食物线索的大脑激活。当将神经影像学数据控制为 BMI 变化时，可以观察到对食物线索的奖励相关 OFC 激活的代偿性增加，表明 CNS 发生了变化，这可能导致体重减轻的后期平台期。这些数据为进一步干预提供了一个有希望的焦点，通过对 CNS 奖励系统的贡献，可以在逆转平台现象和促进进一步体重减轻方面提供切实的好处。
