Department of Neuroscience, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida 33458, USA.
Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida 33458, USA.
Endocrinology. 2023 Jan 9;164(3). doi: 10.1210/endocr/bqad008.
High prevalence of obesity is attributable in part to consumption of highly palatable, fat-rich foods. However, the mechanism controlling dietary fat intake is largely unknown. In this study we investigated the role of brain-derived neurotrophic factor (BDNF) in the control of dietary fat intake in a mouse model that mimics the common human Val-to-Met (Val66Met) polymorphism that impairs BDNF release via the regulated secretory pathway. BdnfMet/Met mice gained weight much faster than wild-type (WT) mice and developed severe obesity due to marked hyperphagia when they were fed HFD. Hyperphagia in these mice worsened when the fat content in their diet was increased. Conversely, mice lacking leptin exhibited similar hyperphagia on chow and HFD. When 2 diets were provided simultaneously, WT and BdnfMet/Met mice showed a comparable preference for the more palatable diet rich in either fat or sucrose, indicating that increased hyperphagia on fat-rich diets in BdnfMet/Met mice is not due to enhanced hedonic drive. In support of this interpretation, WT and BdnfMet/Met mice increased calorie intake to a similar extent during the first day after chow was switched to HFD; however, WT mice decreased HFD intake faster than BdnfMet/Met mice in subsequent days. Furthermore, we found that refeeding after fasting or nocturnal feeding with HFD activated TrkB more strongly than with chow in the hypothalamus of WT mice, whereas TrkB activation under these 2 conditions was greatly attenuated in BdnfMet/Met mice. These results indicate that satiety factors generated during HFD feeding induce BDNF release to suppress excess dietary fat intake.
肥胖的高发率部分归因于人们食用了高可口性、高脂肪食物。然而，控制饮食中脂肪摄入的机制在很大程度上尚不清楚。在这项研究中，我们研究了脑源性神经营养因子（BDNF）在一种模拟人类常见 Val66Met（Val 到 Met 突变，通过调节性分泌途径损害 BDNF 释放）的突变的小鼠模型中对饮食中脂肪摄入的控制作用。与野生型（WT）小鼠相比，BdnfMet/Met 小鼠体重增加得更快，并且由于在高脂肪饮食（HFD）喂养时表现出明显的多食，它们发展为严重肥胖。当这些小鼠的饮食中的脂肪含量增加时，它们的多食症恶化。相反，缺乏瘦素的小鼠在正常饮食和 HFD 上也表现出类似的多食。当同时提供两种饮食时，WT 和 BdnfMet/Met 小鼠对富含脂肪或蔗糖的更可口的饮食表现出类似的偏好，这表明 BdnfMet/Met 小鼠在高脂肪饮食上的多食增加并非由于享乐驱动增强。为了支持这一解释，WT 和 BdnfMet/Met 小鼠在切换到 HFD 后的第一天内对卡路里的摄入量相似；然而，在随后的几天里，WT 小鼠比 BdnfMet/Met 小鼠更快地减少 HFD 的摄入量。此外，我们发现，在 WT 小鼠的下丘脑，与正常饮食相比，禁食后再喂食或夜间喂食 HFD 更能强烈地激活 TrkB，而在这两种情况下，BDNFMet/Met 小鼠的 TrkB 激活大大减弱。这些结果表明，在 HFD 喂养期间产生的饱食因子诱导 BDNF 释放以抑制过量的饮食脂肪摄入。
