Linehan Victoria, Fang Lisa Z, Parsons Matthew P, Hirasawa Michiru
Division of Biomedical Sciences, Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, Newfoundland, A1B 3V6, Canada.
Division of Biomedical Sciences, Faculty of Medicine, Memorial University, 300 Prince Philip Drive, St. John's, Newfoundland, A1B 3V6, Canada.
Mol Metab. 2020 Jun;36:100977. doi: 10.1016/j.molmet.2020.100977. Epub 2020 Mar 18.
Orexin (ORX) and melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus are critical regulators of energy homeostasis and are thought to differentially contribute to diet-induced obesity. However, it is unclear whether the synaptic properties of these cells are altered by obesogenic diets over time.
Rats and mice were fed a control chow or palatable high-fat diet (HFD) for various durations and then synaptic properties of ORX and MCH neurons were examined using exvivo whole-cell patch clamp recording. Confocal imaging was performed to assess the number of excitatory synaptic contacts to these neurons.
ORX neurons exhibited a transient increase in spontaneous excitatory transmission as early as 1 day up to 1 week of HFD, which returned to control levels with prolonged feeding. Conversely, HFD induced a delayed increase in excitatory synaptic transmission to MCH neurons, which progressively increased as HFD became chronic. This increase occurred before the onset of significant weight gain. These synaptic changes appeared to be due to altered postsynaptic sensitivity or the number of active synaptic contacts depending on cell type and feeding duration. However, HFD induced no change in inhibitory transmission in either cell type at any time point.
These results suggest that the effects of HFD on feeding-related neurons are cell type-specific and dynamic. This highlights the importance of considering the feeding duration for research and weight loss interventions. ORX neurons may contribute to early hyperphagia, whereas MCH neurons may play a role in the onset and long-term maintenance of diet-induced obesity.
下丘脑外侧的食欲素（ORX）和促黑素细胞激素（MCH）神经元是能量稳态的关键调节因子，被认为在饮食诱导的肥胖中发挥不同作用。然而，尚不清楚这些细胞的突触特性是否会随着致肥胖饮食时间的推移而改变。
将大鼠和小鼠分别喂食对照饲料或可口的高脂饮食（HFD）不同时长，然后使用离体全细胞膜片钳记录来检测ORX和MCH神经元的突触特性。进行共聚焦成像以评估与这些神经元的兴奋性突触接触数量。
早在喂食HFD的第1天至1周，ORX神经元的自发性兴奋性传递就出现短暂增加，随着喂食时间延长，其恢复到对照水平。相反，HFD诱导MCH神经元的兴奋性突触传递延迟增加，随着HFD变为长期饮食，这种增加逐渐加剧。这种增加在体重显著增加之前就已出现。这些突触变化似乎是由于突触后敏感性改变或活性突触接触数量改变，这取决于细胞类型和喂食时长。然而，在任何时间点，HFD均未诱导两种细胞类型的抑制性传递发生变化。
这些结果表明，HFD对与进食相关神经元的影响具有细胞类型特异性且是动态变化的。这凸显了在研究和减肥干预中考虑喂食时长的重要性。ORX神经元可能促成早期食欲亢进，而MCH神经元可能在饮食诱导肥胖的发生和长期维持中发挥作用。
