Serotonin as a Regulator of Leptin-Mediated Food Intake Control Within a Novel Neuronal Circuit Between the Hypothalamus and Raphe Nuclei
Serotonin as a Regulator of Leptin-Mediated Food Intake Control Within a Novel Neuronal Circuit Between the Hypothalamus and Raphe Nuclei
复制标题
DOI：
10.1210/jendso/bvab048.112
复制
发表时间：
2021-05-03
影响因子：
4.1
通讯作者：
Grillo CA
中科院分区：
文献类型：
--
作者：
Sadek AT;Cowan HB;Jimenez KM;Crawford JN;Maxwell ND;Fadel JR;Reagan LP;Grillo CA
肥胖的发生和恶化涉及脂肪细胞源性激素瘦素的过量产生，瘦素是稳态食欲调节的关键介质和饱腹感的信号。尽管瘦素对食物摄入的下丘脑调节已被广泛研究，但其与厌食神经递质血清素 (5-HT) 协同作用的特征还较少。 5-HT 在中缝背核 (DRN) 中合成，此前已鉴定出该处许多下丘脑核的解剖学投射。我们实验室的初步研究已经：（1）确定了 DRN 中对瘦素有反应的血清素能神经元，投射到下丘脑的弓状核（ARC）；（2）证明注射到 DRN 中的瘦素可显着减少食物摄入量。当前研究的目的是确定 5-HT 在瘦素调节食物摄入中的作用，首先是在 DRN 内，然后是在 DRN 和 ARC 之间。成年雄性 Sprague Dawley 大鼠接受立体定位手术，在 DRN 中植入引导插管。恢复后，动物每天在 DRN 中服用 100 µg 对氯苯丙氨酸 (PCPA)（一种 5-HT 合成抑制剂），持续四天。第四天，还在 DRN 中注射瘦素（5 µg/大鼠），并在 24 小时内测量食物摄入量。方差分析显示 24 小时食物摄入量存在显着差异 [F (3, 18) = 3.972； P = 0.0246]和事后分析表明，与对照大鼠（25.4±0.9克）相比，用瘦素治疗的动物显着减少食物摄入量（17.2±2.0克），而用PCPA治疗的大鼠与对照大鼠没有差异，这表明5-HT的消耗减弱了瘦素在DRN内调节食物摄入的能力。为了检查 5-HT 对瘦素下丘脑作用的作用，随后进行了一项实验，在 ARC 中植入一根额外的插管，以便在治疗的第四天施用瘦素或载体。方差分析显示 24 小时食物摄入量存在显着差异 [F (3, 16) = 5.998； P = 0.0061]和事后分析表明，与对照组（21.8 ± 0.5 g）相比，只有在 ARC 中接受瘦素治疗的大鼠的食物摄入量（14.0 ± 1.5 g）显着减少。死后使用免疫组织化学评估 5-HT 消耗，并随后进行量化。总的来说，这些结果表明瘦素调节食物摄入的能力取决于 5-HT，无论调节区域（即 DRN 或下丘脑）如何。
The onset and exacerbation of obesity involves the overproduction of the adipocyte-derived hormone leptin, a key mediator of homeostatic appetite regulation and a signal for satiety. Although leptin’s hypothalamic regulation of food intake has been extensively investigated, its role in tandem with the anorectic neurotransmitter serotonin (5-HT) has been less characterized. 5-HT is synthesized in the dorsal raphe nucleus (DRN) where anatomical projections to many hypothalamic nuclei have previously been identified. Preliminary studies in our lab have: (1) identified serotonergic neurons responsive to leptin in the DRN that project to the arcuate nucleus (ARC) of the hypothalamus and (2) demonstrated leptin injected into the DRN significantly decreases food intake. The objective of the current study was to identify the role of 5-HT in leptin’s regulation of food intake first within the DRN, then between the DRN and the ARC. Adult male Sprague Dawley rats underwent stereotaxic surgery for guide cannula implantation in the DRN. After recovery, animals were administered 100 µg of p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, in the DRN each day for four days. On the fourth day, leptin was also administered in the DRN (5 µg/rat) and food intake was measured over a 24-hour time course. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 18) = 3.972; P = 0.0246] and post-hoc analysis showed that animals treated with leptin significantly decreased food intake (17.2 ± 2.0 g) compared to control rats (25.4 ± 0.9 g), whereas PCPA-treated rats did not differ from the control rats, suggesting that depletion of 5-HT attenuated leptin’s ability to regulate food intake within the DRN. To examine the role of 5-HT on leptin’s hypothalamic action, a subsequent experiment was conducted by implanting an additional cannula into the ARC for the administration of leptin or vehicle on the fourth day of treatment. ANOVA analysis revealed a significant difference in 24-hour food intake [F (3, 16) = 5.998; P = 0.0061] and post-hoc analysis showed that only rats treated with leptin in the ARC significantly decreased food intake (14.0 ± 1.5 g) compared to controls (21.8 ± 0.5 g). 5-HT depletion was assessed post-mortem using immunohistochemistry and was later quantified. Collectively, these results demonstrate that leptin’s ability to regulate food intake is dependent on 5-HT, regardless of the area of regulation (i.e. DRN or the hypothalamus).