Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction.
Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction.
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DOI：
10.1016/j.molmet.2023.101788
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发表时间：
2023-10
影响因子：
8.1
通讯作者：
Routh, Vanessa H.
中科院分区：
文献类型：
--
作者：
Teegala, Suraj B.;Sarkar, Pallabi;Siegel, Dashiel M.;Sheng, Zhenyu;Hao, Lihong;Bello, Nicholas T.;De Lecea, Luis;Beck, Kevin D.;Routh, Vanessa H.
关键词：
本研究验证了体重减轻后下丘脑外侧下丘脑（LH）下丘脑分泌素/食欲素葡萄糖抑制（GI）神经元的葡萄糖敏感性变化导致腹侧被盖区（VTA）多巴胺神经元的谷氨酸可塑性并驱动食物寻找行为的假设。对C57BL/6J小鼠进行热量限制，使其体重减少15%，并维持该体重1周。采用全细胞膜片钳记录脑切片中LH下丘脑泌素/食欲素GI和VTA多巴胺神经元的葡萄糖敏感性。用条件位置偏好（CPP）评价寻找食物行为。维持1周的卡路里限制15%的体重减轻减少了葡萄糖抑制下丘脑分泌素/食欲素GI神经元，导致神经元激活增加，血糖降低。葡萄糖降低对下丘脑分泌素/食欲素GI神经元激活的影响被百日咳毒素（g蛋白偶联受体亚基Gαi/o抑制剂）和Rp-cAMP（蛋白激酶A抑制剂，PKA）阻断。这表明葡萄糖敏感性是由g - αi/o-腺苷酸环化酶- camp - pka信号通路介导的。饥饿激素ghrelin对hcrt/ox神经元的兴奋作用也被Rp-cAMP阻断，这表明代谢状态的激素信号可能聚集在葡萄糖传感途径上。节食和减肥增加了VTA多巴胺神经元上谷氨酸突触强度（以AMPA/NMDA受体电流比增加为指标）和寻找食物的动机（以CPP为指标）。在热量限制和体重减轻过程中，下丘脑分泌素/食欲素神经元的化学发生抑制阻止了谷氨酸可塑性和寻找食物行为的这些变化。我们假设，这种下丘脑分泌素/食欲素GI神经元的葡萄糖敏感性的变化可能在一定程度上驱动热量限制后的食物寻找行为。热量限制和体重减轻改变了下丘脑分泌素/食欲素GI神经元的葡萄糖敏感性。热量限制会增加中脑多巴胺神经元的谷氨酸信号。下丘脑泌素/食欲素介导热量限制对多巴胺神经元和进食的影响。葡萄糖和胃饥饿素通过蛋白激酶A调节下丘脑分泌素/食欲素神经元。
The present study tests the hypothesis that changes in the glucose sensitivity of lateral hypothalamus (LH) hypocretin/orexin glucose-inhibited (GI) neurons following weight loss leads to glutamate plasticity on ventral tegmental area (VTA) dopamine neurons and drives food seeking behavior. C57BL/6J mice were calorie restricted to a 15% body weight loss and maintained at that body weight for 1 week. The glucose sensitivity of LH hypocretin/orexin GI and VTA dopamine neurons was measured using whole cell patch clamp recordings in brain slices. Food seeking behavior was assessed using conditioned place preference (CPP). 1-week maintenance of calorie restricted 15% body weight loss reduced glucose inhibition of hypocretin/orexin GI neurons resulting in increased neuronal activation with reduced glycemia. The effect of decreased glucose on hypocretin/orexin GI neuronal activation was blocked by pertussis toxin (inhibitor of G-protein coupled receptor subunit Gαi/o) and Rp-cAMP (inhibitor of protein kinase A, PKA). This suggests that glucose sensitivity is mediated by the Gαi/o-adenylyl cyclase-cAMP-PKA signaling pathway. The excitatory effect of the hunger hormone, ghrelin, on hcrt/ox neurons was also blocked by Rp-cAMP suggesting that hormonal signals of metabolic status may converge on the glucose sensing pathway. Food restriction and weight loss increased glutamate synaptic strength (indexed by increased AMPA/NMDA receptor current ratio) on VTA dopamine neurons and the motivation to seek food (indexed by CPP). Chemogenetic inhibition of hypocretin/orexin neurons during caloric restriction and weight loss prevented these changes in glutamate plasticity and food seeking behavior. We hypothesize that this change in the glucose sensitivity of hypocretin/orexin GI neurons may drive, in part, food seeking behavior following caloric restriction. Calorie restriction and weight loss alter glucose sensitivity of hypocretin/orexin GI neurons. Calorie restriction increases glutamate signaling on midbrain dopamine neurons. Hypocretin/orexin mediates the effects of calorie restriction on dopamine neurons and feeding. Glucose and ghrelin regulate hypocretin/orexin neurons via protein kinase A.
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影响因子：
3.4
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Burdakov, Denis
影响因子：
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