Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity
Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity
复制标题
DOI：
10.1152/ajpregu.00462.2015
复制
发表时间：
2016-02-15
影响因子：
2.8
通讯作者：
Levin, Barry E.
中科院分区：
文献类型：
--
作者：
Dunn-Meynell, Ambrose A.;Le Foll, Christelle;Levin, Barry E.
胰淀素增强弓状核（ARC）和腹内侧核（VMN）下丘脑瘦素信号传导，并协同降低选择性饲养饮食诱导的肥胖（DIO）大鼠的食物摄入量和体重。由于DIO 125 I-胰淀素背内侧核-背内侧VMN结合减少，我们推测这有助于DIO腹内侧下丘脑（VMH）瘦素抵抗，而损害VMH（ARC + VMN）降钙素受体（CTR）介导的信号传导通过注射表达CTR mRNA的短发夹部分的腺相关病毒（AAV）将使饮食抵抗（DR）大鼠在高脂肪（45%）时易于肥胖。饮食（HFD）。与AAV对照组大鼠相比，4周龄雄性DR大鼠中VMH CTR消耗80-90%分别使ARC和VMN 125 I标记的瘦素结合减少57%和51%，VMN瘦素诱导的磷酸化信号转导子和转录激活子3阳性神经元减少59%。6周后，VMH CTR耗尽的DR大鼠进食并获得等量的食物和体重，但与对照AAV DR大鼠相比，脂肪垫重18%（相对于胴体重量），瘦素水平高144%，并且具有胰岛素抵抗。在HFD 6周后，VMH CTR耗尽的DR大鼠吃了相同的量，但体重增加了28%，胴体脂肪增加了60%，瘦素水平提高了254%，口服葡萄糖耐量试验期间胰岛素曲线下面积比对照DR大鼠高出132%。因此，损害内源性VMH CTR介导的信号传导减少瘦素信号传导，并导致DR大鼠变得更加肥胖和胰岛素抵抗，无论是在食物和HFD。这些结果表明，内源性VMH胰淀素信号传导是完整的瘦素信号传导和防止HFD诱导的肥胖所必需的。
Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO 125I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80-90% in 4-wk-old male DR rats reduced their ARC and VMN 125I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.