Identification of a GABAergic neural circuit governing leptin signaling deficiency-induced obesity.
Identification of a GABAergic neural circuit governing leptin signaling deficiency-induced obesity.
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作者：
Han Y;He Y;Harris L;Xu Y;Wu Q
已知激素瘦素通过作用于位于下丘脑的刺鼠相关蛋白（AgRP）神经元内的瘦素受体（LepR）信号传导系统来强烈抑制食物摄入。然而，临床研究表明，瘦素作为肥胖症的治疗方案是不可取的，这至少部分归因于对瘦素反应神经回路的复杂二级结构和关键信号传导机制知之甚少。在这里，我们表明，表达LepR的门神经元发送GABA能投射到下丘脑背内侧核（DMH）内表达α3-GABAA受体的神经元，以控制瘦素介导的肥胖表型。我们确定DMH作为一个关键的大脑区域，有助于调节瘦素介导的进食。GABA能AgRP-DMH回路的急性激活促进食物摄入和葡萄糖耐受不良，而DMH中突触后MC 4 R神经元的激活引起完全相反的表型。从AgRP神经元中快速缺失LepR导致肥胖表型，这可以通过阻断DMH中的GABAA受体来挽救。与行为结果相一致，这些DMH神经元显示出对饥饿或高血糖的神经活动抑制。此外，我们发现DMH内的α3-GABAA受体信号传导对瘦素对摄食和体重的中枢作用发挥了有效的双向调节作用。总之，我们的研究结果证明了一种新的GABA能神经回路，通过次级瘦素反应神经回路中独特的α3-GABAA信号传导来控制瘦素介导的进食和能量平衡，构成了治疗肥胖和相关合并症的治疗干预的新途径。
The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptin-mediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptin-responsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities.
影响因子：
4.3
作者：
Liu T;Wang Q;Berglund ED;Tong Q
通讯作者：
Tong Q