Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans^1-3. Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity^4,5. ADCY3 localizes to the primary cilia of neurons ⁶ , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation ⁷ . We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons, that obesity-associated MC4R mutations impair ciliary localization and that inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight. These data suggest that impaired signaling from the primary cilia of MC4R neurons is a common pathway underlying genetic causes of obesity in humans.

中文翻译：

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MC4R与ADCY3在神经元原发性纤毛的亚细胞定位是肥胖遗传易感性的常见途径。

人类肥胖的大多数单基因病例都与编码瘦素-黑皮质素途径成员的基因突变有关。具体来说，黑色素皮质素4受体基因MC4R的突变占人类^1-3所有严重肥胖病例的3-5％。最近，ADCY3（腺苷酸环化酶3）基因突变已牵涉到肥胖^4,5。ADCY3定位于神经元的初级纤毛⁶，细胞器该功能作为枢纽选择信号通路。破坏原发纤毛功能的突变会引起纤毛病，这是一种罕见的隐性多效性疾病，其中肥胖是主要表现⁷。我们证明，MC4R与下丘脑神经元子集的初级纤毛中的ADCY3共定位，与肥胖相关的MC4R突变会损害睫状体的定位，并且抑制腺苷酸环化酶信号传导在这些神经元的初级纤毛中会增加体重。这些数据表明，MC4R神经元原发纤毛的信号传导受损是人类肥胖遗传原因的常见途径。