Classic hormone membrane receptors, such as leucine-rich repeat-containing G protein-coupled receptor (LGR) 1 (follicle-stimulating hormone receptor), LGR2 (luteinizing hormone receptor), and LGR3 (thyrotropin receptor), are crucial in endocrinology and metabolism, and the identification of new receptors can advance this field. LGR4 is a new member of this G protein-coupled receptor family and shows ways of expression and function similar to those of LGR1/2/3. Several recent studies have reported that, unlike LGR5/6, LGR4 plays essential roles in endocrine and metabolic diseases, including hypothalamic-gonadal axis defects, mammary gland dysplasia, osteoporosis, cardiometabolic diseases, and obesity. An inactivating mutation p.R126X in LGR4 leads to osteoporosis, electrolyte disturbance, abnormal sex hormone levels, and weight loss, whereas an activating mutation p.A750T is associated with bone mineral density, insulin resistance, and adiposity. Though several paracrine ligands are known to act on LGR4, the endocrine ligands of LGR4 remain poorly defined. In this review, we highlight LGR4 dysfunction in clinical diseases, animal models, and pathophysiological changes, discuss their known ligands and downstream signaling pathways, and identify unresolved questions and future perspectives of this new receptor.

中文翻译：

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LGR4：内分泌和代谢疾病中的新受体成员。

经典的激素膜受体，例如富含亮氨酸重复序列的 G 蛋白偶联受体 (LGR) 1（卵泡刺激素受体）、LGR2（黄体生成素受体）和 LGR3（促甲状腺激素受体），在内分泌和代谢中至关重要，新受体的识别可以推动这一领域的发展。LGR4 是 G 蛋白偶联受体家族的新成员，其表达方式和功能与 LGR1/2/3 相似。最近的几项研究表明，与LGR5/6不同，LGR4在内分泌和代谢疾病中发挥着重要作用，包括下丘脑-性腺轴缺陷、乳腺发育不良、骨质疏松症、心脏代谢疾病和肥胖。LGR4 中的 p.R126X 失活突变会导致骨质疏松、电解质紊乱、性激素水平异常和体重减轻，而激活突变 p.A750T 与骨矿物质密度、胰岛素抵抗和肥胖有关。尽管已知多种旁分泌配体作用于 LGR4，但 LGR4 的内分泌配体仍不清楚。在这篇综述中，我们重点介绍了 LGR4 在临床疾病、动物模型和病理生理变化中的功能障碍，讨论了其已知的配体和下游信号通路，并确定了这种新受体尚未解决的问题和未来前景。