LGR4: A New Receptor Member in Endocrine and Metabolic Diseases

Overview

Journal Endocr Rev

Publisher Oxford University Press

Specialty Endocrinology

Date 2023 Feb 15

PMID 36791020

Authors

Ningning Zhang

Mingyang Yuan

Jiqiu Wang

Affiliations

Soon will be listed here.

Abstract

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.

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References

Stunkard A, Harris J, Pedersen N, McClearn G . The body-mass index of twins who have been reared apart. N Engl J Med. 1990; 322(21):1483-7. DOI: 10.1056/NEJM199005243222102. View

Loh N, Neville M, Marinou K, Hardcastle S, Fielding B, Duncan E . LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metab. 2015; 21(2):262-273. PMC: 4321886. DOI: 10.1016/j.cmet.2015.01.009. View

Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro V, Dhawan S . Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature. 2017; 546(7656):107-112. PMC: 5651981. DOI: 10.1038/nature22342. View

Mancini A, Howard S, Marelli F, Cabrera C, Barnes M, Sternberg M . LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling. JCI Insight. 2020; 5(11). PMC: 7308048. DOI: 10.1172/jci.insight.133434. View

Danilovich N, Sairam M . Targeting gonadotropin receptor genes: reproductive biology, aging, and related health implications. Endocrine. 2005; 26(3):219-26. DOI: 10.1385/ENDO:26:3:219. View

Huch M, Dorrell C, Boj S, van Es J, Li V, van de Wetering M . In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013; 494(7436):247-50. PMC: 3634804. DOI: 10.1038/nature11826. View

Ruffner H, Sprunger J, Charlat O, Leighton-Davies J, Grosshans B, Salathe A . R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PLoS One. 2012; 7(7):e40976. PMC: 3397969. DOI: 10.1371/journal.pone.0040976. View

Dong H, Sun W, Shen Y, Balaz M, Balazova L, Ding L . Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. Nat Metab. 2022; 4(1):90-105. PMC: 8803606. DOI: 10.1038/s42255-021-00509-1. View

Akbari P, Gilani A, Sosina O, Kosmicki J, Khrimian L, Fang Y . Sequencing of 640,000 exomes identifies variants associated with protection from obesity. Science. 2021; 373(6550). PMC: 10275396. DOI: 10.1126/science.abf8683. View

10.

Kim S, Ryu V, Miyashita S, Korkmaz F, Lizneva D, Gera S . Thyrotropin, Hyperthyroidism, and Bone Mass. J Clin Endocrinol Metab. 2021; 106(12):e4809-e4821. PMC: 8864741. DOI: 10.1210/clinem/dgab548. View

11.

Luo W, Rodriguez M, Valdez J, Zhu X, Tan K, Li D . Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem Cells. 2013; 31(11):2492-505. PMC: 3934101. DOI: 10.1002/stem.1484. View

12.

Shungin D, Winkler T, Croteau-Chonka D, Ferreira T, Locke A, Magi R . New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015; 518(7538):187-196. PMC: 4338562. DOI: 10.1038/nature14132. View

13.

Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z . Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development. 2009; 136(16):2747-56. PMC: 2730404. DOI: 10.1242/dev.033571. View

14.

Jiang X, Cong F . Novel Regulation of Wnt Signaling at the Proximal Membrane Level. Trends Biochem Sci. 2016; 41(9):773-783. DOI: 10.1016/j.tibs.2016.06.003. View

15.

Scopelliti A, Bauer C, Yu Y, Zhang T, Kruspig B, Murphy D . A Neuronal Relay Mediates a Nutrient Responsive Gut/Fat Body Axis Regulating Energy Homeostasis in Adult Drosophila. Cell Metab. 2018; 29(2):269-284.e10. PMC: 6370946. DOI: 10.1016/j.cmet.2018.09.021. View

16.

Kida T, Oyama K, Sone M, Koizumi M, Hidema S, Nishimori K . Lgr4 is required for endometrial receptivity acquired through ovarian hormone signaling. Biosci Biotechnol Biochem. 2014; 78(11):1813-6. DOI: 10.1080/09168451.2014.936353. View

17.

Kang Y, Kim J, Yi H, Joung K, Lee J, Kim H . Serum R-Spondin 1 Is a New Surrogate Marker for Obesity and Insulin Resistance. Diabetes Metab J. 2018; 43(3):368-376. PMC: 6581548. DOI: 10.4093/dmj.2018.0066. View

18.

Chen Y, Mao C, Gu R, Zhao R, Li W, Ma Z . Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification. Circ Res. 2022; 131(12):1037-1054. DOI: 10.1161/CIRCRESAHA.122.321614. View

19.

Neufeld S, Rosin J, Ambasta A, Hui K, Shaneman V, Crowder R . A conditional allele of Rspo3 reveals redundant function of R-spondins during mouse limb development. Genesis. 2012; 50(10):741-9. DOI: 10.1002/dvg.22040. View

20.

Koo B, Spit M, Jordens I, Low T, Stange D, van de Wetering M . Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012; 488(7413):665-9. DOI: 10.1038/nature11308. View