LGR4: A New Receptor Member in Endocrine and Metabolic Diseases

Abstract

Classic hormone membrane receptors, such as leucine-rich repeat-containing G protein-coupled receptor (LGR) 1 (follicle-stimulating hormone receptor/FSHR), LGR2 (luteinizing hormone receptor/LHR), and LGR3 (thyrotropin receptor/TSHR), 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 expression and function ways 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 highlighted LGR4 dysfunction in clinical diseases, animal models, and pathophysiological changes, discussed about their known ligands and downstream signalling pathways, and identified unresolved questions and future perspectives of this new receptor.

Ctnnb1/β-catenin inactivation in UCP1-positive adipocytes augments the browning of white adipose tissue

“… 15 Changes in its activity have been linked to obesity and other metabolic diseases. 16 , 17 Recently, we found that Ctnnb1 deficiency in mature adipocytes could resist high-fat diet-induced obesity without affecting adipocyte identity, which was consistent with recent findings from the MacDougald group. 18 , 19 Canonical WNT pathway agonists could inhibit the expression of Ucp1 in mature brown adipocytes without affecting other differentiation-related genes, such as Ppar γ , C/ebpα , and Fabp4 , 20 while it is noteworthy that Adiponectin -cre-driven Ctnnb1 knockout in BAT has no impact on the expression of Ucp1 , 19 which is the key effector of adaptive thermogenesis.…”

“…The canonical WNT pathway has been shown to influence adipogenesis, obesity, and fat distribution. 16 , 17 A substantial body of literature has focused on the inhibitory effects of canonical WNT signaling during the early stages of adipogenesis. 38 , 39 , 40 In our recent study, we discovered that β-catenin in mature adipocytes exacerbated adipose tissue expansion by regulating the crosstalk among mature adipocytes, macrophages, and preadipocytes during the development of obesity.…”

“… 21 In addition, genetic variations in LRP5 , RSPO3 , and ZNRF3 have been implicated in association with waist-hip ratio (WHR). 16 , 22 , 23 , 24 The serial evidence indicates that components of the canonical WNT pathway play similar roles in adipogenesis but differ in their functions during various stages of adipocyte differentiation. However, the potential role of Ctnnb1 in the process of WAT browning has not been explored.…”

Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice

“…Downstream signaling mediated by LGR4 primarily includes cAMP/PKA, Wnt/β-catenin, Gαq/GSK3β and Gαq/ PKCα signaling pathways. In addition, LGR4 can regulate AKT, extracellular signal-regulated kinase (ERK), and nuclear factor kappa-B (NF-κB) pathways 26 . However, how these signaling pathways regulate intestine epithelium remains unclear, and needs further exploration.…”

Osteoporotic osseointegration: therapeutic hallmarks and engineering strategies

“…Insulin resistance in bone tissue hampers glucose uptake and increases blood glucose levels, thereby impairing Runx2 activity and osteogenic differentiation. In addition, reduced glucose uptake diminishes acetyl-CoA levels and the TCA cycle, which play crucial roles in the posttranslational acetylation and transcriptional activity of osterix and Runx2 43 . Importantly, disrupted glucose metabolism caused by insulin resistance reduces the energy available for physiological processes such as osteoblast differentiation, bone-related protein secretion, and biomineralization.…”