{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The growth hormone receptor (GHR) is a critical mediator of growth hormone (GH) signaling that regulates somatic growth, metabolism, and tissue homeostasis. In the liver, GHR‐mediated pathways are essential for maintaining glucose homeostasis and promoting insulin‐regulated IGF‐I synthesis; disruption of these pathways, as evidenced by decreased Ghr expression in insulin‐resistant mouse models, contributes to abnormal metabolic regulation and impaired somatic growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In skeletal muscle, reductions in GHR expression are linked to diminished anabolic signaling and sarcopenia in aging individuals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Genetic polymorphisms in the GHR gene, particularly the deletion of exon 3 (d3‐GHR), have been shown to modulate the growth response to exogenous GH therapy in various clinical populations including Turner syndrome, children born small for gestational age, and GH‐deficient patients; carriers of the d3‐GHR allele often exhibit enhanced growth velocity and increased IGF‐I generation, although some studies report no significant differences in growth outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " In acromegaly and during early pubertal development, the d3‐GHR isoform has been associated with discrepancies between circulating GH and IGF‐I levels as well as with augmented IGF‐I concentrations, underscoring its role in fine‐tuning endocrine responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, experimental evidence in human hepatoma cells suggests that insulin resistance may impair the insulin‐induced upregulation of GHR expression, a mechanism that could contribute to the metabolic alterations observed in conditions such as nonalcoholic fatty liver disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " At the molecular level, the structural integrity of GHR, including its N‐terminal FERM domain responsible for association with Janus kinase 2 (JAK2), is vital for efficient GH signal transduction and subsequent activation of downstream pathways that control growth and metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiaocheng C Dong, Kyle D Copps, Shaodong Guo, et al. 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