{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Leptin receptor overlapping transcript (LEPROT), also known as OB‐RGRP or endospanin‐1, is an evolutionarily conserved small transmembrane protein that plays a key regulatory role in hormone receptor trafficking and signaling. Experimental studies in mammals have shown that LEPROT functions as a negative modulator of both leptin and growth hormone signaling. For example, overexpression of LEPROT in transgenic mice impairs hepatic growth hormone sensitivity—evidenced by reduced STAT5 phosphorylation and decreased IGF‑1 levels—whereas its silencing increases the cell‐surface presentation of the growth hormone receptor, thereby enhancing downstream signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, analyses of DNA copy number variation at the leptin receptor locus have revealed that structural alterations inversely correlate with leptin receptor (LEPR) expression but positively correlate with LEPROT expression; these findings link LEPROT to metabolic traits such as higher fasting glucose and increased type 2 diabetes risk."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of central energy balance, LEPROT (or endospanin‐1) limits leptin receptor trafficking to the plasma membrane in hypothalamic neurons, thereby contributing to leptin resistance—a key factor in obesity development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, studies in invertebrate models indicate that LEPROT is involved in modulating insulin signaling pathways by maintaining appropriate levels of transcription factors such as FoxO."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its established roles in hormone signaling, emerging evidence across diverse species suggests that LEPROT is implicated in growth regulation and may influence disease processes including cancer. A pan‐cancer analysis revealed that aberrant expression of LEPROT is associated with modifications in the tumor microenvironment—likely via interleukin‐6–mediated JAK/STAT signaling—and may serve as a prognostic marker in certain malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similarly, genome‐wide association studies in livestock have nominated LEPROT as a candidate gene for growth traits, supporting its conserved role in development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Epigenetic studies further corroborate the biological significance of LEPROT regulation, with differential methylation patterns in its promoter region being linked to metabolic parameters such as leptin levels and body mass index in humans."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, LEPROT functions as a key modulator linking nutrient sensing to hormonal and growth factor receptor trafficking. Through its negative regulation of receptor cell‐surface expression, LEPROT influences leptin and growth hormone signaling pathways, thereby impacting energy balance, growth regulation, and potentially tumor progression. Its conserved role across species underscores its importance as a molecular nexus in metabolic regulation.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Thierry Touvier, Françoise Conte-Auriol, Olivier Briand, et al. 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