{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Insulin‐like peptide 5 (INSL5) is a member of the insulin/relaxin superfamily that is predominantly produced by colonic enteroendocrine L‐cells and acts as an endogenous ligand for the relaxin family peptide receptor 4 (RXFP4; also referred to as GPCR142)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Binding studies have demonstrated that INSL5 interacts with its receptor with high affinity and triggers signaling cascades that include inhibition of cyclic AMP accumulation as well as activation of kinases such as ERK1/2 and Akt, thereby implicating it in the regulation of metabolic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n INSL5 levels have been reported to vary with nutritional status, and in rodent models it can act as an orexigenic hormone—its circulating concentration is elevated during fasting and reduced following feeding, contributing to increased food intake during energy deprivation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition to its metabolic role, genetic ablation studies in mice have revealed that loss of INSL5 results in impaired insulin secretion, reduced β‐cell mass, and subfertility characterized by defects in sperm motility and irregular estrous cycles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, INSL5 is expressed in discrete regions of the central nervous system—including the hypothalamus and pituitary—where it modulates intracellular Ca²⁺ signaling in vasopressin neurons, suggesting additional neuroendocrine functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structure–activity relationship studies have identified key residues—particularly on the B‐chain—that are essential for receptor binding and activation, enabling the design of potent analogues and peptidomimetics with improved pharmacological properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In addition, aberrant INSL5 expression has been observed in certain cancers, where it may contribute to tumor progression by promoting glycolytic reprogramming and cell invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, circulating INSL5 has been linked to alterations in metabolic and hormonal parameters in human conditions such as polycystic ovary syndrome, and it may also modulate sperm function by reducing mitochondrial reactive oxygen species."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, INSL5 is a multifunctional gut‐derived hormone that, through activation of RXFP4, participates in the regulation of appetite, glucose homeostasis, reproductive physiology, and potentially tumor biology. Its diverse roles and the ongoing elucidation of its structural determinants provide promising avenues for the development of targeted therapeutics in metabolic, reproductive, and neoplastic disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Changlu Liu, Chester Kuei, Steven Sutton, et al. "}, {"type": "b", "children": [{"type": "t", "text": "INSL5 is a high affinity specific agonist for GPCR142 (GPR100)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M409916200"}], "href": "https://doi.org/10.1074/jbc.M409916200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15525639"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15525639"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hirosato Mashima, Hideki Ohno, Yumi Yamada, et al. 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