{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Beta‐Klotho (KLB) is a single‐pass transmembrane protein that functions as an essential co‐receptor for endocrine fibroblast growth factors (FGFs), notably FGF21 and FGF19. By forming complexes with specific FGF receptors (FGFRs), beta‐Klotho enables these ligands to bind with high affinity and activate their downstream signaling pathways in a tissue‐selective fashion. In adipocytes, for example, beta‐Klotho partners predominantly with FGFR1c to mediate FGF21’s insulin‐sensitizing, energy‐expenditure–enhancing, and “browning” effects on white fat; conversely, in the liver beta‐Klotho couples with FGFR4 to facilitate FGF19’s regulation of bile acid synthesis and metabolic processes. Structural studies have revealed that beta‐Klotho acts as a “zip code”–like targeting subunit that compensates for the low heparin affinity of these hormones, thereby conferring endocrine functionality to FGFs. Moreover, domain mapping has shown that the C‐terminus of FGF21 is critical for its direct binding to beta‐Klotho, while intact beta‐Klotho expression in target tissues is required for full ligand activity, as genetic deletion or tissue‐selective knockouts of beta‐Klotho markedly attenuate FGF21 and FGF19 signaling. Collectively, these findings indicate that beta‐Klotho is a key determinant of the specificity and efficacy of endocrine FGF signaling in the regulation of whole‐body metabolic homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yasushi Ogawa, Hiroshi Kurosu, Masaya Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "BetaKlotho is required for metabolic activity of fibroblast growth factor 21."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0701600104"}], "href": "https://doi.org/10.1073/pnas.0701600104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17452648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17452648"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Masashi Suzuki, Yuriko Uehara, Kaori Motomura-Matsuzaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2007-0313"}], "href": "https://doi.org/10.1210/me.2007-0313"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18187602"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18187602"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alexei Kharitonenkov, James D Dunbar, Holly A Bina, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Metab (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cmet.2012.08.002"}], "href": "https://doi.org/10.1016/j.cmet.2012.08.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22958921"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22958921"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sangwon Lee, Jungyuen Choi, Jyotidarsini Mohanty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures of β-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature25010"}], "href": "https://doi.org/10.1038/nature25010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29342135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29342135"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Chaofeng Yang, Chengliu Jin, Xiaokun Li, et al. 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