@article{5b5c1bb0b9cd4b4487667b962196575e,
title = "The central fibroblast growth factor receptor/beta klotho system: Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform",
abstract = "Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1-3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4.",
keywords = "RRID: AB_2109645, RRID: AB_2532109, RRID: AB_839504, beta-klotho, fibroblast growth factors, in situ hybridization, obesity, type 2 diabetes",
author = "Karin Hultman and Scarlett, {Jarrad M.} and Baquero, {Arian F.} and Anda Cornea and Yu Zhang and Salinas, {Casper B.G.} and Jenny Brown and Morton, {Gregory J.} and Whalen, {Erin J.} and Grove, {Kevin L.} and Koegler, {Frank H.} and Schwartz, {Michael W.} and Mercer, {Aaron J.}",
note = "Funding Information: This research was funded by a collaborative partnership between Novo Nordisk (K.L.G, F.H.K.) and the University of Washington (M.W. S. grant number CMS-431104), as well as NIH grants F32 DK104461 (J.M.S.), R01 DK083042 (M.W.S.), and R01 DK101997 (M.W.S.). Funding Information: K.H., A.F.B., A.C., Y.Z., C.B.G.S., E.J.W., F.H.K., K.L.G., and A.J.M. are employees of Novo Nordisk, which develops, manufactures, and markets therapeutics for the treatment of diabetes and obesity. M.W.S. is a recipient of an early drug discovery grant from Novo Nordisk for the treatment of diabetes and obesity. J.M.S., J.B., and G.J.M. have no conflicts of interest. Funding Information: information National Institutes of Health (NIH), Grant/Award Numbers: R01 DK101997, R01 DK083042, F32 DK104461; Novo Nordisk, Grant/Award Number: CMS-431104The authors would like to acknowledge Pia Mortensen (Novo Nordisk A/S), Deanna Saxbe (Novo Nordisk Research Center Seattle, Inc.), and Jeanette Bannebjerg Johansen (Novo Nordisk A/S) for expert technical assistance. Dr. Jacob Hecksher-Sorenson (Gubra), Dr. Anna Secher (Novo Nordisk A/S), Dr. Birgitte Andersen (Novo Nordisk, A/S), Dr. Sebastian Parlee (Novo Nordisk Research Center Indianapolis, Inc.), and Dr. Alexei Kharitonenkov (Novo Nordisk Research Center Indianapolis, Inc.) provided many valuable discussions during the development and analysis of this project. We would also like to thank Dr. Paul Kievit (OHSU) for providing nonhuman primate samples, and the Edinburgh Brain and Tissue Bank for providing human brain tissue samples. Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",
year = "2019",
month = aug,
day = "15",
doi = "10.1002/cne.24668",
language = "English (US)",
volume = "527",
pages = "2069--2085",
journal = "Journal of Comparative Neurology",
issn = "0021-9967",
publisher = "Wiley-Liss Inc.",
number = "12",
}