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.
| Original language | English (US) |
|---|---|
| Journal | Journal of Comparative Neurology |
| DOIs | |
| State | Published - Jan 1 2019 |
| Externally published | Yes |
Fingerprint
Keywords
- beta-klotho
- fibroblast growth factors
- in situ hybridization
- obesity
- RRID: AB_2109645
- RRID: AB_2532109
- RRID: AB_839504
- type 2 diabetes
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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. / Hultman, Karin; Scarlett, Jarrad M.; Baquero, Arian F.; Cornea, Anda; Zhang, Yu; Salinas, Casper B.G.; Brown, Jenny; Morton, Gregory J.; Whalen, Erin J.; Grove, Kevin; Koegler, Frank H.; Schwartz, Michael W.; Mercer, Aaron J.
In: Journal of Comparative Neurology, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The central fibroblast growth factor receptor/beta klotho system
T2 - Comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform
AU - Hultman, Karin
AU - Scarlett, Jarrad M.
AU - Baquero, Arian F.
AU - Cornea, Anda
AU - Zhang, Yu
AU - Salinas, Casper B.G.
AU - Brown, Jenny
AU - Morton, Gregory J.
AU - Whalen, Erin J.
AU - Grove, Kevin
AU - Koegler, Frank H.
AU - Schwartz, Michael W.
AU - Mercer, Aaron J.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - beta-klotho
KW - fibroblast growth factors
KW - in situ hybridization
KW - obesity
KW - RRID: AB_2109645
KW - RRID: AB_2532109
KW - RRID: AB_839504
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85062768118&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062768118&partnerID=8YFLogxK
U2 - 10.1002/cne.24668
DO - 10.1002/cne.24668
M3 - Article
C2 - 30809795
AN - SCOPUS:85062768118
JO - Journal of Comparative Neurology
JF - Journal of Comparative Neurology
SN - 0021-9967
ER -