The pancreas provides a potential drug candidate for brain disease
Osaka University researchers show FGF21, a factor secreted by the pancreas, promotes
remyelination in the central nervous system after injury
Brain functions are maintained by the neural network. Neural network is formed by theconnection between the neurite, and this connection is supported by the wrapping ofmyelin. Demyelination is detected in the patients of several diseases, such as multiple
sclerosis, and is associated with neurological dysfunctions. A new study in The Journal ofClinical Investigation by scientists at Osaka University shows that fibroblast growth factor(FGF) 21 promotes remyelination in mice and may be a promising key molecule for treating
demyelinating diseases.
In normal development, oligodendrocyte precursor cells (OPCs) differentiate into
oligodendrocytes, which are required for myelination. OPCs will proliferate around thelesions of demyelination after injury and contribute to spontaneous remyelination, but themolecular mechanism of OPCs proliferation is not fully clarified. Osaka University Associate
Professor Rieko Muramatsu focused on the blood leakage around demyelinating lesion.
“Factors in the blood cannot reach the normal brain because central nervous system has
blood-brain barrier. In demyelination diseases like multiple sclerosis, the blood-brain barrieraround the lesion is disrupted,” she said.
Muramatsu suspected that with the breach, factors from peripheral organs secreted into
the blood could now reach the brain.
To test her hypothesis, “We disrupted the vascular barrier and myelin structures in mice byinjecting Lysophosphatidylcholine (LPC). We looked for circulating factors that promote
OPCs proliferation and found FGF21 as a candidate,” she said.
FGF21 is secreted by the pancreas.
Mice treated with LPC showed high levels of FGF21 around demyelinated lesions leading toremyelination. This was not the case in mutant mice that could not express FGF21. Other
mice that received direct administration of FGF21 to demyelinated lesions caused by LPC
injection also showed increased remyelination and better recovery of neurological function.
In addition, the researchers found OPCs expressed higher levels of β–klotho, co-receptor forFGF21, following LPC injection. Without this expression, FGF21 could not promoteremyelination.
“FGF21 is known to regulates metabolism, but its effects on OPC proliferation wereunexpected,” said Muramatsu.
The results suggest that FGF21 has therapeutic potential for demyelinating diseases. FGF21
analogs are already being used for clinical studies on diabetes, which means its
development for remyelination could go faster than had it been an untested compound.

“There are many drugs that inhibit demyelination, but none that promote remyelination.
FGF21 is a new candidate that deserves more testing. The most important finding is that weshow the peripheral milieu promotes central nervous system remyelination.”

Figure 1.Remyelination is promoted by peripheral FGF21. (credit: Osaka University)

Figure 2.FGF21 knockout mice (FGF21 KO) show inhibition of remyelination and functional
recovery after demyelination.

Figure 3.FGF21 treatment promotes human OPC proliferation.
Article: “Peripherally-derived FGF21 promotes remyelination in the central nervous system”
Journal: The Journal of Clinical Investigation
DOI: 10.1172/JCI94337
Authors: Kuroda M, Muramatsu R, Maedera N, Koyama Y, Hamaguchi M, Fujimura H,Yoshida M, Konishi M, Itoh N, Mochizuki H, Yamashita T.
Primary keyword: White matter
Additional keyword(s): Regeneration
Funding: Japan Science and Technology Agency, Japan Society for the Promotion of Science
Grant-in-Aid for Scientific Research (B), Grant-in-Aid for Scientific Research (S), Center for
Gender Equality Promotion at Osaka University