Role of hypothalamic MAPK/ERK signaling and central action of FGF1 in diabetes remission

Jenny M. Brown, Marie A. Bentsen, Dylan M. Rausch, Bao Anh Phan, Danielle Wieck, Huzaifa Wasanwala, Miles E. Matsen, Nikhil Acharya, Nicole E. Richardson, Xin Zhao, Peng Zhai, Anna Secher, Gregory J. Morton, Tune H. Pers, Michael W. Schwartz, Jarrad M. Scarlett*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

17 Citationer (Scopus)
37 Downloads (Pure)

Abstract

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family, is induced for at least 24 h. Further, we show that this prolonged response is required for the sustained antidiabetic action of FGF1 since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

OriginalsprogEngelsk
Artikelnummer102944
TidsskriftiScience
Vol/bind24
Udgave nummer9
Antal sider19
ISSN2589-0042
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
The authors are grateful for the technical assistance provided Helle Kinggaard Lilja-Fischer, Cecilia Ratner, Birgitte Holst, and the Single-cell Omics Platform at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. The authors thank Nathanial Peters at the University of Washington Keck Imaging Center for technical assistance and the National Institutes of Health (S10-OD-016240) for support to the W.M. Keck Foundation Center for Advanced Studies in Neural Signaling. J.M.B. was supported by National Heart, Lung, and Blood Institute T32 training grant HL-007312 and the Diabetes Research Center Samuel and Althea Stroum Endowed Graduate Fellowship, and H.W. was supported by the NIDDK-funded Diabetes, Obesity and Metabolism Training Grant (T32 DK007247) at the University of Washington. This work was supported by NIH-NIDDK grants: K08DK114474 (J.M.S.), R01DK101997 (M.W.S.), R01DK089056 (G.J.M.), R01DK083042 (G.J.M. and M.W.S.), and an American Diabetes Association Innovative Basic Science Award (ADA; G.J.M.). This work was also supported by the NIH-NIDDK?funded Nutrition Obesity Research Center (NORC; P30DK035816) and the Diabetes Research Center (DRC; P30DK017047) at the University of Washington. Additional funding to support these studies was provided to J.M.S. by the UW Royalty Research Fund (RRF; A139339) and to T.H.P. by the Lundbeck Foundation (Grant number R190-2014-3904). Funding was also provided to M.W.S. by Novo Nordisk (CMS-431104) and to M.A.B. by the Novo Nordisk Foundation (NNF17OC0024328) and the Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF10CC1016515). J.M.B. M.W.S. and J.M.S. conceived the project. J.M.B. M.A.B. T.H.P. M.W.S. and J.M.S. designed the experiments. J.M.B. M.A.B. D.M.R. B.A.P. D.W. H.W. M.E.M. N.E.R. and J.M.S. performed the experiments. J.M.B. M.A.B. D.M.R. B.A.P. X.Z. P.Z. A.S. G.J.M, T.H.P. M.W.S. and J.M.S. acquired, analyzed, and interpreted the data. J.M.B. M.A.B. D.M.R. M.W.S. and J.M.S. drafted and revised the manuscript. All authors approved the final version of the manuscript. J.M.S. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.

Funding Information:
The authors are grateful for the technical assistance provided Helle Kinggaard Lilja-Fischer, Cecilia Ratner, Birgitte Holst, and the Single-cell Omics Platform at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen. The authors thank Nathanial Peters at the University of Washington Keck Imaging Center for technical assistance and the National Institutes of Health ( S10-OD-016240 ) for support to the W.M. Keck Foundation Center for Advanced Studies in Neural Signaling. J.M.B. was supported by National Heart, Lung, and Blood Institute T32 training grant HL-007312 and the Diabetes Research Center Samuel and Althea Stroum Endowed Graduate Fellowship, and H.W. was supported by the NIDDK-funded Diabetes, Obesity and Metabolism Training Grant ( T32 DK007247 ) at the University of Washington. This work was supported by NIH-NIDDK grants: K08DK114474 (J.M.S.), R01DK101997 (M.W.S.), R01DK089056 (G.J.M.), R01DK083042 (G.J.M. and M.W.S.), and an American Diabetes Association Innovative Basic Science Award (ADA; G.J.M.). This work was also supported by the NIH-NIDDK–funded Nutrition Obesity Research Center (NORC; P30DK035816) and the Diabetes Research Center (DRC; P30DK017047 ) at the University of Washington. Additional funding to support these studies was provided to J.M.S. by the UW Royalty Research Fund (RRF; A139339 ) and to T.H.P. by the Lundbeck Foundation (Grant number R190-2014-3904 ). Funding was also provided to M.W.S. by Novo Nordisk ( CMS-431104 ) and to M.A.B. by the Novo Nordisk Foundation ( NNF17OC0024328 ) and the Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( NNF10CC1016515 ).

Publisher Copyright:
© 2021 The Authors

Citationsformater