Novel metabolic role for BDNF in pancreatic β-cell insulin secretion.
Animals
Brain-Derived Neurotrophic Factor
/ genetics
Calcium
/ metabolism
Cells, Cultured
Glucose
/ metabolism
Glucose Intolerance
Humans
Insulin Secretion
Insulin-Secreting Cells
/ metabolism
Islets of Langerhans
/ metabolism
Male
Mice
Mice, Knockout
Muscle Fibers, Skeletal
/ metabolism
Protein Isoforms
/ genetics
Receptor, trkB
/ chemistry
Signal Transduction
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 04 2020
23 04 2020
Historique:
received:
25
06
2019
accepted:
26
03
2020
entrez:
25
4
2020
pubmed:
25
4
2020
medline:
1
8
2020
Statut:
epublish
Résumé
BDNF signaling in hypothalamic circuitries regulates mammalian food intake. However, whether BDNF exerts metabolic effects on peripheral organs is currently unknown. Here, we show that the BDNF receptor TrkB.T1 is expressed by pancreatic β-cells where it regulates insulin release. Mice lacking TrkB.T1 show impaired glucose tolerance and insulin secretion. β-cell BDNF-TrkB.T1 signaling triggers calcium release from intracellular stores, increasing glucose-induced insulin secretion. Additionally, BDNF is secreted by skeletal muscle and muscle-specific BDNF knockout phenocopies the β-cell TrkB.T1 deletion metabolic impairments. The finding that BDNF is also secreted by differentiated human muscle cells and induces insulin secretion in human islets via TrkB.T1 identifies a new regulatory function of BDNF on metabolism that is independent of CNS activity. Our data suggest that muscle-derived BDNF may be a key factor mediating increased glucose metabolism in response to exercise, with implications for the treatment of diabetes and related metabolic diseases.
Identifiants
pubmed: 32327658
doi: 10.1038/s41467-020-15833-5
pii: 10.1038/s41467-020-15833-5
pmc: PMC7181656
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Protein Isoforms
0
Receptor, trkB
EC 2.7.10.1
Glucose
IY9XDZ35W2
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1950Subventions
Organisme : NIDDK NIH HHS
ID : U24 DK098085
Pays : United States
Références
Rorsman, P. & Braun, M. Regulation of insulin secretion in human pancreatic islets. Annu. Rev. Physiol. 75, 155–179 (2013).
pubmed: 22974438
doi: 10.1146/annurev-physiol-030212-183754
Huang, E. J. & Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).
pubmed: 12676795
doi: 10.1146/annurev.biochem.72.121801.161629
Minichiello, L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 10, 850–860 (2009).
pubmed: 19927149
doi: 10.1038/nrn2738
Tessarollo, L. Pleiotropic functions of neurotrophins in development. Cytokine Growth Factor Rev. 9, 125–137 (1998).
pubmed: 9754707
doi: 10.1016/S1359-6101(98)00003-3
Chao, M. V., Rajagopal, R. & Lee, F. S. Neurotrophin signalling in health and disease. Clin. Sci. 110, 167–173 (2006).
pubmed: 16411893
doi: 10.1042/CS20050163
pmcid: 16411893
Gray, J. et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 55, 3366–3371 (2006).
pubmed: 17130481
pmcid: 2413291
doi: 10.2337/db06-0550
Xu, B. & Xie, X. Neurotrophic factor control of satiety and body weight. Nat. Rev. Neurosci. 17, 282–292 (2016).
pubmed: 27052383
pmcid: 4898883
doi: 10.1038/nrn.2016.24
Yeo, G. S. et al. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nat. Neurosci. 7, 1187–1189 (2004).
pubmed: 15494731
doi: 10.1038/nn1336
pmcid: 15494731
Rios, M. BDNF and the central control of feeding: accidental bystander or essential player? Trends Neurosci. 36, 83–90 (2013).
pubmed: 23333344
pmcid: 3568936
doi: 10.1016/j.tins.2012.12.009
Tonra, J. R. et al. Brain-derived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/lepr(db) mice. Diabetes 48, 588–594 (1999).
pubmed: 10078561
doi: 10.2337/diabetes.48.3.588
Dupont-Versteegden, E. E. et al. Exercise-induced gene expression in soleus muscle is dependent on time after spinal cord injury in rats. Muscle Nerve 29, 73–81 (2004).
pubmed: 14694501
doi: 10.1002/mus.10511
Gomez-Pinilla, F., Ying, Z., Opazo, P., Roy, R. R. & Edgerton, V. R. Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle. Eur. J. Neurosci. 13, 1078–1084 (2001).
pubmed: 11285004
doi: 10.1046/j.0953-816x.2001.01484.x
Matthews, V. B. et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 52, 1409–1418 (2009).
pubmed: 19387610
doi: 10.1007/s00125-009-1364-1
Chacon-Fernandez, P. et al. Brain-derived neurotrophic factor in megakaryocytes. J. Biol. Chem. 291, 9872–9881 (2016).
pubmed: 27006395
pmcid: 4858990
doi: 10.1074/jbc.M116.720029
Fujimura, H. et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb. Haemost. 87, 728–734 (2002).
pubmed: 12008958
doi: 10.1055/s-0037-1613072
pmcid: 12008958
Lommatzsch, M. et al. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol. Aging 26, 115–123 (2005).
pubmed: 15585351
doi: 10.1016/j.neurobiolaging.2004.03.002
pmcid: 15585351
Stoilov, P., Castren, E. & Stamm, S. Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem. Biophys. Res. Commun. 290, 1054–1065 (2002).
pubmed: 11798182
doi: 10.1006/bbrc.2001.6301
pmcid: 11798182
Eizirik, D. L. et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 8, e1002552 (2012).
pubmed: 22412385
pmcid: 3297576
doi: 10.1371/journal.pgen.1002552
Kitamura, T. The role of FOXO1 in beta-cell failure and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 9, 615–623 (2013).
pubmed: 23959366
doi: 10.1038/nrendo.2013.157
pmcid: 23959366
Fulgenzi, G. et al. BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation. J. Cell Biol. 210, 1003–1012 (2015).
pubmed: 26347138
pmcid: 4576863
doi: 10.1083/jcb.201502100
Rose, C. R. et al. Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426, 74–78 (2003).
pubmed: 14603320
doi: 10.1038/nature01983
pmcid: 14603320
Zariwala, H. A. et al. A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo. J. Neurosci. 32, 3131–3141 (2012).
pubmed: 22378886
pmcid: 3315707
doi: 10.1523/JNEUROSCI.4469-11.2012
Gilon, P., Chae, H. Y., Rutter, G. A. & Ravier, M. A. Calcium signaling in pancreatic beta-cells in health and in Type 2 diabetes. Cell Calcium 56, 340–361 (2014).
pubmed: 25239387
doi: 10.1016/j.ceca.2014.09.001
pmcid: 25239387
Gilon, P. & Henquin, J. C. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr. Rev. 22, 565–604 (2001).
pubmed: 11588141
pmcid: 11588141
Poitout, V. et al. Morphological and functional characterization of beta TC-6 cells—an insulin-secreting cell line derived from transgenic mice. Diabetes 44, 306–313 (1995).
pubmed: 7533732
doi: 10.2337/diab.44.3.306
pmcid: 7533732
Teillon, S., Calderon, G. A. & Rios, M. Diminished diet-induced hyperglycemia and dyslipidemia and enhanced expression of PPARalpha and FGF21 in mice with hepatic ablation of brain-derived neurotropic factor. J. Endocrinol. 205, 37–47 (2010).
pubmed: 20097691
doi: 10.1677/JOE-09-0405
pmcid: 20097691
McMahon, D. K. et al. C2C12 cells: biophysical, biochemical, and immunocytochemical properties. Am. J. Physiol. 266, C1795–1802 (1994).
pubmed: 8023908
doi: 10.1152/ajpcell.1994.266.6.C1795
pmcid: 8023908
Cuppini, R. et al. BDNF expression in rat skeletal muscle after acute or repeated exercise. Arch. Ital. Biol. 145, 99–110 (2007).
pubmed: 17639782
pmcid: 17639782
Ogborn, D. I. & Gardiner, P. F. Effects of exercise and muscle type on BDNF, NT-4/5, and TrKB expression in skeletal muscle. Muscle Nerve 41, 385–391 (2010).
pubmed: 19813200
doi: 10.1002/mus.21503
pmcid: 19813200
Mousavi, K. & Jasmin, B. J. BDNF is expressed in skeletal muscle satellite cells and inhibits myogenic differentiation. J. Neurosci. 26, 5739–5749 (2006).
pubmed: 16723531
pmcid: 6675269
doi: 10.1523/JNEUROSCI.5398-05.2006
Lyons, W. E. et al. Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc. Natl Acad. Sci. USA 96, 15239–15244 (1999).
pubmed: 10611369
doi: 10.1073/pnas.96.26.15239
Yang, H., An, J. J., Sun, C. & Xu, B. Regulation of energy balance via BDNF expressed in nonparaventricular hypothalamic neurons. Mol. Endocrinol. 30, 494–503 (2016).
pubmed: 27003443
pmcid: 4853567
doi: 10.1210/me.2015-1329
Radka, S. F., Holst, P. A., Fritsche, M. & Altar, C. A. Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res. 709, 122–301 (1996).
pubmed: 8869564
doi: 10.1016/0006-8993(95)01321-0
Naegelin, Y. et al. Measuring and validating the levels of brain-derived neurotrophic factor in human serum. eNeuro https://doi.org/10.1523/ENEURO.0419-17.2018 (2018).
Ono, M. et al. Brain-derived neurotrophic factor reduces blood glucose level in obese diabetic mice but not in normal mice. Biochem. Biophys. Res. Commun. 238, 633–637 (1997).
pubmed: 9299565
doi: 10.1006/bbrc.1997.7220
Hanyu, O. et al. Brain-derived neurotrophic factor modulates glucagon secretion from pancreatic alpha cells: its contribution to glucose metabolism. Diabetes Obes. Metab. 5, 27–37 (2003).
pubmed: 12542722
doi: 10.1046/j.1463-1326.2003.00238.x
pmcid: 12542722
Gilon, P., Jonas, J. C. & Henquin, J. C. Culture duration and conditions affect the oscillations of cytoplasmic calcium concentration induced by glucose in mouse pancreatic islets. Diabetologia 37, 1007–1014 (1994).
pubmed: 7851679
doi: 10.1007/BF00400464
pmcid: 7851679
Fernandes, B. S. et al. Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med. 13, 289 (2015).
pubmed: 26621529
pmcid: 4666054
doi: 10.1186/s12916-015-0529-7
Kaess, B. M. et al. Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community. J. Am. Heart Assoc. 4, e001544 (2015).
pubmed: 25762803
pmcid: 4392437
doi: 10.1161/JAHA.114.001544
Munkholm, K., Vinberg, M. & Kessing, L. V. Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis. Mol. Psychiatry 21, 216–228 (2016).
pubmed: 26194180
doi: 10.1038/mp.2015.54
pmcid: 26194180
Sandrini, L. et al. Association between obesity and circulating brain-derived neurotrophic factor (BDNF) levels: systematic review of literature and meta-analysis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19082281 (2018).
Qin, X. Y. et al. Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer’s disease: a meta-analysis study (N=7277). Mol. Psychiatry 22, 312–320 (2017).
pubmed: 27113997
doi: 10.1038/mp.2016.62
pmcid: 27113997
Dorsey, S. G. et al. In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model. Neuron 51, 21–28 (2006).
pubmed: 16815329
doi: 10.1016/j.neuron.2006.06.009
pmcid: 16815329
Liebl, D. J., Klesse, L. J., Tessarollo, L., Wohlman, T. & Parada, L. F. Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice. Proc. Natl Acad. Sci. USA 97, 2297–2302 (2000).
pubmed: 10681461
doi: 10.1073/pnas.040562597
pmcid: 10681461
Thorens, B. et al. Ins1(Cre) knock-in mice for beta cell-specific gene recombination. Diabetologia 58, 558–565 (2015).
pubmed: 25500700
doi: 10.1007/s00125-014-3468-5
pmcid: 25500700
Rios, M. et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Mol. Endocrinol. 15, 1748–1757 (2001).
pubmed: 11579207
doi: 10.1210/mend.15.10.0706
pmcid: 11579207
Marciniak, A. et al. Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology. Nat. Protoc. 9, 2809–2822 (2014).
pubmed: 25393778
doi: 10.1038/nprot.2014.195
pmcid: 25393778
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
pubmed: 22743772
pmcid: 22743772
doi: 10.1038/nmeth.2019
Zhu, L. et al. beta-arrestin-2 is an essential regulator of pancreatic beta-cell function under physiological and pathophysiological conditions. Nat. Commun. 8, 14295 (2017).
pubmed: 28145434
pmcid: 5296650
doi: 10.1038/ncomms14295
Golson, M. L., Bush, W. S. & Brissova, M. Automated quantification of pancreatic beta-cell mass. Am. J. Physiol. Endocrinol. Metab. 306, E1460–1467 (2014).
pubmed: 24760991
pmcid: 4059986
doi: 10.1152/ajpendo.00591.2013