A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

Cell Reports

Volumn 17, Issue 7, 2016, Pages 1795-1806

  Picard, Alexandre ^a   Soyer, Josselin ^a   Berney, Xavier ^a   Tarussio, David ^a   Quenneville, Simon ^a   Jan, Maxime ^b   Grouzmann, Eric ^c   Burdet, Frédéric ^b   Ibberson, Mark ^b   Thorens, Bernard ^a  

^a UNIVERSITY OF LAUSANNE   (Switzerland)

^b SWISS INSTITUTE OF BIOINFORMATICS   (Switzerland)

^c LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

Author keywords

autonomic nervous system; dorsal vagal complex; FGF15; FGF19; genetic screen; glucagon secretion; glucose sensing; hypothalamus; neuroglucopenia; QTL mapping

Indexed keywords

MESSENGER RNA; DEOXYGLUCOSE; FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR 15, MOUSE; GLUCAGON;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CHROMOSOME 7; CONTROLLED STUDY; DORSOMEDIAL HYPOTHALAMIC NUCLEUS; FGF15 GENE; FIRING RATE; GENE EXPRESSION; GENE IDENTIFICATION; GENE SILENCING; GENETIC SCREENING; GENOME ANALYSIS; GLUCAGON RELEASE; MALE; MOUSE; NEUROGLUCOPENIA; NEUROLOGIC DISEASE; NONHUMAN; PARASYMPATHETIC NERVE; PARASYMPATHETIC TONE; PRIORITY JOURNAL; QUANTITATIVE TRAIT LOCUS; REGULATOR GENE; RNA SEQUENCE; TRANSCRIPTOMICS; VAGUS NERVE; VAGUS NERVE DORSAL NUCLEUS; AGING; ANIMAL; C57BL MOUSE; CHOLINERGIC SYSTEM; CHROMOSOME; DRUG EFFECTS; GENETICS; GENOME; HYPOTHALAMUS; METABOLISM; SECRETION (PROCESS);

AGING; ANIMALS; CHROMOSOMES, MAMMALIAN; DEOXYGLUCOSE; FIBROBLAST GROWTH FACTORS; GENE SILENCING; GENETIC TESTING; GENOME; GLUCAGON; HYPOTHALAMUS; MICE, INBRED C57BL; PARASYMPATHETIC NERVOUS SYSTEM; QUANTITATIVE TRAIT LOCI;

EID: 84994462725     PISSN: None     EISSN: 22111247     Source Type: Journal    
DOI: 10.1016/j.celrep.2016.10.041     Document Type: Article

References (49)

1. Alquier, T., Kawashima, J., Tsuji, Y., Kahn, B.B., Role of hypothalamic adenosine 5′-monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia. Endocrinology 148 (2007), 1367–1375.
2. Andreux, P.A., Williams, E.G., Koutnikova, H., Houtkooper, R.H., Champy, M.F., Henry, H., Schoonjans, K., Williams, R.W., Auwerx, J., Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell 150 (2012), 1287–1299.
3. Berthoud, H.R., Fox, E.A., Powley, T.L., Localization of vagal preganglionics that stimulate insulin and glucagon secretion. Am. J. Physiol. 258 (1990), R160–R168.
4. Broman, K.W., Sen, S., A Guide to QTL Mapping with R/qtl. 2009, Springer.
5. Burcelin, R., Crivelli, V., Dacosta, A., Roy-Tirelli, A., Thorens, B., Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet. Am. J. Physiol. Endocrinol. Metab. 282 (2002), E834–E842.
6. Chan, O., Sherwin, R., Influence of VMH fuel sensing on hypoglycemic responses. Trends Endocrinol. Metab. 24 (2013), 616–624.
7. Chesler, E.J., Lu, L., Wang, J., Williams, R.W., Manly, K.F., WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior. Nat. Neurosci. 7 (2004), 485–486.
8. Cryer, P.E., Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N. Engl. J. Med. 369 (2013), 362–372.
9. Dunand, M., Gubian, D., Stauffer, M., Abid, K., Grouzmann, E., High-throughput and sensitive quantitation of plasma catecholamines by ultraperformance liquid chromatography-tandem mass spectrometry using a solid phase microwell extraction plate. Anal. Chem. 85 (2013), 3539–3544.
10. Evans, M.L., McCrimmon, R.J., Flanagan, D.E., Keshavarz, T., Fan, X., McNay, E.C., Jacob, R.J., Sherwin, R.S., Hypothalamic ATP-sensitive K + channels play a key role in sensing hypoglycemia and triggering counterregulatory epinephrine and glucagon responses. Diabetes 53 (2004), 2542–2551.
11. Franken, P., Chollet, D., Tafti, M., The homeostatic regulation of sleep need is under genetic control. J. Neurosci. 21 (2001), 2610–2621.
12. Frizzell, R.T., Jones, E.M., Davis, S.N., Biggers, D.W., Myers, S.R., Connolly, C.C., Neal, D.W., Jaspan, J.B., Cherrington, A.D., Counterregulation during hypoglycemia is directed by widespread brain regions. Diabetes 42 (1993), 1253–1261.
13. Houtkooper, R.H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., Williams, R.W., Auwerx, J., Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497 (2013), 451–457.
14. Inagaki, T., Choi, M., Moschetta, A., Peng, L., Cummins, C.L., McDonald, J.G., Luo, G., Jones, S.A., Goodwin, B., Richardson, J.A., et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2 (2005), 217–225.
15. Jackson, P.A., Cardin, S., Coffey, C.S., Neal, D.W., Allen, E.J., Penaloza, A.R., Snead, W.L., Cherrington, A.D., Effect of hepatic denervation on the counterregulatory response to insulin-induced hypoglycemia in the dog. Am. J. Physiol. Endocrinol. Metab. 279 (2000), E1249–E1257.
16. Jung, D., Inagaki, T., Gerard, R.D., Dawson, P.A., Kliewer, S.A., Mangelsdorf, D.J., Moschetta, A., FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J. Lipid Res. 48 (2007), 2693–2700.
17. Karnani, M., Burdakov, D., Multiple hypothalamic circuits sense and regulate glucose levels. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300 (2011), R47–R55.
18. Kir, S., Beddow, S.A., Samuel, V.T., Miller, P., Previs, S.F., Suino-Powell, K., Xu, H.E., Shulman, G.I., Kliewer, S.A., Mangelsdorf, D.J., FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331 (2011), 1621–1624.
19. Koutnikova, H., Laakso, M., Lu, L., Combe, R., Paananen, J., Kuulasmaa, T., Kuusisto, J., Häring, H.U., Hansen, T., Pedersen, O., et al. Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics. PLoS Genet., 5, 2009, e1000591.
20. Lamy, C.M., Sanno, H., Labouèbe, G., Picard, A., Magnan, C., Chatton, J.Y., Thorens, B., Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab. 19 (2014), 527–538.
21. Levin, B.E., Becker, T.C., Eiki, J., Zhang, B.B., Dunn-Meynell, A.A., Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia. Diabetes 57 (2008), 1371–1379.
22. Magnan, C., Collins, S., Berthault, M.F., Kassis, N., Vincent, M., Gilbert, M., Pénicaud, L., Ktorza, A., Assimacopoulos-Jeannet, F., Lipid infusion lowers sympathetic nervous activity and leads to increased beta-cell responsiveness to glucose. J. Clin. Invest. 103 (1999), 413–419.
23. Marcelin, G., Jo, Y.H., Li, X., Schwartz, G.J., Zhang, Y., Dun, N.J., Lyu, R.M., Blouet, C., Chang, J.K., Chua, S. Jr., Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol. Metab. 3 (2013), 19–28.
24. Marty, N., Dallaporta, M., Thorens, B., Brain glucose sensing, counterregulation, and energy homeostasis. Physiology (Bethesda) 22 (2007), 241–251.
25. McCrimmon, R.J., Shaw, M., Fan, X., Cheng, H., Ding, Y., Vella, M.C., Zhou, L., McNay, E.C., Sherwin, R.S., Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57 (2008), 444–450.
26. Miki, T., Liss, B., Minami, K., Shiuchi, T., Saraya, A., Kashima, Y., Horiuchi, M., Ashcroft, F., Minokoshi, Y., Roeper, J., Seino, S., ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat. Neurosci. 4 (2001), 507–512.
27. Morton, G.J., Matsen, M.E., Bracy, D.P., Meek, T.H., Nguyen, H.T., Stefanovski, D., Bergman, R.N., Wasserman, D.H., Schwartz, M.W., FGF19 action in the brain induces insulin-independent glucose lowering. J. Clin. Invest. 123 (2013), 4799–4808.
28. Mounien, L., Marty, N., Tarussio, D., Metref, S., Genoux, D., Preitner, F., Foretz, M., Thorens, B., Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons. FASEB J. 24 (2010), 1747–1758.
29. O'Malley, D., Reimann, F., Simpson, A.K., Gribble, F.M., Sodium-coupled glucose cotransporters contribute to hypothalamic glucose sensing. Diabetes 55 (2006), 3381–3386.
30. Owen, B.M., Mangelsdorf, D.J., Kliewer, S.A., Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 26 (2015), 22–29.
31. Paxinos, G., Watson, C., The Rat Brain in Stereotaxic Coordinates. 1982, Academic Press.
32. Peirce, J.L., Broman, K.W., Lu, L., Williams, R.W., A simple method for combining genetic mapping data from multiple crosses and experimental designs. PLoS ONE, 2, 2007, e1036.
33. Potthoff, M.J., Boney-Montoya, J., Choi, M., He, T., Sunny, N.E., Satapati, S., Suino-Powell, K., Xu, H.E., Gerard, R.D., Finck, B.N., et al. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway. Cell Metab. 13 (2011), 729–738.
34. Ritter, S., Li, A.J., Wang, Q., Dinh, T.T., Minireview: The value of looking backward: the essential role of the hindbrain in counterregulatory responses to glucose deficit. Endocrinology 152 (2011), 4019–4032.
35. Rosen, G.D., Chesler, E.J., Manly, K.F., Williams, R.W., An informatics approach to systems neurogenetics. Methods Mol. Biol. 401 (2007), 287–303.
36. Routh, V.H., Glucose-sensing neurons: are they physiologically relevant?. Physiol. Behav. 76 (2002), 403–413.
37. Routh, V.H., Glucose sensing neurons in the ventromedial hypothalamus. Sensors (Basel) 10 (2010), 9002–9025.
38. Ryan, K.K., Kohli, R., Gutierrez-Aguilar, R., Gaitonde, S.G., Woods, S.C., Seeley, R.J., Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats. Endocrinology 154 (2013), 9–15.
39. Salmon, P., Trono, D., Production and titration of lentiviral vectors. Crawley, J.N., (eds.) Current Protocols in Neuroscience, 2006, John Wiley & Sons, 10.1002/0471142901.
40. Stanley, S., Domingos, A.I., Kelly, L., Garfield, A., Damanpour, S., Heisler, L., Friedman, J., Profiling of glucose-sensing neurons reveals that GHRH neurons are activated by hypoglycemia. Cell Metab. 18 (2013), 596–607.
41. Steinbusch, L., Labouèbe, G., Thorens, B., Brain glucose sensing in homeostatic and hedonic regulation. Trends Endocrinol. Metab. 26 (2015), 455–466.
42. Taborsky, G.J. Jr., Mundinger, T.O., Minireview: The role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology 153 (2012), 1055–1062.
43. Tarussio, D., Metref, S., Seyer, P., Mounien, L., Vallois, D., Magnan, C., Foretz, M., Thorens, B., Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis. J. Clin. Invest. 124 (2014), 413–424.
44. Thorens, B., Sensing of glucose in the brain. Handbook Exp. Pharmacol. 209 (2012), 277–294.
45. Unger, R.H., Orci, L., Glucagon and the A cells: physiology and pathophysiology. N. Engl. J. Med. 304 (1981), 1518–1524.
46. Verberne, A.J., Sabetghadam, A., Korim, W.S., Neural pathways that control the glucose counterregulatory response. Front. Neurosci., 8, 2014, 38.
47. Vergnes, L., Lee, J.M., Chin, R.G., Auwerx, J., Reue, K., Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels. Cell Metab. 17 (2013), 916–928.
48. Wong, N., Morahan, G., Stathopoulos, M., Proietto, J., Andrikopoulos, S., A novel mechanism regulating insulin secretion involving Herpud1 in mice. Diabetologia 56 (2013), 1569–1576.
49. Zhao, X.Y., Lin, J.D., Long noncoding RNAs: a new regulatory code in metabolic control. Trends Biochem. Sci. 40 (2015), 586–596.