Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans

Molecular Metabolism

Volumn 4, Issue 8, 2015, Pages 551-560

  Hansen, Jakob Schiøler ^a,b   Clemmesen, Jens Otto ^b   Secher, Niels Henry ^b   Hoene, Miriam ^c   Drescher, Andrea ^c   Weigert, Cora ^c,d   Pedersen, Bente Klarlund ^a   Plomgaard, Peter ^a,b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b Rigshospitalet   (Denmark)

^c UNIVERSITY OF TÜBINGEN   (Germany)

^d GERMAN CENTER FOR DIABETES RESEARCH DZD   (Germany)

Author keywords

Exercise; Hepatic; Hepatokine; Liver

Indexed keywords

FIBROBLAST GROWTH FACTOR 21; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INSULIN; LACTIC ACID;

ARTERY CATHETERIZATION; ARTICLE; BRACHIAL ARTERY; CONTROLLED STUDY; EXERCISE; GENE EXPRESSION; GLYCEMIC CONTROL; HUMAN; HYPERGLYCEMIA; INSULIN BLOOD LEVEL; LACTATE BLOOD LEVEL; LIVER VEIN; MALE; NORMAL HUMAN; PHYSICAL ACTIVITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN METABOLISM; PROTEIN SECRETION; SIGNAL TRANSDUCTION; SPLANCHNIC NERVE; UPREGULATION;

EID: 84937724386     PISSN: None     EISSN: 22128778     Source Type: Journal    
DOI: 10.1016/j.molmet.2015.06.001     Document Type: Article

References (55)

1. Nishimura T., Nakatake Y., Konishi M., Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochimica et Biophysica Acta 2000, 1492:203-206.
2. Kharitonenkov A., Shiyanova T.L., Koester A., Ford A.M., Micanovic R., Galbreath E.J., et al. FGF-21 as a novel metabolic regulator. Journal of Clinical Investigation 2005, 115:1627-1635.
3. Markan K.R., Naber M.C., Ameka M.K., Anderegg M.D., Mangelsdorf D.J., Kliewer S.A., et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 2014, 63(12):4057-4063.
4. Gaich G., Chien J.Y., Fu H., Glass L.C., Deeg M.A., Holland W.L., et al. The effects of LY2405319, an FGF21 Analog, in obese human subjects with type 2 diabetes. Cell Metabolism 2013, 18:333-340.
5. Galman C., Lundasen T., Kharitonenkov A., Bina H.A., Eriksson M., Hafstrom I., et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metabolism 2008, 8:169-174.
6. Potthoff M.J., Inagaki T., Satapati S., Ding X., He T., Goetz R., et al. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proceedings of the National Academy of Sciences of the United States of America 2009, 106:10853-10858.
7. Mai K., Bobbert T., Groth C., Assmann A., Meinus S., Kraatz J., et al. Physiological modulation of circulating FGF21: relevance of free fatty acids and insulin. American Journal of Physiology. Endocrinology and Metabolism 2010, 299:E126-E130.
8. Laeger T., Henagan T.M., Albarado D.C., Redman L.M., Bray G.A., Noland R.C., et al. FGF21 is an endocrine signal of protein restriction. Journal of Clinical Investigation 2014, 124:3913-3922.
9. Arafat A.M., Kaczmarek P., Skrzypski M., Pruszynska-Oszmalek E., Kolodziejski P., Szczepankiewicz D., et al. Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?. Diabetologia 2013, 56:588-597.
10. Habegger K.M., Stemmer K., Cheng C., Muller T.D., Heppner K.M., Ottaway N., et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 2013, 62:1453-1463.
11. Berglund E.D., Kang L., Lee-Young R.S., Hasenour C.M., Lustig D.G., Lynes S.E., et al. Glucagon and lipid interactions in the regulation of hepatic AMPK signaling and expression of PPARalpha and FGF21 transcripts invivo. American Journal of Physiology. Endocrinology and Metabolism 2010, 299:E607-E614.
12. Lin Z., Gong Q., Wu C., Yu J., Lu T., Pan X., et al. Dynamic change of serum FGF21 levels in response to glucose challenge in human. Journal of Clinical Endocrinology and Metabolism 2012, 97:E1224-E1228.
13. Hojman P., Pedersen M., Nielsen A.R., Krogh-Madsen R., Yfanti C., Akerstrom T., et al. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 2009, 58:2797-2801.
14. Badman M.K., Pissios P., Kennedy A.R., Koukos G., Flier J.S., Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metabolism 2007, 5:426-437.
15. Inagaki T., Dutchak P., Zhao G., Ding X., Gautron L., Parameswara V., et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metabolism 2007, 5:415-425.
16. Lundasen T., Hunt M.C., Nilsson L.M., Sanyal S., Angelin B., Alexson S.E., et al. PPARalpha is a key regulator of hepatic FGF21. Biochemical and Biophysical Research 2007, 360:437-440.
17. Wasserman D.H., Spalding J.A., Lacy D.B., Colburn C.A., Goldstein R.E., Cherrington A.D. Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work. American Journal of Physiology 1989, 257:E108-E117.
18. Wasserman D.H., Williams P.E., Lacy D.B., Goldstein R.E., Cherrington A.D. Exercise-induced fall in insulin and hepatic carbohydrate metabolism during muscular work. American Journal of Physiology 1989, 256:E500-E509.
19. Emhoff C.A., Messonnier L.A., Horning M.A., Fattor J.A., Carlson T.J., Brooks G.A. Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold. Journal of Applied Physiology (1985) 2013, 114:297-306.
20. Wasserman D.H., Spalding J.A., Bracy D., Lacy D.B., Cherrington A.D. Exercise-induced rise in glucagon and ketogenesis during prolonged muscular work. Diabetes 1989, 38:799-807.
21. Wahren J., Sato Y., Ostman J., Hagenfeldt L., Felig P. Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise. Journal of Clinical Investigation 1984, 73:1367-1376.
22. Longuet C., Sinclair E.M., Maida A., Baggio L.L., Maziarz M., Charron M.J., et al. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metabolism 2008, 8:359-371.
23. Wasserman D.H., Cherrington A.D. Hepatic fuel metabolism during muscular work: role and regulation. American Journal of Physiology 1991, 260:E811-E824.
24. Frayn K.N. Metabolic regulation - a human perspective 2010, Wiley-Blackwell. Third Edition.
25. Hoene M., Weigert C. The stress response of the liver to physical exercise. Exercise Immunology Review 2010, 16:163-183.
26. Kim K.H., Kim S.H., Min Y.K., Yang H.M., Lee J.B., Lee M.S. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One 2013, 8:e63517.
27. Xu J., Lloyd D.J., Hale C., Stanislaus S., Chen M., Sivits G., et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009, 58:250-259.
28. Izumiya Y., Bina H.A., Ouchi N., Akasaki Y., Kharitonenkov A., Walsh K. FGF21 is an Akt-regulated myokine. FEBS Letters 2008, 582:3805-3810.
29. Kim K.H., Jeong Y.T., Oh H., Kim S.H., Cho J.M., Kim Y.N., et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nature Medicine 2013, 19:83-92.
30. Keipert S., Ost M., Johann K., Imber F., Jastroch M., van Schothorst E.M., et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. American Journal of Physiology. Endocrinology and Metabolism 2014, 306:E469-E482.
31. Hansen J., Brandt C., Nielsen A.R., Hojman P., Whitham M., Febbraio M.A., et al. Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. Endocrinology 2011, 152:164-171.
32. Skak C., Keiding S. Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearance in man. Liver 1987, 7:155-162.
33. Osada T., Radegran G. Femoral artery inflow in relation to external and total work rate at different knee extensor contraction rates. Journal of Applied Physiology (1985) 2002, 92:1325-1330.
34. Hoene M., Franken H., Fritsche L., Lehmann R., Pohl A.K., Haring H.U., et al. Activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the liver of mice is related to plasma glucose levels after acute exercise. Diabetologia 2010, 53:1131-1141.
35. Lindegaard B., Hvid T., Grondahl T., Frosig C., Gerstoft J., Hojman P., et al. Expression of fibroblast growth factor-21 in muscle is associated with lipodystrophy, insulin resistance and lipid disturbances in patients with HIV. PLoS One 2013, 8:e55632.
36. Emanuelli B., Vienberg S.G., Smyth G., Cheng C., Stanford K.I., Arumugam M., et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. Journal of Clinical Investigation 2014, 124:515-527.
37. Fisher S.J., Kahn C.R. Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. Journal of Clinical Investigation 2003, 111:463-468.
38. Kharitonenkov A., Wroblewski V.J., Koester A., Chen Y.F., Clutinger C.K., Tigno X.T., et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007, 148:774-781.
39. Mai K., Andres J., Biedasek K., Weicht J., Bobbert T., Sabath M., et al. Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes 2009, 58:1532-1538.
40. Habegger K.M., Heppner K.M., Geary N., Bartness T.J., DiMarchi R., Tschop M.H. The metabolic actions of glucagon revisited. Nature Clinical Practice Endocrinology & Metabolism 2010, 6:689-697.
41. Dushay J.R., Toschi E., Mitten E.K., Fisher F.M., Herman M.A., Maratos-Flier E. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 2015, 4:51-57.
42. Chavez A.O., Molina-Carrion M., bdul-Ghani M.A., Folli F., Defronzo R.A., Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 2009, 32:1542-1546.
43. Dushay J., Chui P.C., Gopalakrishnan G.S., Varela-Rey M., Crawley M., Fisher F.M., et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010, 139:456-463.
44. Zhang X., Yeung D.C., Karpisek M., Stejskal D., Zhou Z.G., Liu F., et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008, 57:1246-1253.
45. Unger R.H., Cherrington A.D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. Journal of Clinical Investigation 2012, 122:4-12.
46. Koliaki C., Szendroedi J., Kaul K., Jelenik T., Nowotny P., Jankowiak F., et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metabolism 2015, 21:739-746.
47. Ding X., Boney-Montoya J., Owen B.M., Bookout A.L., Coate K.C., Mangelsdorf D.J., et al. betaKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metabolism 2012, 16:387-393.
48. Fon T.K., Bookout A.L., Ding X., Kurosu H., John G.B., Wang L., et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Molecular Endocrinology 2010, 24:2050-2064.
49. Mashili F.L., Austin R.L., Deshmukh A.S., Fritz T., Caidahl K., Bergdahl K., et al. Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity. Diabetes-Metabolism Research and Reviews 2011, 27:286-297.
50. Lee M.S., Choi S.E., Ha E.S., An S.Y., Kim T.H., Han S.J., et al. Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-kappaB. Metabolism 2012, 61:1142-1151.
51. Berglund E.D., Li C.Y., Bina H.A., Lynes S.E., Michael M.D., Shanafelt A.B., et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 2009, 150:4084-4093.
52. Adams A.C., Halstead C.A., Hansen B.C., Irizarry A.R., Martin J.A., Myers S.R., et al. LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS One 2013, 8:e65763.
53. Cho Y.M., Merchant C.E., Kieffer T.J. Targeting the glucagon receptor family for diabetes and obesity therapy. Pharmacology & Therapeutics 2012, 135:247-278.
54. Day J.W., Ottaway N., Patterson J.T., Gelfanov V., Smiley D., Gidda J., et al. Anew glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nature Chemical Biology 2009, 5:749-757.
55. Patel V., Joharapurkar A., Dhanesha N., Kshirsagar S., Patel K., Bahekar R., et al. Co-agonist of glucagon and GLP-1 reduces cholesterol and improves insulin sensitivity independent of its effect on appetite and body weight in diet-induced obese C57 mice. Canadian Journal of Physiology and Pharmacology 2013, 91:1009-1015.