IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling

Cell Reports

Volumn 19, Issue 2, 2017, Pages 267-280

  Timper, Katharina ^a,b,c   Denson, Jesse Lee ^a,b,c   Steculorum, Sophie Marie ^a,b,c   Heilinger, Christian ^a,b,c   Engström Ruud, Linda ^a,b,c   Wunderlich, Claudia Maria ^a,b,c   Rose John, Stefan ^d   Wunderlich, F Thomas ^a,b,c   Brüning, Jens Claus ^a,b,c,e  

^a MAX PLANCK INSTITUTE FOR NEUROLOGICAL RESEARCH   (Germany)

^b UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^c UNIVERSITY OF COLOGNE   (Germany)

^d UNIVERSITY OF KIEL   (Germany)

^e GERMAN CENTER FOR DIABETES RESEARCH DZD   (Germany)

Author keywords

CNS; energy homeostasis; glucose homeostasis; interleukin 6; interleukin 6 trans signaling; obesity

Indexed keywords

GLUCOSE; GLYCOPROTEIN GP 130; INSULIN; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; LEPTIN; PROTEIN KINASE B; STAT3 PROTEIN; INTERLEUKIN-6, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; ENERGY; ENZYME PHOSPHORYLATION; FEEDING BEHAVIOR; FOREBRAIN; GENE EXPRESSION; GLUCOSE HOMEOSTASIS; GLUCOSE TOLERANCE; GP130 GENE; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; HYPOTHALAMUS; INSULIN SENSITIVITY; MOLECULARLY TARGETED THERAPY; MOUSE; NERVE CELL; NONHUMAN; OBESITY; PROTEIN CEREBROSPINAL FLUID LEVEL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; ANIMAL; ANIMAL FOOD; BIOSYNTHESIS; ENERGY METABOLISM; GENETICS; HUMAN; METABOLISM; MOUSE MUTANT; PATHOLOGY; PATHOPHYSIOLOGY;

ANIMAL NUTRITIONAL PHYSIOLOGICAL PHENOMENA; ANIMALS; CYTOKINE RECEPTOR GP130; ENERGY METABOLISM; GLUCOSE; HUMANS; HYPOTHALAMUS; INTERLEUKIN-6; MICE; MICE, OBESE; NEURONS; OBESITY; PROSENCEPHALON;

EID: 85017296367     PISSN: None     EISSN: 22111247     Source Type: Journal    
DOI: 10.1016/j.celrep.2017.03.043     Document Type: Article

References (72)

1. Belgardt, B.F., Brüning, J.C., CNS leptin and insulin action in the control of energy homeostasis. Ann. N Y Acad. Sci. 1212 (2010), 97–113.
2. Belgardt, B.F., Okamura, T., Brüning, J.C., Hormone and glucose signalling in POMC and AgRP neurons. J. Physiol. 587 (2009), 5305–5314.
3. Belgardt, B.F., Mauer, J., Wunderlich, F.T., Ernst, M.B., Pal, M., Spohn, G., Brönneke, H.S., Brodesser, S., Hampel, B., Schauss, A.C., et al. Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proc. Natl. Acad. Sci. USA 107 (2010), 6028–6033.
4. Benrick, A., Schéle, E., Pinnock, S.B., Wernstedt-Asterholm, I., Dickson, S.L., Karlsson-Lindahl, L., Jansson, J.O., Interleukin-6 gene knockout influences energy balance regulating peptides in the hypothalamic paraventricular and supraoptic nuclei. J. Neuroendocrinol. 21 (2009), 620–628.
5. Buettner, C., Pocai, A., Muse, E.D., Etgen, A.M., Myers, M.G. Jr., Rossetti, L., Critical role of STAT3 in leptin's metabolic actions. Cell Metab. 4 (2006), 49–60.
6. Burton, M.D., Sparkman, N.L., Johnson, R.W., Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior. J. Neuroinflammation, 8, 2011, 54.
7. Burton, M.D., Rytych, J.L., Freund, G.G., Johnson, R.W., Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice. Brain Behav. Immun. 30 (2013), 66–72.
8. Cai, D., Yuan, M., Frantz, D.F., Melendez, P.A., Hansen, L., Lee, J., Shoelson, S.E., Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat. Med. 11 (2005), 183–190.
9. Campbell, I.L., Abraham, C.R., Masliah, E., Kemper, P., Inglis, J.D., Oldstone, M.B., Mucke, L., Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl. Acad. Sci. USA 90 (1993), 10061–10065.
10. Campbell, I.L., Erta, M., Lim, S.L., Frausto, R., May, U., Rose-John, S., Scheller, J., Hidalgo, J., Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J. Neurosci. 34 (2014), 2503–2513.
11. Carey, A.L., Bruce, C.R., Sacchetti, M., Anderson, M.J., Olsen, D.B., Saltin, B., Hawley, J.A., Febbraio, M.A., Interleukin-6 and tumor necrosis factor-alpha are not increased in patients with Type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia 47 (2004), 1029–1037.
12. Carey, A.L., Steinberg, G.R., Macaulay, S.L., Thomas, W.G., Holmes, A.G., Ramm, G., Prelovsek, O., Hohnen-Behrens, C., Watt, M.J., James, D.E., et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55 (2006), 2688–2697.
13. Ellingsgaard, H., Ehses, J.A., Hammar, E.B., Van Lommel, L., Quintens, R., Martens, G., Kerr-Conte, J., Pattou, F., Berney, T., Pipeleers, D., et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc. Natl. Acad. Sci. USA 105 (2008), 13163–13168.
14. Ellingsgaard, H., Hauselmann, I., Schuler, B., Habib, A.M., Baggio, L.L., Meier, D.T., Eppler, E., Bouzakri, K., Wueest, S., Muller, Y.D., et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17 (2011), 1481–1489.
15. Ernst, M.B., Wunderlich, C.M., Hess, S., Paehler, M., Mesaros, A., Koralov, S.B., Kleinridders, A., Husch, A., Münzberg, H., Hampel, B., et al. Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J. Neurosci. 29 (2009), 11582–11593.
16. Fischer, M., Goldschmitt, J., Peschel, C., Brakenhoff, J.P., Kallen, K.J., Wollmer, A., Grötzinger, J., Rose-John, S., I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat. Biotechnol. 15 (1997), 142–145.
17. Gruber, S., Straub, B.K., Ackermann, P.J., Wunderlich, C.M., Mauer, J., Seeger, J.M., Büning, H., Heukamp, L., Kashkar, H., Schirmacher, P., et al. Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Rα signaling. Cell Rep. 4 (2013), 669–680.
18. Heinrich, P.C., Behrmann, I., Haan, S., Hermanns, H.M., Müller-Newen, G., Schaper, F., Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374 (2003), 1–20.
19. Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T., Kishimoto, T., Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63 (1990), 1149–1157.
20. Hill, J.W., Elias, C.F., Fukuda, M., Williams, K.W., Berglund, E.D., Holland, W.L., Cho, Y.R., Chuang, J.C., Xu, Y., Choi, M., et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11 (2010), 286–297.
21. Hotamisligil, G.S., Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int. J. Obes. 32:Suppl 7 (2008), S52–S54.
22. Hsu, M.P., Frausto, R., Rose-John, S., Campbell, I.L., Analysis of IL-6/gp130 family receptor expression reveals that in contrast to astroglia, microglia lack the oncostatin M receptor and functional responses to oncostatin M. Glia 63 (2015), 132–141.
23. Jones, S.A., Scheller, J., Rose-John, S., Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 121 (2011), 3375–3383.
24. Jostock, T., Müllberg, J., Ozbek, S., Atreya, R., Blinn, G., Voltz, N., Fischer, M., Neurath, M.F., Rose-John, S., Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur. J. Biochem. 268 (2001), 160–167.
25. Kim, H.J., Higashimori, T., Park, S.Y., Choi, H., Dong, J., Kim, Y.J., Noh, H.L., Cho, Y.R., Cline, G., Kim, Y.B., et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53 (2004), 1060–1067.
26. Kim, Y.D., Kim, Y.H., Cho, Y.M., Kim, D.K., Ahn, S.W., Lee, J.M., Chanda, D., Shong, M., Lee, C.H., Choi, H.S., Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models. Diabetologia 55 (2012), 1482–1494.
27. Kleinridders, A., Schenten, D., Könner, A.C., Belgardt, B.F., Mauer, J., Okamura, T., Wunderlich, F.T., Medzhitov, R., Brüning, J.C., MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10 (2009), 249–259.
28. Klöckener, T., Hess, S., Belgardt, B.F., Paeger, L., Verhagen, L.A., Husch, A., Sohn, J.W., Hampel, B., Dhillon, H., Zigman, J.M., et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat. Neurosci. 14 (2011), 911–918.
29. Könner, A.C., Brüning, J.C., Selective insulin and leptin resistance in metabolic disorders. Cell Metab. 16 (2012), 144–152.
30. Könner, A.C., Janoschek, R., Plum, L., Jordan, S.D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G.S., et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5 (2007), 438–449.
31. Kraakman, M.J., Kammoun, H.L., Allen, T.L., Deswaerte, V., Henstridge, D.C., Estevez, E., Matthews, V.B., Neill, B., White, D.A., Murphy, A.J., et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 21 (2015), 403–416.
32. Langhans, W., Anorexia of infection: current prospects. Nutrition 16 (2000), 996–1005.
33. Li, G., Klein, R.L., Matheny, M., King, M.A., Meyer, E.M., Scarpace, P.J., Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience 115 (2002), 879–889.
34. Lin, H.V., Plum, L., Ono, H., Gutiérrez-Juárez, R., Shanabrough, M., Borok, E., Horvath, T.L., Rossetti, L., Accili, D., Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59 (2010), 337–346.
35. Liu, L., Duff, K., A technique for serial collection of cerebrospinal fluid from the cisterna magna in mouse. J. Vis. Exp., 2008.
36. März, P., Heese, K., Hock, C., Golombowski, S., Müller-Spahn, F., Rose-John, S., Otten, U., Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered in cerebrospinal fluid of Alzheimer's disease patients. Neurosci. Lett. 239 (1997), 29–32.
37. März, P., Cheng, J.G., Gadient, R.A., Patterson, P.H., Stoyan, T., Otten, U., Rose-John, S., Sympathetic neurons can produce and respond to interleukin 6. Proc. Natl. Acad. Sci. USA 95 (1998), 3251–3256.
38. Matthews, V.B., Allen, T.L., Risis, S., Chan, M.H., Henstridge, D.C., Watson, N., Zaffino, L.A., Babb, J.R., Boon, J., Meikle, P.J., et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53 (2010), 2431–2441.
39. Mauer, J., Chaurasia, B., Goldau, J., Vogt, M.C., Ruud, J., Nguyen, K.D., Theurich, S., Hausen, A.C., Schmitz, J., Brönneke, H.S., et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15 (2014), 423–430.
40. Mauer, J., Denson, J.L., Brüning, J.C., Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 36 (2015), 92–101.
41. Michalopoulou, M., Nikolaou, C., Tavernarakis, A., Alexandri, N.M., Rentzos, M., Chatzipanagiotou, S., Cambouri, C., Vassilopoulos, D., Soluble interleukin-6 receptor (sIL-6R) in cerebrospinal fluid of patients with inflammatory and non inflammatory neurological diseases. Immunol. Lett. 94 (2004), 183–189.
42. Milanski, M., Degasperi, G., Coope, A., Morari, J., Denis, R., Cintra, D.E., Tsukumo, D.M., Anhe, G., Amaral, M.E., Takahashi, H.K., et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29 (2009), 359–370.
43. Mohamed-Ali, V., Goodrick, S., Rawesh, A., Katz, D.R., Miles, J.M., Yudkin, J.S., Klein, S., Coppack, S.W., Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 82 (1997), 4196–4200.
44. Naitoh, Y., Fukata, J., Tominaga, T., Nakai, Y., Tamai, S., Mori, K., Imura, H., Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats. Biochem. Biophys. Res. Commun. 155 (1988), 1459–1463.
45. Narazaki, M., Yasukawa, K., Saito, T., Ohsugi, Y., Fukui, H., Koishihara, Y., Yancopoulos, G.D., Taga, T., Kishimoto, T., Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 82 (1993), 1120–1126.
46. Navarra, P., Tsagarakis, S., Faria, M.S., Rees, L.H., Besser, G.M., Grossman, A.B., Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway. Endocrinology 128 (1991), 37–44.
47. Ostrowski, K., Rohde, T., Zacho, M., Asp, S., Pedersen, B.K., Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J. Physiol. 508 (1998), 949–953.
48. Pedersen, B.K., Febbraio, M.A., Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88 (2008), 1379–1406.
49. Perello, M., Raingo, J., Leptin activates oxytocin neurons of the hypothalamic paraventricular nucleus in both control and diet-induced obese rodents. PLoS ONE, 8, 2013, e59625.
50. Plum, L., Belgardt, B.F., Brüning, J.C., Central insulin action in energy and glucose homeostasis. J. Clin. Invest. 116 (2006), 1761–1766.
51. Plum, L., Ma, X., Hampel, B., Balthasar, N., Coppari, R., Münzberg, H., Shanabrough, M., Burdakov, D., Rother, E., Janoschek, R., et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J. Clin. Invest. 116 (2006), 1886–1901.
52. Quintana, A., Erta, M., Ferrer, B., Comes, G., Giralt, M., Hidalgo, J., Astrocyte-specific deficiency of interleukin-6 and its receptor reveal specific roles in survival, body weight and behavior. Brain Behav. Immun. 27 (2013), 162–173.
53. Ropelle, E.R., Flores, M.B., Cintra, D.E., Rocha, G.Z., Pauli, J.R., Morari, J., de Souza, C.T., Moraes, J.C., Prada, P.O., Guadagnini, D., et al. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition. PLoS Biol., 8, 2010.
54. Rose-John, S., Heinrich, P.C., Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300 (1994), 281–290.
55. Rothaug, M., Becker-Pauly, C., Rose-John, S., The role of interleukin-6 signaling in nervous tissue. Biochim. Biophys. Acta 1863:6 Pt A (2016), 1218–1227.
56. Schéle, E., Fekete, C., Egri, P., Füzesi, T., Palkovits, M., Keller, É., Liposits, Z., Gereben, B., Karlsson-Lindahl, L., Shao, R., et al. Interleukin-6 receptor α is co-localised with melanin-concentrating hormone in human and mouse hypothalamus. J. Neuroendocrinol. 24 (2012), 930–943.
57. Schéle, E., Benrick, A., Grahnemo, L., Egecioglu, E., Anesten, F., Pálsdóttir, V., Jansson, J.O., Inter-relation between interleukin (IL)-1, IL-6 and body fat regulating circuits of the hypothalamic arcuate nucleus. J. Neuroendocrinol. 25 (2013), 580–589.
58. Schöbitz, B., Pezeshki, G., Pohl, T., Hemmann, U., Heinrich, P.C., Holsboer, F., Reul, J.M., Soluble interleukin-6 (IL-6) receptor augments central effects of IL-6 in vivo. FASEB J. 9 (1995), 659–664.
59. Steensberg, A., van Hall, G., Osada, T., Sacchetti, M., Saltin, B., Klarlund Pedersen, B., Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. 529 (2000), 237–242.
60. Thaler, J.P., Yi, C.X., Schur, E.A., Guyenet, S.J., Hwang, B.H., Dietrich, M.O., Zhao, X., Sarruf, D.A., Izgur, V., Maravilla, K.R., et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122 (2012), 153–162.
61. Timper, K., Dalmas, E., Dror, E., Rütti, S., Thienel, C., Sauter, N.S., Bouzakri, K., Bédat, B., Pattou, F., Kerr-Conte, J., et al. Glucose-dependent insulinotropic peptide stimulates glucagon-like peptide 1 production by pancreatic islets via interleukin 6, produced by α cells. Gastroenterology 151 (2016), 165–179.
62. Tsaousidou, E., Paeger, L., Belgardt, B.F., Pal, M., Wunderlich, C.M., Brönneke, H., Collienne, U., Hampel, B., Wunderlich, F.T., Schmidt-Supprian, M., et al. Distinct roles for JNK and IKK activation in agouti-related peptide neurons in the development of obesity and insulin resistance. Cell Rep. 9 (2014), 1495–1506.
63. Tsien, J.Z., Chen, D.F., Gerber, D., Tom, C., Mercer, E.H., Anderson, D.J., Mayford, M., Kandel, E.R., Tonegawa, S., Subregion- and cell type-restricted gene knockout in mouse brain. Cell 87 (1996), 1317–1326.
64. Valdearcos, M., Robblee, M.M., Benjamin, D.I., Nomura, D.K., Xu, A.W., Koliwad, S.K., Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep. 9 (2014), 2124–2138.
65. Vogt, M.C., Brüning, J.C., CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol. Metab. 24 (2013), 76–84.
66. Wallenius, K., Wallenius, V., Sunter, D., Dickson, S.L., Jansson, J.O., Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem. Biophys. Res. Commun. 293 (2002), 560–565.
67. Wallenius, V., Wallenius, K., Ahrén, B., Rudling, M., Carlsten, H., Dickson, S.L., Ohlsson, C., Jansson, J.O., Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 8 (2002), 75–79.
68. Wellen, K.E., Hotamisligil, G.S., Inflammation, stress, and diabetes. J. Clin. Invest. 115 (2005), 1111–1119.
69. Wunderlich, F.T., Ströhle, P., Könner, A.C., Gruber, S., Tovar, S., Brönneke, H.S., Juntti-Berggren, L., Li, L.S., van Rooijen, N., Libert, C., et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12 (2010), 237–249.
70. Wunderlich, C.M., Delić, D., Behnke, K., Meryk, A., Ströhle, P., Chaurasia, B., Al-Quraishy, S., Wunderlich, F., Brüning, J.C., Wunderlich, F.T., Cutting edge: inhibition of IL-6 trans-signaling protects from malaria-induced lethality in mice. J. Immunol. 188 (2012), 4141–4144.
71. Xu, A.W., Ste-Marie, L., Kaelin, C.B., Barsh, G.S., Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology 148 (2007), 72–80.
72. Xu, Q., Tam, M., Anderson, S.A., Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J. Comp. Neurol. 506 (2008), 16–29.