Neuro-endocrine mechanisms of Interleukin-1ß-mediated resetting of glucose homeostasis

• Antragstellerin: Professorin Adriana del Rey, Ph.D.
• Fachliche Zuordnung: Endokrinologie, Diabetologie, Metabolismus
• Förderung: Förderung von 2008 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 94171388

• Erstellungsjahr: 2014

Zusammenfassung der Projektergebnisse

It is widely known that insulin is the par excellence hormone to induce hypoglycemia, and to stimulate glucose uptake by several peripheral tissues. However, it is still unclear which is/are the endogenous mediator(s) that facilitate glucose uptake by long lasting activated neural cells, as insulin does, for example, in muscle and fat. Besides its well-recognized immunological effects, it has been shown that Interleukin-1β (IL-1β) can also affect the endocrine and the nervous systems. Our original finding that IL-1β, either exogenously administered or endogenously produced, can induce hypoglycemia in normal and diabetic (Type 2) mice independently of insulin was the starting point of this project. We have previously shown that IL- 1β -induced hypoglycemia cannot be totally explained by the capacity of the cytokine to induce glucose uptake in peripheral tissues. Most intriguing was the fact that, as opposed to the response to hypoglycemia caused by insulin, neither a sustained neuro-endocrine counterregulation nor overt neurological symptoms are observed during the marked and long-lasting hypoglycemia induced by IL-1β. These findings, together with the fact that IL-1β can fix glycemia at very low levels and even after a glucose load, indicated that the cytokine could affect the set point of glucoregulation. Because the physiological regulation of glucose homeostasis is extremely complex and multifactorial, the aim of this project was to start studying some mechanisms that could underlie IL-1-induced hypoglycemia, particularly when it is triggered at central nervous system levels. A second aim was to explore our hypothesis that IL-1β can provide glucose to the brain. The most important findings obtained during this grant period are briefly summarized below: 1) IL-1β and insulin, at doses that induce hypoglycemia of a comparable magnitude and duration, elicit different neuroendocrine responses, particularly in the noradrenergic and serotonergic activity in the hypothalamus and in feeding behavior. 2) IL-1β-induced hypoglycemia depends on the occupancy of IL-1 receptors in the brain. Furthermore, the same dose of the cytokine injected in the brain induces a much more prolonged hypoglycemia than when it is administered peripherally. 3) We have shown earlier that peripherally produced IL-1 can induce its own production in the brain. We have now found that this feed-forward mechanism can also be triggered directly from the brain. This is relevant not only for physiological processes such as learning, but also during pathological conditions, such as neurodegenerative diseases, when IL-1 is produced primarily in the brain. Furthermore, brain-borne IL-1 can also increase its auto-production in the spleen, indicating that there is a brain-to-periphery pathway of IL-1 induction. 4) We have described here for the first time that mice that lack the Kir6.2 unit of the ATPsensitive K+ channel (which is present in several tissues, including glucose-sensing neurons in the hypothalamus) have alterations in the concentration and metabolism of catecholamines and indolamines in defined brain regions, both under basal conditions and also in response to IL-1β. Furthermore, IL-1β induces an even more pronounced hypoglycemia in Kir6.2 knock-out mice. 5) Nuclear magnetic resonance spectroscopy (MRS) studies allowed us to show that, contrary to insulin and despite hypoglycemia, IL-1β stimulates the energetic metabolism of the brain. 6) The adapter protein MyD88 is essential for IL-1to cause hypoglycemia, to induce the expression of its own gene at central and peripheral levels, and to stimulate brain energetic metabolism. 7) IL-1, endogenously produced by neurons and astrocytes, increases glucose uptake by these cells. This effect is observed under basal conditions, and is even more marked when the cells are stimulated with a specific glutamate agonist. In summary, the most important outcome of this project is that brain-borne IL-1 can affect gluco-regulation and stimulate brain metabolism by mechanisms that are insulin-independent, and MyD88-dependent. Thus, the cytokine seems to protect the brain from the hypoglycemia that it induces. These effects are based on the rare capacity of IL-1 to induce its own production in the brain. We provide also direct evidence that the IL-1 produced by neurons and astrocytes can facilitate glucose uptake by these cells in an auto/paracrine fashion and in an activitydependent manner. These findings can contribute to explain the role of the increased expression of the cytokine that, as we have very recently shown, occurs during learning, a process that implies increased neuronal activity.

Projektbezogene Publikationen (Auswahl)

• IL-1β and insulin elicit different neuro-endocrine responses to hypoglycemia. Annals of the New York Academy of Sciences, Vol.1153. 2009: Neuroimmunomodulation: From Fundamental Biology to Therapy, pp. 82–88.
  Ota K., Wildmann J., Ota T., Besedovsky H., del Rey A.
  
• Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen. Brain, Behavior, and Immunity, Vol. 23. 2009, Issue 6, pp. 776–783.
  del Rey A., Randolf A., Wildmann, J., Besedovsky, H.O., Jessop S.
  
• Interleukin-1 resets glucose homeostasis at central and peripheral levels: relevance for immunoregulation. Neuroimmunomodulation, Vol. 17. 2010, No. 3, pp 139-141.
  Besedovsky H.O., del Rey A.
  
• New Insights into Cytokine Gene Expression in the Rat Hypothalamus Following Endotoxin Challenge. Neurochemical Research, Vol. 35. 2010, Issue 6, pp 909–911.
  Jessop D.S., Besedovsky H.O., del Rey A.
  
• Central and Peripheral Cytokines Mediate Immune-Brain Connectivity. Neurochemical Research, Vol. 36. 2011, Issue 1, pp 1–6.
  Besedovsky H.O., del Rey A.
  
• A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning. Brain, Behavior, and Immunity, Vol. 33. 2013, pp. 15–23.
  del Rey A., Balschun D., Wetzel W., Randolf A., Besedovksy H.O.
  
• Physiologic versus diabetogenic effects of Interleukin-1: a question of weight. Current Pharmaceutical Design, Vol. 20. 2014, Number 29 , pp. 4733-4740.
  Besedovsky H.O., del Rey A.
  
• The immune-neuro-endocrine network in health and disease. In: The Wiley-Blackwell Handbook of Psychoneuroimmunology, eds: A. W. Kusnecov and H. Anisman, John Wiley & Sons, Oxford, UK, 2014, pp. 99-119.
  del Rey A., Besedovsky H.O.
  
• Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner. Molecular Psychiatry, Vol. 21.2016, pp. 1309–1320.
  A. del Rey, M. Verdenhalven, A.C. Lörwald, C. Meyer, M. Hernangómez, A. Randolf, E. Roggero, A.M. König, J.T. Heverhagen, C. Guaza, H.O. Besedovsky