Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus

• Published in: Nature medicine Vol. 19; no. 3; pp. 358 - 363
• Main Authors: Kiechl, Stefan, Wittmann, Jürgen, Giaccari, Andrea, Knoflach, Michael, Willeit, Peter, Bozec, Aline, Moschen, Alexander R, Muscogiuri, Giovanna, Sorice, Gian Pio, Kireva, Trayana, Summerer, Monika, Wirtz, Stefan, Luther, Julia, Mielenz, Dirk, Billmeier, Ulrike, Egger, Georg, Mayr, Agnes, Oberhollenzer, Friedrich, Kronenberg, Florian, Orthofer, Michael, Penninger, Josef M, Meigs, James B, Bonora, Enzo, Tilg, Herbert, Willeit, Johann, Schett, Georg
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2013; Nature Publishing Group
• Subjects: 631/80/86; 692/420; 692/699/2743/137/773; 692/700/565; Adult; Aged; Animals; Biomedicine; Cancer Research; Cell Line; Cell receptors; Diabetes; Diabetes Mellitus, Type 2 - prevention & control; DNA binding proteins; Enzyme Activation; Female; Genetic aspects; HEK293 Cells; Humans; Infectious Diseases; Insulin resistance; Insulin Resistance - physiology; letter; Liver - metabolism; Male; Metabolic Diseases; Mice; Middle Aged; Molecular Medicine; Neurosciences; NF-kappa B - metabolism; Physiological aspects; Prognosis; Prospective Studies; RANK Ligand - antagonists & inhibitors; RANK Ligand - metabolism; Risk factors; Italy; Austria; Germany
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3084

Stefan Kiechl and colleagues show that blockade of receptor activator of nuclear factor-κB (RANKL) signaling in hepatocytes by cell type–specific genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes. They also show epidemiological evidence that elevated serum concentrations of soluble RANKL are a risk factor for the development of this disease.
Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver
1
,
2
,
3
. There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and β-cell dysfunction, although the molecular mechanisms involved are incompletely understood
3
,
4
,
5
,
6
. We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (
P
< 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.