Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.
Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.
Netea
Mihai G
MG
Department of Internal Medicine and Nijmegen University Center for Infectious Diseases, Geert Grooteplein 8, 6500 HB, Nijmegen, The Netherlands. m.netea@aig.umcn.nl
Joosten
Leo A B
LA
Lewis
Eli
E
Jensen
Dalan R
DR
Voshol
Peter J
PJ
Kullberg
Bart Jan
BJ
Tack
Cees J
CJ
van Krieken
Han
H
Kim
Soo-Hyun
SH
Stalenhoef
Anton F
AF
van de Loo
Fons A
FA
Verschueren
Ineke
I
Pulawa
Leslie
L
Akira
Shizuo
S
Eckel
Robert H
RH
Dinarello
Charles A
CA
van den Berg
Wim
W
van der Meer
Jos W M
JW
D000818:Animals; D001835:Body Weight; D004435:Eating; D004734:Energy Metabolism; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006963:Hyperphagia / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000172:deficiency* / Q000235:genetics; D053727:Interleukin-18 Receptor alpha Subunit; D008099:Liver / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D006023:Glycoproteins; C508573:Il18r1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C118370:interleukin-18 binding protein; D005947:Glucose