Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance

Mihai G. Netea; Leo A.B. Joosten; Eli Lewis; Dalan R. Jensen; Peter J. Voshol; Bart Jan Kullberg; Cees J. Tack; Han Van Krieken; Soo Hyun Kim; Anton F. Stalenhoef; Fons A. Van De Loo; Ineke Verschueren; Leslie Pulawa; Shizuo Akira; Robert H. Eckel; Charles A. Dinarello; Wim Van Den Berg; Jos W.M. Van Der Meer

doi:10.1038/nm1415

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance

Mihai G. Netea, Leo A.B. Joosten, Eli Lewis, Dalan R. Jensen, Peter J. Voshol, Bart Jan Kullberg, Cees J. Tack, Han Van Krieken, Soo Hyun Kim, Anton F. Stalenhoef, Fons A. Van De Loo, Ineke Verschueren, Leslie Pulawa, Shizuo Akira, Robert H. Eckel, Charles A. Dinarello, Wim Van Den Berg, Jos W.M. Van Der Meer

Research output: Contribution to journal › Article › peer-review

111 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	650-656
Number of pages	7
Journal	Nature Medicine
Volume	12
Issue number	6
DOIs	https://doi.org/10.1038/nm1415
State	Published - 1 Jun 2006
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nm1415

Cite this

Netea, M. G., Joosten, L. A. B., Lewis, E., Jensen, D. R., Voshol, P. J., Kullberg, B. J., Tack, C. J., Van Krieken, H., Kim, S. H., Stalenhoef, A. F., Van De Loo, F. A., Verschueren, I., Pulawa, L., Akira, S., Eckel, R. H., Dinarello, C. A., Van Den Berg, W., & Van Der Meer, J. W. M. (2006). Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nature Medicine, 12(6), 650-656. https://doi.org/10.1038/nm1415

@article{b02254c6f4aa4630a44ba1234f57a9a8,

title = "Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance",

abstract = "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.",

author = "Netea, {Mihai G.} and Joosten, {Leo A.B.} and Eli Lewis and Jensen, {Dalan R.} and Voshol, {Peter J.} and Kullberg, {Bart Jan} and Tack, {Cees J.} and {Van Krieken}, Han and Kim, {Soo Hyun} and Stalenhoef, {Anton F.} and {Van De Loo}, {Fons A.} and Ineke Verschueren and Leslie Pulawa and Shizuo Akira and Eckel, {Robert H.} and Dinarello, {Charles A.} and {Van Den Berg}, Wim and {Van Der Meer}, {Jos W.M.}",

note = "Funding Information: M.G.N. was supported by a Vidi grant from Netherlands Foundation of Scientific Research (NWO). P.J.V. was supported by Zon-MW Veni grant 916-36-071. We thank G. Fantuzzi for her help with the leptin-resistance experiments, and critically reading the manuscript.",

year = "2006",

month = jun,

day = "1",

doi = "10.1038/nm1415",

language = "English",

volume = "12",

pages = "650--656",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "6",

}

Netea, MG, Joosten, LAB, Lewis, E, Jensen, DR, Voshol, PJ, Kullberg, BJ, Tack, CJ, Van Krieken, H, Kim, SH, Stalenhoef, AF, Van De Loo, FA, Verschueren, I, Pulawa, L, Akira, S, Eckel, RH, Dinarello, CA, Van Den Berg, W & Van Der Meer, JWM 2006, 'Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance', Nature Medicine, vol. 12, no. 6, pp. 650-656. https://doi.org/10.1038/nm1415

TY - JOUR

T1 - Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance

AU - Netea, Mihai G.

AU - Joosten, Leo A.B.

AU - Lewis, Eli

AU - Jensen, Dalan R.

AU - Voshol, Peter J.

AU - Kullberg, Bart Jan

AU - Tack, Cees J.

AU - Van Krieken, Han

AU - Kim, Soo Hyun

AU - Stalenhoef, Anton F.

AU - Van De Loo, Fons A.

AU - Verschueren, Ineke

AU - Pulawa, Leslie

AU - Akira, Shizuo

AU - Eckel, Robert H.

AU - Dinarello, Charles A.

AU - Van Den Berg, Wim

AU - Van Der Meer, Jos W.M.

N1 - Funding Information: M.G.N. was supported by a Vidi grant from Netherlands Foundation of Scientific Research (NWO). P.J.V. was supported by Zon-MW Veni grant 916-36-071. We thank G. Fantuzzi for her help with the leptin-resistance experiments, and critically reading the manuscript.

PY - 2006/6/1

Y1 - 2006/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33745009509&partnerID=8YFLogxK

U2 - 10.1038/nm1415

DO - 10.1038/nm1415

M3 - Article

C2 - 16732281

AN - SCOPUS:33745009509

SN - 1078-8956

VL - 12

SP - 650

EP - 656

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this