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Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4 Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-Fed Mice

Saberi, Maziyar; Woods, Niels Bjarne LU ; de Luca, Carl; Schenk, Simon; Lu, Juu Chin; Bandyopadhyay, Gautam; Verma, Inder M. and Olefsky, Jerrold M. (2009) In Cell Metabolism 10(5). p.419-429
Abstract

Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (Tlr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6 recipient mice to generate hematopoietic cell-specific Tlr4 deletion mutant (BMT-Tlr4-/-) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4-/- mice became obese but did not develop fasting hyperinsulinemia and had improved hepatic and... (More)

Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (Tlr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6 recipient mice to generate hematopoietic cell-specific Tlr4 deletion mutant (BMT-Tlr4-/-) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4-/- mice became obese but did not develop fasting hyperinsulinemia and had improved hepatic and adipose insulin sensitivity during euglycemic clamp studies, compared to HFD BMT-WT controls. HFD BMT-Tlr4-/- mice also showed markedly reduced adipose tissue inflammatory markers and macrophage content. In summary, our results indicate that Tlr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice.

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author
organization
publishing date
type
Contribution to journal
publication status
published
keywords
HUMDISEASE
in
Cell Metabolism
volume
10
issue
5
pages
419 - 429
publisher
Cell Press
external identifiers
  • scopus:70350389389
ISSN
1550-4131
DOI
10.1016/j.cmet.2009.09.006
language
English
LU publication?
no
id
2fd3bb2f-ab3c-4aac-985f-129f035960bf
date added to LUP
2017-01-24 16:35:49
date last changed
2017-10-22 05:25:29
@article{2fd3bb2f-ab3c-4aac-985f-129f035960bf,
  abstract     = {<p>Chronic low-grade inflammation, particularly in adipose tissue, is an important modulator of obesity-induced insulin resistance. The Toll-like receptor 4 (Tlr4) is a key initiator of inflammatory responses in macrophages. We performed bone marrow transplantation (BMT) of Tlr4lps-del or control C57Bl/10J donor cells into irradiated wild-type C57Bl6 recipient mice to generate hematopoietic cell-specific Tlr4 deletion mutant (BMT-Tlr4<sup>-/-</sup>) and control (BMT-WT) mice. After 16 weeks of a high-fat diet (HFD), BMT-WT mice developed obesity, hyperinsulinemia, glucose intolerance, and insulin resistance. In contrast, BMT-Tlr4<sup>-/-</sup> mice became obese but did not develop fasting hyperinsulinemia and had improved hepatic and adipose insulin sensitivity during euglycemic clamp studies, compared to HFD BMT-WT controls. HFD BMT-Tlr4<sup>-/-</sup> mice also showed markedly reduced adipose tissue inflammatory markers and macrophage content. In summary, our results indicate that Tlr4 signaling in hematopoietic-derived cells is important for the development of hepatic and adipose tissue insulin resistance in obese mice.</p>},
  author       = {Saberi, Maziyar and Woods, Niels Bjarne and de Luca, Carl and Schenk, Simon and Lu, Juu Chin and Bandyopadhyay, Gautam and Verma, Inder M. and Olefsky, Jerrold M.},
  issn         = {1550-4131},
  keyword      = {HUMDISEASE},
  language     = {eng},
  month        = {11},
  number       = {5},
  pages        = {419--429},
  publisher    = {Cell Press},
  series       = {Cell Metabolism},
  title        = {Hematopoietic Cell-Specific Deletion of Toll-like Receptor 4 Ameliorates Hepatic and Adipose Tissue Insulin Resistance in High-Fat-Fed Mice},
  url          = {http://dx.doi.org/10.1016/j.cmet.2009.09.006},
  volume       = {10},
  year         = {2009},
}