Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice.
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.
Saberi
Maziyar
M
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
Woods
Niels-Bjarne
NB
de Luca
Carl
C
Schenk
Simon
S
Lu
Juu Chin
JC
Bandyopadhyay
Gautam
G
Verma
Inder M
IM
Olefsky
Jerrold M
JM
D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D055786:Gene Knockout Techniques; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D051197:Toll-Like Receptor 4