Short-Term Versus Long-Term Effects of Adipocyte Toll-Like Receptor 4 Activation on Insulin Resistance in Male Mice.
Chronic exposure to high-saturated fat diets (HFDs) increases the prevalence of obesity and contributes to the development of low-grade inflammation and insulin resistance. A possible mediator accounting for obesity-associated inflammation and insulin resistance is Toll-like receptor 4 (TLR4). We investigated the role of adipocyte TLR4 in lipid and glucose homeostasis through an inducible, adipocyte-specific deletion of TLR4 in a mouse model that is referred to as the "Tadipo" mouse. Consistent with a critical role for inflammation as a positive force for healthy adipose tissue expansion, chronic HFD exposure results in exacerbated whole-body and muscle insulin resistance in the absence of TLR4 in the adipocyte. Elimination of TLR4 in adipocytes affects TLR4 expression in other tissues, with reduced TLR4 expression in peritoneal macrophages and in the liver. In contrast, TLR4 deletion from adipocytes protects whole-body insulin sensitivity after an acute lipid challenge during a hyperinsulinemic euglycemic clamp. Our results therefore demonstrate dichotomous effects of TLR4 on adipose tissue functionality, with an important positive role of TLR4 during a chronic HFD challenge due to the lack of adipose tissue remodeling and a negative role of TLR4 as a mediator of insulin resistance in the adipocyte during an acute challenge with saturated fatty acids.
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Caroline
C
Tao
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
William L
WL
Holland
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Qiong A
QA
Wang
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Mengle
M
Shao
Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Lin
L
Jia
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Kai
K
Sun
Metabolic Phenotyping Core, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Xiaoli
X
Lin
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Yi-Chun
YC
Kuo
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Joshua A
JA
Johnson
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.|Metabolic Phenotyping Core, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Ruth
R
Gordillo
Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Joel K
JK
Elmquist
Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Philipp E
PE
Scherer
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
D004041:Dietary Fats; D051197:Toll-Like Receptor 4