Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet.
OBJECTIVE
Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice.


METHODS
Male and female littermate Tlr2(+/+) and Tlr2(-/-) mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production.


RESULTS
While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2(-/-) mice were protected from the adverse effects of HFD compared with Tlr2(+/+) littermate controls. Female Tlr2(-/-) mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2(-/-) mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2(-/-) mice did not increase IL-1beta expression in response to a NEFA mixture, whereas Tlr2(+/+) control tissues did.


CONCLUSIONS
These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.
Ehses
J A
JA
Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, 950 W 28th Ave, Vancouver, BC, Canada V5Z 4H4. ehses@interchange.ubc.ca
Meier
D T
DT
Wueest
S
S
Rytka
J
J
Boller
S
S
Wielinga
P Y
PY
Schraenen
A
A
Lemaire
K
K
Debray
S
S
Van Lommel
L
L
Pospisilik
J A
JA
Tschopp
O
O
Schultze
S M
SM
Malipiero
U
U
Esterbauer
H
H
Ellingsgaard
H
H
Rütti
S
S
Schuit
F C
FC
Lutz
T A
TA
Böni-Schnetzler
M
M
Konrad
D
D
Donath
Marc Y
MY
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect; D002478:Cells, Cultured; D004041:Dietary Fats / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D051195:Toll-Like Receptor 2
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