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Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

Benomar, Yacir, Amine, Hamza, Crépin, Délphine, Al Rifai, Sarah, Riffault, Laure, Gertler, Arieh, Taouis, Mohammed·2016·Diabetes
DOI 10.2337/db15-1029
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Abstract

Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.

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Metadata

Authors
Benomar, Y., Amine, H., Crépin, D., Al Rifai, S., Riffault, L., Gertler, A., & Taouis, M.
Affiliations
  • UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France
  • Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel
Venue
Diabetes
Publisher
American Diabetes Association
Published
2016-01-06
Volume
65
Issue
4
Pages
913-926
ISSN
  • 0012-1797
  • 1939-327X
DOI
10.2337/db15-1029
Cited by
76
References
12
Language
en

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