Decreasing CB 1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice

Abstract : Objective: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types, including hepatocytes. Here, we sought to identify the role of CB1R in KCs in obesity-induced hepatic insulin resistance. Methods: We used intravenously administered beta-D-glucan-encapsulated siRNA to knock-down CB1R gene expression selectively in KCs. Results: We demonstrate that a robust knock-down of the expression of Cnr1, the gene encoding CB1R, results in improved glucose tolerance and insulin sensitivity in diet-induced obese mice, without affecting hepatic lipid content or body weight. Moreover, Cnr1 knock-down in KCs was associated with a shift from pro-inflammatory M1 to anti-inflammatory M2 cytokine profile and improved insulin signaling as reflected by increased insulin-induced Akt phosphorylation. Conclusion: These findings suggest that CB1R expressed in KCs plays a critical role in obesity-related hepatic insulin resistance via a pro inflammatory mechanism. Published by Elsevier GmbH.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01708117
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mardi 13 février 2018 - 12:50:43
Dernière modification le : mardi 6 août 2019 - 15:14:33

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Tony Jourdan, Sarah Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, et al.. Decreasing CB 1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice. Molecular metabolism, Elsevier, 2017, 6 (11), pp.1517 - 1528. ⟨https://www.sciencedirect.com/science/article/pii/S2212877817305847?via%3Dihub⟩. ⟨10.1016/j.molmet.2017.08.011⟩. ⟨hal-01708117⟩

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