Program in Molecular Medicine; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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.
CB(1) receptors, inflammation, insulin resistance, Kupffer cells, siRNA
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DOI of Published Version
Mol Metab. 2017 Nov;6(11):1517-1528. doi: 10.1016/j.molmet.2017.08.011. Epub 2017 Sep 1. Link to article on publisher's site
Jourdan, Tony; Nicoloro, Sarah M.; Zhou, Zhou; Shen, Yuefei; Liu, Jie; Coffey, Nathan J.; Cinar, Resat; Godlewski, Grzegorz; Gao, Bin; Aouadi, Myriam; Czech, Michael P.; and Kunos, George, "Decreasing CB1 receptor signaling in Kupffer cells improves insulin sensitivity in obese mice" (2017). UMass Metabolic Network Publications. 152.
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