Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1

Zhenggang Yang, Barbara B Kahn, Hang Shi, Bing-Zhong Xue
Journal of Biological Chemistry 2010 June 18, 285 (25): 19051-9
In this study, we aim to determine cellular mechanisms linking nutrient metabolism to the regulation of inflammation and insulin resistance. The nutrient sensors AMP-activated protein kinase (AMPK) and SIRT1 show striking similarities in nutrient sensing and regulation of metabolic pathways. We find that the expression, activity, and signaling of the major isoform alpha1AMPK in adipose tissue and macrophages are substantially down-regulated by inflammatory stimuli and in nutrient-rich conditions, such as exposure to lipopolysaccharide (LPS), free fatty acids (FFAs), and diet-induced obesity. Activating AMPK signaling in macrophages by 5-aminoimidazole-4-carboxamide-1-beta4-ribofuranoside or constitutively active alpha1AMPK (CA-alpha1) significantly inhibits; although inhibiting alpha1AMPK by short hairpin RNA knock-down or dominant-negative alpha1AMPK (DN-alpha1) increases LPS- and FFA-induced tumor necrosis factor alpha expression. Chromatin immunoprecipitation and luciferase reporter assays show that activation of AMPK by CA-alpha1 in macrophages significantly inhibits LPS- or FFA-induced NF-kappaB signaling. More importantly, in a macrophage-adipocyte co-culture system, we find that inactivation of macrophage AMPK signaling inhibits adipocyte insulin signaling and glucose uptake. Activation of AMPK by CA-alpha1 increases the SIRT1 activator NAD(+) content and SIRT1 expression in macrophages. Furthermore, alpha1AMPK activation mimics the effect of SIRT1 on deacetylating NF-kappaB, and the full capacity of AMPK to deacetylate NF-kappaB and inhibit its signaling requires SIRT1. In conclusion, AMPK negatively regulates lipid-induced inflammation, which acts through SIRT1, thereby contributing to the protection against obesity, inflammation, and insulin resistance. Our study defines a novel role for AMPK in bridging the signaling between nutrient metabolism and inflammation.

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