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      Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation

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          Abstract

          Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that AMPK has on NLRP3-inlflammasome and IL-1β biology. This in turn can result in subsequent negative downstream effects on glucose, lipid and insulin metabolism. Nutrient stress in the form of obesity can impact AMPK and whole-body metabolism, leading to complications such as type 2 diabetes and cancer risk. There is a lack of data regarding the nature and extent that nutrient status has on AMPK and metabolic-inflammation. However, emerging work elucidates to a direct role of individual nutrients on AMPK and metabolic-inflammation, as a possible means of modulating AMPK activity. The posit being to use such nutritional agents to re-configure metabolic-inflammation towards more oxidative phosphorylation and promote the resolution of inflammation. The complex paradigm will be discussed within the context of if/how dietary components, nutrients including fatty acids and non-nutrient food components, such as resveratrol, berberine, curcumin and the flavonoid genistein, modulate AMPK dependent processes relating to inflammation and metabolism.

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          Most cited references60

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          Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.

          Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.
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            Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

            Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
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              Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.

              Adipose tissue macrophage (ATM)-driven inflammation plays a key role in insulin resistance; however, factors activating ATMs are poorly understood. Using a proteomics approach, we show that markers of classical activation are absent on ATMs from obese humans but are readily detectable on airway macrophages of patients with cystic fibrosis, a disease associated with chronic bacterial infection. Moreover, treating macrophages with glucose, insulin, and palmitate-conditions characteristic of the metabolic syndrome-produces a "metabolically activated" phenotype distinct from classical activation. Markers of metabolic activation are expressed by proinflammatory ATMs in obese humans/mice and are positively correlated with adiposity. Metabolic activation is driven by independent proinflammatory and anti-inflammatory pathways, which regulate balance between cytokine production and lipid metabolism. We identify PPARγ and p62/SQSTM1 as two key proteins that promote lipid metabolism and limit inflammation in metabolically activated macrophages. Collectively, our data provide important mechanistic insights into pathways that drive the metabolic-disease-specific phenotype of macrophages.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                09 October 2018
                October 2018
                : 19
                : 10
                : 3092
                Affiliations
                [1 ]Unit of Molecular Metabolism, Lund University Diabetes Center, Clinical Research Center, Lund University, 205 02 Malmö, Sweden; claire.lyons@ 123456med.lu.se
                [2 ]Nutrigenomics Research Group, UCD Institute of Food and Health, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, 4 Dublin, Ireland
                [3 ]Institute of Global Food Security, Queen’s University Belfast BT7 1NN, Northern Ireland, UK
                Author notes
                [* ]Correspondence: helen.roche@ 123456ucd.ie ; Tel.: +353-1-716-6845
                Article
                ijms-19-03092
                10.3390/ijms19103092
                6213547
                30304866
                6b6eb6a7-5756-41b7-82a4-6b2a8e9ee909
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 07 September 2018
                : 06 October 2018
                Categories
                Review

                Molecular biology
                ampk,il-1β,nlrp3,nutrition,dietary fatty acids,metabolic-inflammation,nutrigenomics
                Molecular biology
                ampk, il-1β, nlrp3, nutrition, dietary fatty acids, metabolic-inflammation, nutrigenomics

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