32 Chapter 2 express the markers associated with classical activation (37,46). The presence of the CD36 marker was confirmed in adipose tissue macrophages from obese subjects and was not seen in macrophages of lean individuals. This macrophage subset is defined as metabolically activated and specific markers for this type of macrophages are suggested to be macrophage scavenger receptor 1 (Msr1), ATP-binding cassette A1 (ABCA1), and the adipose differentiation-related protein (Perilipin-2, PLIN2), in addition to CD11c and CD36 (37,46). MACROPHAGE METABOLIC REPROGRAMMING Since macrophages are key sentinel cells in charge of detecting alterations in their microenvironment, they need to be able to respond rapidly. To do so, they also need flexible metabolic pathways and must be able to reprogram their metabolism for proper activation and function. In fact, when macrophages polarize to a different phenotype, they also modify how they process their energy substrates, such as glucose or fatty acids. One of the first differences shown in macrophage metabolism related to polarization differences was seen in amino acid metabolism, in which classically activated macrophages were found to convert arginine to NO and citrulline by inducible NO synthase (iNOS) activity, while alternatively activated macrophages convert arginine in proline and polyamines through arginase-1 (47). Following this initial observation, our knowledge has expanded and it is now known that macrophages can also reprogram the way they generate ATP for energy. Nonpolarized or alternatively activated macrophages are involved in processes that are less time-pressured and use beta-oxidation of fatty acids and mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. This is achieved by lipolysis of triglycerides (48), generating fatty acids that will be oxidized by beta-oxidation, and obtaining acetyl-CoA plus NADH and FADH2. The first will enter the tricarboxylic acid (TCA) cycle, while the latter are used to produce ATP by OXPHOS. In addition, these macrophages can produce pyruvate from glycolysis, convert this to acetylCoA, which is then used by the TCA cycle to give electrons in the form of NADH and FADH2 to the OXPHOS complexes (Figure 3A). In response to pro-inflammatory stimuli, macrophages reprogram their metabolism to create energy and biosynthetic precursors rapidly in order to fight fast-growing microbes. This phenomenon is similar to the Warburg effect observed in tumor cells (49) and favors aerobic glycolysis over OXPHOS. While this is an inefficient way of generating ATP as compared to the TCA cycle (2 ATPs compared to 36 per glucose molecule), it can be quickly induced which is beneficial when trying to fight microbes that quickly replicate (50). As a result of this metabolic reprogramming, the excess carbon from glycolysis in classically activated macrophages is secreted as lactate instead of being used to produce acetyl-CoA from pyruvate, and the TCA cycle is broken at two
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