Control of macrophage activation by Akt signaling and metabolic input

Harvard School Of Public Health, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Appropriate macrophage activation requires metabolic reprogramming, but the underlying basis remains poorly understood. This knowledge gaps contrasts with the extensive literature on other aspects of macrophage activation, including signal transduction and transcriptional regulation. Here we show that during M2 activation, activation of Akt/mTORC1 signaling by IL-4 leads to increased production of Acetyl-CoA (Ac-CoA), leading to enhanced histone acetylation and transcriptional control of the M2 program. Importantly, only a subset of M2 genes is regulated by the Akt-mTORC1 axis. Our preliminary data also indicates that Akt signaling may integrate signals reflecting the cellular and organismal metabolic state to control of M2 activation. Physiological feeding increases Akt signaling and M2 polarization of adipose tissue macrophages (ATMs), while diet-induced obesity reduces Akt activity and M2 activation in ATMs. Because ATM M2 activation is important for maintaining insulin sensitivity, Akt signaling may couple physiological increases in metabolic signals to an adaptive M2 response, while chronic metabolic stress corrupts the Akt pathway to impair M2 polarization and promote metabolic dysregulation. Here we will pursue these findings in two Aims. First, we will determine the basis by which Akt/mTORC1 signaling couple's histone acetylation to the induction of a subset of the M2 program. Second, we will examine a role for Akt signaling in ATM M2 activation and metabolic homeostasis using a mouse model of diet-induced obesity.