Diet-NFkB interactions in the transcriptional regulation of metabolic homeostasis

Abstract

Project Summary/Abstract: Metabolic and innate immune responses, two primitive systems critical for the long-term homeostasis of multi- cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges. Unfortunately, as humans appear evolutionarily unprepared for modern diets, over-nutrition and dietary imbalances often leads to mis-regulation of these responses and the development of metabolic dysfunction. Uncovering the integration of these ancestral metabolic and innate immune systems thus advances both understanding of basic physiology and the complex etiology associated with metabolic disease. An over- arching goal of the research proposed here is to establish a framework of innate immune-metabolic signaling networks employing invertebrate models. Utilizing Drosophila, a powerful integrative physiology model, new insights derived from previous studies have revealed a role for the innate immune transcription factor NF-kB in modulating metabolic target gene expression during adaptation to dietary changes. NF-kB transcription factors, evolutionarily conserved regulators of innate immunity, are emerging as a critical node in the bidirectional communication and coordination of metabolic and innate immune signaling pathway interactions. It was uncovered that NF-kB antagonism of Foxo function (a key nutrient-responsive transcription factor) is crucial to influence metabolic target genes in diverse cell types to shape distinctive aspects of lipid metabolism (largely linked to catabolism - usage, breakdown, and mobilization). This antagonism subsequently balances energy homeostasis with diet-dependent nutrient supply and promotes metabolic adaptation. These findings highlight a critical need to explore the distinct molecular and cellular mechanisms, governed by ancient innate immune signaling pathways, that may shape the equilibrium between normal physiology and pathology associated with diet-mediated disruptions in lipid metabolism. To this end, it is possible that diet- and NF-kB-dependent antagonism of metabolic transcription factor function may be central to the integration of innate immune- metabolic signaling networks. Drosophila provide an invaluable, genetically tractable model to characterize such mechanisms; as these signaling networks are conserved from insects to humans, and many ancestral insect tissues combine functions of nutrient and pathogen sensing organs, highlighting the inherent association between metabolic state and innate immune function. There are three specific aims to this proposal: (i) to explore interactions between NF-kB and histone deacetylases in the control of diet-dependent chromatin remodeling and lipid metabolism, (ii) to determine whether unique signaling mechanisms direct diet- and NF-kB-dependent transcriptional attenuation (vs activation) of metabolic target genes, and (ii) to characterize NF-kB-modulated gene regulatory networks shaped by dietary imbalances and chromatin remodeling. Exploiting Drosophila to explore the origin of innate immune-metabolic interactions holds promise for an enhanced rate of uncovering novel mechanisms that underly lipid-metabolic imbalances and metabolic dysfunction.