Genetic Modeling of Diet, NFkB, and Metabolic Interactions

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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, over-nutrition and dietary imbalances are associated with pathogen-independent (sterile) innate immune signaling pathway activation, leading to mis-regulation of these systems and instigating metabolic dysfunction and disorders (such as obesity and diabetes). NF-kB transcription factors, evolutionarily conserved regulators of innate immunity, are emerging as a critical node in this bidirectional coordination of metabolic and innate immune responses across taxa. Uncovering the ancestral integration of metabolic systems and NF-kB function, shaped by diet and nutrition, thus advances understanding of both basic physiology and the complex etiology associated with metabolic diseases. The overarching goal of this proposal is to elucidate a framework of NF-kB-centric innate immune-metabolic signaling networks using tractable invertebrate models coupled with cell-based mammalian models. Drosophila provide a powerful integrative physiology model (tractable both in terms of in vivo genetics and diets) to build this framework; as these signaling networks are conserved from insects to mammals. Mainly utilizing Drosophila, new insights derived from previous studies have revealed an evolutionarily conserved role for the innate immune transcription factor NF-kB in modulating metabolic target gene expression during adaptation to dietary changes. 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. 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.