Multi-Omic Analysis of BMP-Insulin Signaling Crosstalk in Lipid Metabolism during Aging

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Project Summary The incidence of obesity and overweight health stress in the United States and elsewhere has elevated dramatically in the last 50 years, increasing the risk of age-related health disorders including cardiovascular disease, cancer, and Alzheimer’s disease. A comprehensive understanding of the underlying biological mechanisms that drive lipid storage and lipid mobilization is a critical piece in facing this challenge. The nematode Caenorhabditis elegans has emerged as a powerful model system in which to identify mechanisms of lipid homeostasis. We identified TGFβ/BMP signaling as one such mechanism. We focused on the TGFβ/BMP-related ligand DBL-1, discovering that DBL-1/BMP is required for normal lipid accumulation in the animal. DBL-1/BMP promotes lipid storage in part by downregulation of insulin/IGF-1-like signaling (IIS), which is mediated by the DAF-2 insulin receptor and the DAF-16 FoxO transcription factor. Moreover, DBL-1/BMP signaling modulates outcomes in a C. elegans model of Alzheimer’s disease, which may be related to its functions in lipid metabolism. We now seek to identify the mechanisms of crosstalk and the downstream effectors of BMP and IIS in lipid metabolism during aging using a multi-Omic approach. We hypothesize that DBL-1/BMP signaling through its Smad transcription factors crosstalks with IIS via DAF-16/FoxO to regulate lipid metabolism, fat accumulation, and adult physiology. To test this hypothesis, we will address the following specific aims: (1) Determine the transcriptional network mediating BMP and IIS regulation of lipid metabolism; (2) Identify how DAF-16/FoxO genome occupancy is influenced by DBL-1/BMP signaling; and (3) Determine the metabolic profiles dictated by DBL-1/BMP and IIS activity. Taken together, these experiments, using next-generation Omics methodologies, will characterize the complete picture of transcriptional and lipid dynamics directed by BMP and IIS signaling (and their cross-regulatory interaction) in an intact organism during aging. This integration of approaches and fields using the C. elegans model is not easily applied in other systems, particularly in the context of whole-organism aging. These studies will also generate detailed transcriptomes and metabolomes needed for future hypothesis-driven research. Due to the high degree of conservation of these signaling pathways, we anticipate valuable insight into universal mechanistic principles regulating lipid homeostasis and its contribution to age-related illnesses including metabolic syndrome and Alzheimer’s disease.