Abstract
Vitamin D is well known for its traditional role in bone mineral homeostasis; however, recent evidence suggests that vitamin D also plays a significant role in metabolic control. This study served to investigate putative linkages between vitamin D deficiency (VDD) and metabolic disruption of bioactive lipids by MS imaging. Our approach employed infrared-matrix-assisted laser desorption electrospray ionization MS imaging for lipid metabolite profiling in 6-month-old zebrafish fed either a VDD or a vitamin D-sufficient (VDS) diet. Using a lipidomics pipeline, we found that VDD zebrafish had a greater abundance of bioactive lipids (N-acyls, endocannabinoids [ECs], diacylglycerols/triacylglycerols, bile acids/bile alcohols, and vitamin D derivatives) suggestive of increased EC tone compared with VDS zebrafish. Tandem MS was performed on several differentially expressed metabolites with sufficient ion abundances to aid in structural elucidation and provide additional support for MS annotations. To confirm activation of the EC pathways, we subsequently examined expression of genes involved in EC biosynthesis, metabolism, and receptor signaling in adipose tissue and liver from VDD and VDS zebrafish. Gene expression changes were congruent with increased EC tone, with VDD zebrafish demonstrating increased synthesis and metabolism of anandamide compared with VDS zebrafish. Taken together, our data suggest that VDD may promote accumulation of bioactive lipids and increased EC tone in zebrafish.
Highlights
Our lab established a linkage between vitamin D deficiency (VDD) and metabolic dyshomeostasis, where low levels of vitamin D resulted in stunted growth and central adiposity in zebrafish by 6 months post fertilization.[35]
Journal Pre-proof that incorporated key metabolic organs including adipose tissue (AT), liver, intestines, spleen, and kidney, we utilized a series of data analysis tools including MSiReader, METLIN, and METASPACE, to discover and annotate ions that were significantly more abundant in the VDD fish
We chose to focus our investigation on putative identification of ions more abundant in the VDD fish compared to the vitamin D-sufficient (VDS) fish given the robust fatty phenotype we previously published.[35]
Summary
Vitamin D (calciferol) is a prohormone traditionally associated with bone mineral homeostasis; recent research has implicated a role for vitamin D in additional physiological and cellular processes including metabolic control, cell differentiation, oxidative stress, xenobiotic metabolism, neurodevelopment, and immune function.[1,2,3,4,5,6,7,8,9] Leading to these discoveries, are studies demonstrating that vitamin D deficiency (VDD) can result in dysregulation of essential cellular processes associated with autoimmune disease, poor bone health, and cardiometabolic diseases such as obesity, Journal Pre-proof insulin resistance (IR), and type 1 and type 2 diabetes (T1D, T2D). 10,11,12,13,14,15,16 In relation to human cardiometabolic functions, vitamin D status has been demonstrated to be inversely related to triglyceride and cholesterol levels, fasting blood glucose, and insulin.[17,18] Vitamin D status has been demonstrated to impact body composition, with VDD individuals demonstrating greater waist circumferences and body fat percentages as seen in obese populations.[17,18] Children born to VDD mothers have metabolic profiles high in fatty acids (linoleate, linolenate, myristate, oleate, palmitate, palmitoleate) and amines/derivatives (alanine, glutamate, hypoxyanthine, lactate, phenylalanine, proline, urea) known to be biomarkers of inflammation and insulin resistance.[19,20,21] accumulating evidence suggests a link between vitamin D status and metabolic health, where VDD populations present elevated levels of fatty acids characteristic of cardiometabolic disease.Fatty acids and fatty amines fall into the category of bioactive lipids. Vitamin D (calciferol) is a prohormone traditionally associated with bone mineral homeostasis; recent research has implicated a role for vitamin D in additional physiological and cellular processes including metabolic control, cell differentiation, oxidative stress, xenobiotic metabolism, neurodevelopment, and immune function.[1,2,3,4,5,6,7,8,9] Leading to these discoveries, are studies demonstrating that vitamin D deficiency (VDD) can result in dysregulation of essential cellular processes associated with autoimmune disease, poor bone health, and cardiometabolic diseases such as obesity, Journal Pre-proof insulin resistance (IR), and type 1 and type 2 diabetes (T1D, T2D). Bioactive lipids are endogenous signaling lipids known to play critical roles in cellular function by maintaining membrane integrity, and have been implicated in cardiovascular disease, immune response, endocannabinoid tone, and inflammation.[22,23] Included in this category are bile acids, eicosanoids, docosanoids, sphingolipids, and endocannabinoids (ECs), to name a few. Stimulation of the EC system by cannabis has been associated with reduced concentrations of serum
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