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Our goal is to identify metabolic mechanisms responsible for the optimal coupling of mitochondrial oxidative metabolism and lipogenesis in the liver during the embryonic-to-post-hatch transition period in chickens. The scientific premises for this proposal arise from the following facts 1) Mortality rates in broiler chickens are highest during the first 3-4 days after hatch (0.5 to 3%), especially in small-egg derived hatchlings from younger flocks (2-3% mortality rates). Early life mortality is of significant economic burden to the poultry industry. 2) Significant remodeling of mitochondrial metabolism and new lipid synthesis (lipogenesis) occurs during embryonic-to-post-hatch development in chickens. Further, disruption of mitochondrial oxidative networks (e.g. β-oxidation, tricarboxylic acid (TCA) cycle flux, ketogenesis and mitochondrial respiration) and lipogenesis in a variety of species is known to adversely impact hepatocellular and whole body metabolic function. 3) Advances in intermediary metabolism research has not kept pace with the rapid advances in genomic and transcriptomic research, towards addressing key issues in poultry production. Here, we lack a clear understanding of how genetic or transcriptomic modifications correlate with those at the level of the metabolome, ultimately contributing to the metabolic phenotype.We will test the hypothesis that during healthy embryonic-to-post-hatch transition in chickens, the onset of hepatocellular stress is prevented because of the optimal coupling between mitochondrial oxidative networks, lipogenesis and anti-oxidant defense in the liver.We will integrate state-of-the-art metabolic profiling techniques utilizing stable isotope-based mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy to determine changes in mitochondrial metabolism and lipogenesis. Targeted GC-MS and LC-MS/MS based metabolomics and patterns of gene expression profiles will supplement metabolic flux analysis. Our goal is to identify the ideal metabolic networks suitable for nutritional, hormonal or genetic perturbations. Furthermore, these studies will establish mitochondrial health and efficiency as a central paradigm towards improving the overall metabolic health of the hatchling. We will test our hypothesis with the following two objectives.Objective 1: We will characterize how specific networks involved in mitochondrial oxidative metabolism (β-oxidation, TCA cycle flux, ketogenesis and oxidative phosphorylation (OXPHOS)) and lipogenesis in the liver, co-exist to promote a healthy embryonic-to-post-hatch transition in chickens. We will utilize day 14, 16,18 and 20 embryos (e14, e16, e18, e20) and post-hatch day 0, 3, 5 and 7 chicks (ph0, ph3, ph5, ph7) to investigate the remodeling of mitochondrial oxidative metabolism, lipogenesis and antioxidant defense. These time points were selected based on our preliminary data which demonstrate a clear 'metabolic shift' where a) high rates of hepatic β-oxidation co-exist with low rates of lipogenesis in the developing embryo and b) high rates of lipogenesis co-exist with low rates of β-oxidation in the neonatal liver. Cutting edge metabolic profiling in the liver will determine: 1) mitochondrial oxidative flux and lipogenesis, using stable isotopes, MS and NMR; 2) toxic lipid deposition using LC-MS/MS based metabolomics; 3) OXPHOS, reactive oxygen species (ROS) production and hepatocellular stress, and 4) anti-oxidant defense mechanisms.Objective 2: To test the hypothesis that the developmental adaptation of mitochondrial oxidative networks is disrupted in the liver of the smaller-egg derived embryos and hatchlings (from young broiler breeder hens; 25-Wks old), compared to their larger-egg counterparts (45-Wk old hens). Objective 2 will further test the ability of branched chain amino acids (BCAAs; leucine, isoleucine, valine) to modulate mitochondrial oxidative metabolism and lipogenesis. The scientific premise for Objective 2 arises from the following observations. 1) Smaller-egg derived hatchlings (from younger flocks) have lower yolk sac lipids, lower body weights, and higher mortality and morbidity, when compared to their larger-egg counterparts. 2. Emerging data from our lab and others, in a variety of model systems illustrate a close interaction between BCAAs and mitochondrial lipid metabolism. Interestingly, plasma BCAAs are 2-fold lower in smaller-egg derived embryos compared to their larger counterparts. Taken together, we hypothesize that experimental injection in ovo of BCAAs will improve liver function, by modulating mitochondrial oxidative metabolism and lipogenesis. Embryos (e18, e20) and hatchlings (ph3, ph7) derived from small and large eggs, obtained from broiler flocks of ages of 25- and 45-Wks will be utilized for this study. Metabolic profiling will be done following 5-days (from e13 to e17) of in ovo saline or BCAAs injection. Mitochondrial pathways, lipogenesis and their relationship to ROS production, hepatocellular stress and anti-oxidant defense will be tested as in Objective 1. RNA-sequencing analysis will be conducted to detect the prominent correlations between nutrient fluxes and gene expression profiles, in order to identify central regulatory networks in the liver suitable for targeted perturbations.

Sunny, N.; Porter, To, .
University of Iceland
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