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<p>Providing wholesome pork products to consumers involves raising healthy pigs to grow well and be feed efficient from birth to market. Raising these pigs starts with ensuring the sow is healthy and provided good nutrition in gestation and lactation. Therefore, this dissertation primarily focuses on research of gut modifying feed additives fed to sows in gestation and lactation (and to their progeny in Chapter 3) to enhance reproductive performance and litter growth to weaning (and in the nursery). In Chapter 2, a total of 606 sows and their progeny were used to determine if feeding gestating and lactating sows a proprietary strain of Pichia guilliermondi as a whole-cell inactivated yeast product (WCY; CitriStim, ADM Animal Nutrition, Quincy, IL) improves sow and litter performance in a commercial production system. Sows were fed a control (CON) diet or control diet fortified with 0.15% of the WCY from d 35 of gestation through lactation. Sows supplemented with WCY in gestation and lactation had a greater number of total born piglets by 0.45 pigs (P < 0.04), piglets born alive (P < 0.04), heavier born alive litter weights (P < 0.001), and greater post cross-foster litter size (P < 0.001) compared to CON fed sows. Litter size at weaning was increased by 0.54 pigs when sows were fed WCY compared to CON (P < 0.001). However, litter weaning weights and 21-day adjusted litter weaning weights were similar (P > 0.158) with the 21-day adjusted litter weaning weights being numerically greater for the WCY sows. The average piglet weaning weights from CON fed sows were heavier by 0.35 kg compared to WCY (P < 0.001). This increase in body weight of piglets from CON fed sows is partially explained by their 0.93 days longer lactation (P < 0.001) and may also be due to the smaller litter size nursed throughout lactation. The percent of litters treated for scours decreased from 38.3% to 14.2% when sows were fed WCY (P < 0.001). The distribution of birth and weaning weights was not different (P > 0.2461) between treatments.</p><p>Chapter 3 encompasses a sow experiment where progeny were followed onto the nursery for a 28-d study. Forty-seven sows and their progeny were used to determine if feeding gestating and lactating sows a Bacillus licheniformis direct-fed microbial (DFM), an organic acid blend of medium and short-chain fatty acids (OA), or in combination improves sow lactation feed and water intake, litter growth, and subsequent reproductive performance. At weaning, offspring were fed a positive control diet (PC), negative control diet (NC), or a diet representative of their dam’s treatment to determine if there is an additive benefit to also feeding DFM and/or OA to nursery pigs in addition to their dams. On approximately d 80 of gestation, sows were fed one of four diets in a 2  2 factorial design: 1) gestation control (CON), 2) CON with DFM (1.6x109 CFU/kg of complete feed), 3) CON with 0.4% OA, 4) CON with both DFM and OA. Dietary treatments were also fed throughout lactation. Sows fed the OA diets had fewer mummies per litter (P < 0.010) compared to diets not containing OA. Sows fed diets with the DFM gave birth to lighter pigs born alive (1.5 vs. 1.7 kg; P < 0.003) compared to non-DFM fed sows, and a tendency for an interaction (P < 0.092) existed where feeding DFM+OA lessened the decrease in born alive BW. There was a tendency (P < 0.093) for pigs from DFM fed sows to also be lighter at weaning (5.8 vs. 6.2 kg) compared to pigs from sows not fed DFM, with no differences in litter sizes at weaning (P < 0.815). There was a tendency (P < 0.079) for the DFM to decrease the amount of sow BW loss in lactation compared to sows not fed the DFM (approximately 6 vs. 8% BW loss, respectively). The maintained BW in lactation was likely related to DFM sows numerically (P < 0.124) consuming 8.4% more feed during d 7-14 of lactation and 6.4% more feed (P < 0.234) from d 1 of lactation to weaning. The interaction was approaching a trend (P < 0.133) where sows fed DFM returned to estrus 1.0 day sooner than CON, but only 0.4 days sooner when sows were fed the DFM+OA diet.</p><p>Progeny weaned from these sows (n = 384, Initial BW = 6.15 kg) were blocked by initial BW and sex and allotted (6 pigs/pen, 8 pens/treatment) to one of 8 nursery treatments. Pigs from CON sows were fed a negative (NC; no antibiotics, no pharmacological Zn or Cu) or positive (PC; neomycin-oxytetracycline in phases 1 and 2 (827 and 551 ppm) and carbadox in phases 3 and 4 (55 ppm)) control diet. Pigs from sows fed DFM, OA, or DFM+OA were fed the NC diet or a diet representative of their dam’s treatment. Diets with DFM contained 1.6x109 CFU/kg of complete feed and diets with OA contained 0.5, 0.4, 0.3, and 0.0% OA in phases 1-4, respectively. Weaning weight was used as a covariate for nursery performance due to the DFM offspring being significantly lighter at weaning. For all phases and overall, PC fed pigs had greater ADG (P < 0.003) and ADFI (P < 0.059) than NC pigs. PC fed pigs had greater G:F (P < 0.010) than NC pigs for all phases and overall except d 21-28 (P < 0.532). Feeding DFM or OA in sow diets improved (interaction; P < 0.049) nursery pig G:F, but DFM+OA offspring had similar G:F compared to NC pigs from CON fed sows for d 7-14, 0-14, 0-21, and 0-28. Feeding DFM or OA to sows and their progeny decreased ADFI (interaction; P < 0.042) but improved G:F (interaction; P < 0.028) for d 7-14 and 0-14 with DFM+OA having similar performance to NC. For d 14-21 and 0-21, feeding DFM or OA to sows and their progeny decreased ADFI whereas DFM+OA increased ADFI above NC (interaction; P < 0.019). Overall, d 0-28, feeding DFM or OA to sows and their progeny improved G:F (interaction; P < 0.001) with DFM+OA having poorer G:F compared to NC. When the DFM was fed to sows and nursery pigs, progeny harvested on d 6 post-weaning had a decreased ratio of villus height to crypt depth (P < 0.035) compared to sows and pigs not consuming the DFM (average 1.34 vs. 1.67). Comparing pigs fed PC vs. NC from CON fed sows, expression of interleukin 10 (IL-10) was greater (0.51-fold increase; P < 0.046) for NC pigs than PC pigs. Expression of occludin (OCLN) was lower (P < 0.010) when OA was fed to the sows and pigs compared to when OA was not fed to the sows and pigs (0.78 vs. 1.00, respectively).</p><p>Chapter 4 is the only chapter that does not include maternal nutrition. In this chapter, maternal line gilts (Topigs Norsvin TN70) were bred with frozen semen from Duroc boars born from 2000 to 2017 divided into two genetic groups: semen from boars born in 2000 to 2005 and 2011 to 2017. These genetic groups had vastly different terminal sire indexes (TSI) of 88.2 and 112.0 for 2000 to 2005 and 2011 to 2017, respectively. A total of 155 pigs were weaned into 44 pens in a wean-to-finish facility to determine if genetics from two decades of sires and sex of the progeny impact progeny growth performance and carcass characteristics. The expected large growth performance differences indicated by the TSI’s of the two genetic groups were not observed. However, barrows had greater feed intake (P < 0.031) and fatter carcasses (P < 0.004) than the more feed efficient (P < 0.006) and leaner (P < 0.015) gilts in this study. Modern swine genetics have been selected to be leaner and results from this study agree, although the differences in live scan and carcass measurements were not as large as expected. The lack of differences between genetic groups could possibly be due to environmental differences including nutrition and rearing conditions from when these sires were alive compared to what was experienced by these progeny.</p><p>In conclusion, feeding gestating and lactating sows a proprietary strain of Pichia guilliermondi as a whole-cell inactivated yeast product increased the number of piglets born and weaned as well as decreased the prevalence of scours during lactation. Feeding a Bacillus licheniformis DFM to sows may decrease pig born alive weight and subsequent weaning weight but reduce sow BW loss through 6.4% more lactation feed intake, quickening the return to estrus. Other than decreasing the number of mummies per litter, feeding the OA alone or in combination did not improve sow reproductive or litter growth performance in this study. Feeding DFM or OA to sows or their offspring may improve nursery feed efficiency but did not result in a difference in ADG or final BW in this study. Feeding the combination diet (DFM+OA) to the sow and nursery pigs tended to increase ADFI. Feeding antibiotics post-weaning continued to improve pig growth performance resulting in 2.7 kg heavier pigs at the end of the 28-d nursery period. Lastly, the expected large growth performance differences indicated by the TSI’s of two genetic groups created by using frozen semen from boars born in 2000 to 2005 and 2011 to 2017 were not observed.</p>

Obesity, type 2 diabetes, and cardiovascular diseases are major problems in today's society, causing millions of deaths every year. One of the main risk factors for these diseases is a dysregulation of the fatty acid metabolism, where the balance between release and uptake of fatty acids is disturbed. Thus, understanding how fatty acid metabolism works is of great importance in the battle against these diseases. The human fatty acid release and uptake can be unraveled by measuring the difference in metabolite concentrations between an artery before the adipose tissue and a vein draining the tissue. Such measurements are called arterio-venous. However, due to the complexity of the fatty acid mechanisms, the resulting measurements alone are not enough to understand all of the involved reactions governing the metabolism. One analytical tool to decipher such complex mechanisms is mathematical modeling. A few mathematical models have previously used arterio-venous data of the fatty acid metabolism, but none of the previous models describe a full day including several meals and nightly fast. In this project, I combine mathematical modeling and arterio-venous data to investigate the mechanisms of fatty acid metabolism during three consecutive meals and fasting. The resulting mathematical model can explain arterio-venous data of free fatty acids, triglycerides, and glycerol. The model predictions show that re-esterification of monacylglycerides, a mechanism that has not been considered before when analyzing arterio-venous data, is of importance to be able to accurately describe the fatty acid metabolism. Additionally, the model predicts that there is a hormonal regulation during the night. Finally, it is shown that many of the previous simple calculations used to approximate metabolic reactions do not capture the desired reactions but instead calculate more complex properties, while the use of the model allows for a more detailed analysis separating all of the different reaction rates. These results give new insights into the complex mechanisms of fatty acid metabolism and provide a new tool to analyze arterio-venous data more comprehensively. In the future, this can lead to a better understanding of metabolic diseases such as obesity, type 2 diabetes, and cardiovascular diseases.

Tree peony (Paeonia section Moutan DC.) species are woody oil crops with high unsaturated fatty acid content, including α-linolenic acid (ALA/18:3; >40% of the total fatty acid). Comparative transcriptome analyses were carried out to uncover the underlying mechanisms responsible for high and low ALA content in the developing seeds of P. rockii and P. lutea, respectively. Expression analysis of acyl lipid metabolism genes revealed upregulation of select genes involved in plastidial fatty acid synthesis, acyl editing, desaturation, and triacylglycerol assembly in seeds of P. rockiirelative to P. lutea. Also, in association with ALA content in seeds, transcript levels for fatty acid desaturases (SAD, FAD2, and FAD3), which encode enzymes necessary for polyunsaturated fatty acid synthesis, were higher in P. rockii compared to P. lutea. Furthermore, the overexpression of PrFAD2 and PrFAD3 in Arabidopsis increased linoleic and ALA content, respectively, and modulated the final ratio 18:2/18:3 in the seed oil. In conclusion, we identified the key steps and validated the necessary desaturases that contribute to efficient ALA synthesis in a woody oil crop. Together, these results will aid to increase essential fatty acid content in seeds of tree peonies and other crops of agronomic interest.

Fatty acid synthase (FASN), the sole cytosolic mammalian enzyme for de novo lipid synthesis, is crucial for cancer cell survival and associates with poor prognosis. FASN overexpression has been found to cause resistance to genotoxic insults. Here we tested the hypothesis that FASN regulates DNA repair to facilitate survival against genotoxic insults and found that FASN suppresses NF-κB but increases specificity protein 1 (SP1) expression. NF-κB and SP1 bind to a composite element in the poly(ADP-ribose) polymerase 1 (PARP-1) promoter in a mutually exclusive manner and regulate PARP-1 expression. Up-regulation of PARP-1 by FASN in turn increases Ku protein recruitment and DNA repair. Furthermore, lipid deprivation suppresses SP1 expression, which is able to be rescued by palmitate supplementation. However, lipid deprivation or palmitate supplementation has no effect on NF-κB expression. Thus, FASN may regulate NF-κB and SP1 expression using different mechanisms. Altogether, we conclude that FASN regulates cellular response against genotoxic insults by up-regulating PARP-1 and DNA repair via NF-κB and SP1.

Transcriptome analysis based on deep expressed sequence tag (EST) sequencing allows quantitative comparisons of gene expression across multiple species. Using pyrosequencing, we generated over 7 million ESTs from four stages of developing seeds of Ricinus communis, Brassica napus, Euonymus alatus and Tropaeolum majus, which differ in their storage tissue for oil, their ability to photosynthesize and in the structure and content of their triacylglycerols (TAG). The larger number of ESTs in these 16 datasets provided reliable estimates of the expression of acyltransferases and other enzymes expressed at low levels. Analysis of EST levels from these oilseeds revealed both conserved and distinct species-specific expression patterns for genes involved in the synthesis of glycerolipids and their precursors. Independent of the species and tissue type, ESTs for core fatty acid synthesis enzymes maintained a conserved stoichiometry and a strong correlation in temporal profiles throughout seed development. However, ESTs associated with non-plastid enzymes of oil biosynthesis displayed dissimilar temporal patterns indicative of different regulation. The EST levels for several genes potentially involved in accumulation of unusual TAG structures were distinct. Comparison of expression of members from multi-gene families allowed the identification of specific isoforms with conserved function in oil biosynthesis. In all four oilseeds, ESTs for Rubisco were present, suggesting its possible role in carbon metabolism, irrespective of light availability. Together, these data provide a resource for use in comparative and functional genomics of diverse oilseeds. Expression data for more than 350 genes encoding enzymes and proteins involved in lipid metabolism are available at the 'ARALIP' website ().

The current epidemic of obesity has been linked to an increase in fat intake associated with the Western diet. Nutrient-induced stimulation of enteroendocrine cells in the small intestine leads to the release of hormones that contribute to satiety and the control of food intake. In particular, ingested fat, specifically in the form of free fatty acids, is potent activator of enteroendocrine cells in the proximal small intestine. However, the underlying signaling cascade that free fatty acids initiate in these enteroendocrine cells, which leads to secretion of satiety hormones, is not known. In general, my research is focused on identifying nutrient-responsive pathways in enteroendocrine cells involved with the release of satiety signals and using this information to begin to develop novel drug delivery strategies to reduce food intake. In general, my results revealed that activation of the fatty acid receptor GPR120 was ecessary for the linoleic acid-induced intracellular calcium rise, a necessary precursor for hormone release. Using patch clamp recording, I discovered that linoleic acid activated enteroendocrine cells by inducing membrane depolarization, a process requiring the calcium-activated, monovalent cation permeable channel TRPM5, which is activated downstream of GPR120. To validate the unexpected finding that TRPM5 was involved in fattyacid signaling, I performed experiments using bitter compounds, whose transduction pathway is known to involve TRPM5. Enteroendocrine cells express the bitter taste receptors and release cholecystokinin in response to bitter stimuli, suggesting the probable role of gut in initiation of protective behavior against ingestion of potentially harmful substances. Armed with the data on the specifics of the fatty acid transduction, I performed experiments using nanoparticles to determine their utility for delivering pharmaceuticals specifically to the enteroendocrine cells. I fabricated and characterized PLGA nanoparticles and performed intracellular uptake studies in order to optimally delivery payloads inside cells. Finally, I validated their use by using cell-based assays to determine the effects of internalized PLGA nanoparticles on ion channels and signaling pathways involved in CCK release. Taken together, this dissertation research has identified the signaling pathways (pharmacological targets) involved in fatty acid-mediated satiety hormone release and validated the potential therapeutic use of nanoparticle-mediated drug delivery for the eventual control of food intake.

Consumer evaluation, proximate data, Warner-Bratzler shear force (WBSF), fatty acid (FA) composition and volatile compounds were analyzed from the Longissimus thoracis (LT), Tricep brachii (TB) and Gluteus medius (GM) muscles finished on conventional feedlot (FL) and forages, including a perennial legume, birdsfoot trefoil (BFT; Lotus corniculatus), and a grass, meadow brome (Bromus riparius Rehmann, Grass). Representative retail forage (USDA Certified Organic Grass-fed, COGF) and conventional beef (USDA Top Choice, TC) were investigated (n = 6) for LT. Additionally, the effects of diet on Gluteus medius (GM) and Tricep brachii (TB) muscles were explored. Forage-finished beef scored lower (P < 0.05) in most of the affected sensory attributes except BFT which was similar to grain-finished beef. In forage-finished beef GM was more liked and in FL, TB was similar to GM except juiciness where it scored greater. The fat percent was found to be greatest (P < 0.05) in TC followed by BFT and FL. Nutritionally beneficial ratios of FAs were observed in forage-finished diet. Fatty acid concentrations were majorly affected (P ≤ 0.046) by diet. Few long-chain PUFAs were affected (P ≤ 0.015) by muscle type. No FA was a effected (P > 0.05) by the interaction of muscle and diet. 3-hydroxy-2-butanone, known to evoke a buttery sensation was affected (P = 0.011) by diet with greater (P < 0.05) concentration in GM across all diets. Strecker degradation products were affected (P ≤ 0.014) by muscle type being prominent in GM. Meanwhile, 2-ethyl-3,5-dimethyl-pyrazine was greatest (P < 0.05) in BFT. All pyrazine compounds were (P < 0.05) greater in GM. These results indicate that when consumer evaluated beef of finishing diets, FL beef was rated highly. Additionally, not all forages produce similar beef. There were similar ratings for BFT for all attributes except flavor having lower values compared with FL. The chemical composition of BFT beef was found to be intermediary and similar to both FL and Grass beef in many cases. Diet was found to interact with muscle for sensory and chemical measures. The GM and TB of FL did not differ (P < 0.05), while within forage treatments sensory response and chemical composition varied. These results indicate the meat quality of secondary beef muscles is more greatly impacted by forage diets.

The prevalence of obesity, which is considered as a disease, has been increasing uncontrollably over the last two decades. Obesity is a state of disregulated energy homeostasis characterized by hypothalamic resistance to adiposity signals (insulin and leptin). While many factors are involved in the development of obesity, excess dietary fat has been proposed as one of the main causal factors. This causes disrupted energy homeostasis by inducing both leptin and insulin resistance in the central nervous system. Although brain tissue was considered to be insulin independent for a long time, insulin is now recognized to have important functions in the brain in the regulation of feeding behavior, energy expenditure and peripheral metabolism to maintain energy homeostasis. Recently, our lab discovered that insulin has an anorectic effect when it is applied into the central nucleus of the amygdala (CeA), a response that is similar to its effect when it is intracerebroventricularly (icv) administered into the hypothalamus. Our lab also demonstrated that rats fed a high fat diet lost the anorectic response to CeA insulin and became insulin resistant. These data suggested that insulin signaling in the amygdala had an important role in controlling food intake and energy expenditure in similar ways to the hypothalamus. It also suggests that a high fat diet inhibits amygdala insulin signaling in the CeA. Both in vitro cell culture and in vivo animal studies have been used to investigate the effects of dietary fats on insulin signaling in neuronal cells and in the amygdala. Using both hypothalamic GT1-7 cells and primary amygdala cells in culture, the saturated fatty acid palmitic acid was shown to inhibit insulin signaling (Akt phosphorylation). This response appears to be related to the activation of PKC-θ since the inhibitory effect of palmitic acid on Akt phosphorylation was greater in GT1-7 cells transfected with PKC-θ compared to wild type cells and was abolished in GT1-7 cells transfected with PKC-θ siRNA. Further investigations in vivo confirmed that insulin stimulated Akt and mTOR signaling in the CeA of rats and that the insulin stimulation of Akt phosphorylation, but not mTOR phosphorylation, was inhibited in rats fed a high fat diet for 3 days or by infusing palmitic acid into the CeA for 3 days. These experiments also identified that fatty acid and insulin signaling in the CeA differentially affected Akt and mTOR signaling in the hypothalamus and suggest that these neural connections might be important components of the neural pathways through which insulin in the amygdala affects food intake and peripheral metabolism. This research has provided novel insight into the effects of dietary fats on insulin signaling in an area of the brain, the CeA, that is now recognized to have effects on energy balance and peripheral metabolism.