Nutritional Factors Impacting Intestinal Lipid Metabolism Using a Model of Low Birth Weight Swine

  • Author / Creator
    Fontaine, Melanie A
  • Introduction: Non-communicable diseases (NCDs) such as obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD) are increasing at an alarming rate globally. A common feature in these conditions is increased adiposity leading to insulin resistance (IR). Dyslipidemia is a major contributing factor to increased CVD risk during conditions of IR and obesity, with intestinal lipid metabolism being of interest to our laboratory. Diet greatly impacts risk and outcome for NCDs, making the intestine (the main organ handling dietary intake) of interest to this thesis. Current rodent models for investigating intestinal adaptations during IR are not ideal for translation to humans due to critical differences in lipid metabolism. Therefore, a focus of this thesis was to develop a large animal model that would more closely mimic early insulin resistance in humans. Epidemiological studies have a shown a strong correlation between low birth weight (LBW) and an increase in NCD risk in adulthood. Along with physiological and metabolic similarities to humans, swine have the highest spontaneous production of LBW offspring among mammals due to uterine capacity. It is not known to what extent the intestine would be affected in LBW swine induced to develop early IR and dyslipidemia, and if mechanisms can be found that translate to humans. Objectives: To develop a LBW swine model and determine if a high-fat, high-carbohydrate diet is necessary to induce early insulin resistance. To assess the swine LBW phenotype under conditions of an (i) post-weaning, 6-week, age without dietary invention; (ii) early weaning and introduction of solid feed; and (iii) lipid-lowering and insulin-sensitizing effects of vaccenic acid (VA) during a high-fat, high-carbohydrate diet intervention. Methods: Low birth weight (less than the 95% CI of the mean) and normal birth weight (NBW, within or above the 95% CI of the mean) male Landrace-Large White x Duroc crossed production piglets were selected at birth from the University of Alberta’s Swine Research and Technology Center (SRTC). In Study 1, swine were fed control or high-fat, high-carbohydrate (HFHC) diet for 6 weeks, post-weaning, until 13 weeks of age. An adapted 2-step modified oral glucose tolerance and fat challenge test (MOGTT) was completed to assess insulin and glucose metabolism, as well as mesenteric lymph cannulation to assess intestinal lipid metabolism. For Study 2, swine were fed control diet until 6 weeks of age to assess the influence of age and diet. In Study 3, swine were weaned early (at 2 weeks of age) and fed control diet until 13 weeks of age to test the influence of weaning. In the final study (Study 4), swine were fed either control, HFHC or HFHC enriched in VA for 6 weeks, post-weaning, until MOGTT and lymph cannulation was completed at 10 weeks of age. All studies had biochemical and protein analysis related to lipid metabolism completed. Results: When fed a control diet, LBW offspring had a trend towards a modest increase in insulin sensitivity. In contrast, when fed a HFHC diet, LBW offspring had impaired glucose tolerance relative to control. Interestingly, both LBW groups showed signs of impaired intestinal lipid metabolism, irrespective of diet and insulin status when compared to normal birth weight counterparts. When fed control diet, the LBW characteristics were not observed at 6 weeks of age, nor when weaned at 2 weeks of age, suggestive of a post-natal adaptation impacted by solid feed introduction. Enriching the HFHC diet with VA resulted in improved dyslipidemia and a mild reduction in insulin resistance in the metabolically challenged LBW swine model. Conclusion: Our data provide experimental evidence that LBW swine develop impaired intestinal lipid metabolism during early phases of insulin resistance and is consistent with data in both rodent and human studies. Our data reveal that a postnatal HFHC diet can induce early insulin resistance in this model and influence lipid metabolism. The observed alterations in insulin and lipid metabolism indicate that LBW swine can be used as a translational model for humans. Low birth weight swine may be of high relevance in situations where rodent models are limited in their translation to human diseases such as CVD and the Metabolic Syndrome.

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  • Degree
    Master of Science
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