Investigating Diet and Exercise Modifications on Delta-6 Desaturase and Ghrelin Regulation of Skeletal Muscle and White Adipose Tissue Lipid Metabolism

Evidence supports a role for delta-6 desaturase (D6D) and ghrelin in regulating white adipose tissue (WAT) and skeletal muscle metabolism, particularly in the context of lifestyle modifications such as dietary fat consumption and exercise training. Changes in D6D activity, an enzyme involved in omega-3 polyunsaturated fatty acid (n-3 PUFA) metabolism, are associated with ¬¬¬altered whole-body glucose metabolism and increased risk of developing metabolic diseases such as Type 2 diabetes (T2D). In addition to signaling hunger and stimulating growth hormone (GH) release, ghrelin contributes to the control of WAT lipolysis. Studies have shown that circulating ghrelin levels change with high-fat diet (HFD) consumption and exercise. However, it is unknown how D6D and ghrelin regulate adipose and skeletal muscle metabolism in the context of different lifestyle modifications. In the first part of the thesis, reduced D6D activity partially protected Fads2+/- mice from high-fat diet (HFD)-induced impairments in glucose tolerance. We also investigated the impact of different n-3 PUFA using a Fads2-/- mice. Mice were fed either a flaxseed (contains alpha-linolenic acid) or menhaden (eicosapentaenoic and docosahexaenoic acid) oil diet. Flax-fed Fads2-/- mice had increased insulin sensitivity and decreased body weight compared to menhaden-fed Fads2-/- mice. However, neither of these studies showed changes in whole-body energy expenditure, skeletal muscle lipid species content and composition, or other protein markers of glucose or fatty acid uptake, storage or oxidation. To our knowledge, these novel studies are the first to investigate the effect of D6D activity on skeletal muscle glucose and lipid metabolism. These findings suggest that dietary fat consumption (regardless of quantity or composition) does not influence the effects of D6D activity at the level of skeletal muscle. The last part of this thesis investigated the role of ghrelin in modulating B-adrenergic-stimulated WAT lipolysis. Although the acylated isoform (AG) blunted WAT lipolysis in LFD-fed rats, 5 days and 6 weeks of HFD consumption both impaired ghrelin’s anti-lipolytic effect, which was not restored with exercise training. This study showed that HFD-feeding impairs ghrelin’s ability to regulate WAT lipolysis. Collectively, this thesis demonstrates that D6D and ghrelin regulation of peripheral tissue metabolism is dependent on dietary fat content and composition.