Multifaceted Bioactivity of Alaskan Marine Algae Against Metabolic Syndrome Targets

Coastal seaweeds are fundamental components of traditional diet and medicine for indigenous cultures worldwide, especially among Native American and Alaska Native (NA/AN) tribes and First Nations. Indigenous communities have consumed seaweed for generations, and these marine resources form an important part of the communities' traditional ecological knowledge, providing important nutrients as well as a source of novel bioactive phytochemicals. For this project, six species of coastal Alaskan seaweed were evaluated in multiple in vitro assay systems for their potential to attenuate underlying causes of diabetes and obesity, and the underlying phytochemistry that might play a role in the observed bioactivity was investigated.;Chapter 1 presents an overview of the potential role of Alaskan seaweeds in metabolic syndrome, summarizing the relevant literature and studies of the underlying causes of metabolic syndrome. A review of seaweed phlorotannins and their traditional ecological uses by NA/AN are briefly described in Chapter 2.;The first study (Chapter 3) examined the chemical antioxidant capacity of these macroalgae samples. The antioxidant capability was assessed by measuring radical quenching and ferrous iron chelation in a series of colorimetric assays. The highest radical scavenging activity was exhibited by Fucus distichus and Saccharina groenlandica fractions (IC 50 4.29 -- 5.12 mug/mL). F. distichus and Alaria marginata demonstrated the greatest inhibitory potential of nitric oxide (NO) inhibition and radical oxygen species (ROS) generation in an in vitro macrophage culture. These results suggest that Alaskan seaweed extracts contain powerful antioxidant phytochemicals that could offset oxidative stress-related chronic health conditions.;A second study (Chapter 4) explored the inhibition of the carbohydrate-hydrolyzing enzymes, alpha-glucosidase and alpha-amylase. F. distichus and A. marginata significantly reduced enzyme activity, even more potent than the known pharmaceutical acarbose. F. distichus subfractions were potent mixed-mode inhibitors of alpha-glucosidase and alpha-amylase, with IC50 values of 0.89 and 13.9 mug/mL, respectively. The observed bioactivity of the F. distichus fractions was associated with the presence of fucophloroethol oligomers with degrees of polymerization up to 18 monomer units. These findings suggest that coastal Alaskan seaweeds are sources of alpha-glucosidase and alpha- amylase inhibitory phlorotannins, and thus have potential to limit the degradation of carbohydrates and alleviate postprandial hyperglycemic spikes.;Finally, investigations into the anti-inflammatory potential of Alaskan seaweed were carried out using multiple in vitro cell models (Chapter 5). Extracts from the brown seaweeds were most effective at reducing gene expression of five preliminary inflammatory markers. F. distichus was selected for further study, and subfractions FD-18 and FD-24 significantly inhibited an array of 12 inflammatory markers in LPS-induced macrophage cells. This phenomenon appeared to proceed via reduction in expression of toll-like receptor 4 (TLR4). In 3T3-L1 adipocytes, the active subfractions FD-18 and FD-24 lowered lipid levels to 48.5% and 45.9% of the untreated control, respectively. The two subfractions also reduced inflammatory gene markers in a dose-dependent manner, while increasing adipogenic genes. The fraction FD-24 was found to contain higher phlorotannin oligomers (> 9 DP), while FD-18 contained a monoglycosyldiacylglycerol possessing two eicosatetraenoic acid (C20:4 o-3) fatty acid residues. These results suggest that brown Alaskan seaweeds, especially F. distichus, contain multiple phytochemicals capable of ameliorating inflammation and are able to reduce the potential lipid accumulation in mature adipocyte cell systems.;Collectively, these findings suggest that Alaskan seaweeds classes of phytochemicals that modulate multiple pathways associated with the development of metabolic syndrome. The bioactive phytochemicals were capable of combatting oxidative damage, reducing metabolic overload through lowered digestive enzyme activity, and lowering the expression of chronic inflammation makers and inhibiting lipid accumulation in mature adipocytes. Thus, this thesis highlights the potential of Alaskan seaweed as a dietary agent to support human health and protect against insulin resistance and obesity.