UC Davis

Obesity constitutes a major global public health threat. It can lead to a cluster of metabolic disorders and a higher risk of developing various types of pathological conditions and diseases. Among multiple environmental factors, high fat diets (HFD) play an important role in the development of obesity. Flavonoids are one of the most abundant categories of bioactive compounds present in the human diet. My dissertation work identified mechanisms by which the flavan-3-ol (-)-epicatechin (EC), could mitigate high fat diet-induced obesity-associated intestinal permeabilization and metabolic endotoxemia. Chapter one looked at the protective effects of EC from HFD-induced intestinal barrier permeabilization and endotoxemia and its implications for steatosis and insulin resistance in vivo. We subsequently found that the luminal content of total bile acid and select secondary bile acids, particularly deoxycholic acid, were increased by HFD consumption. The second chapter focused on investigating if EC could prevent DCA-induced intestinal permeabilization in vitro. Such effect could in turn, help prevent the paracellular transport of lipopolysaccharides (LPS) from the lumen into the bloodstream. The last chapter provided additional mechanistic insight into how flavan-3-ols and procyanidins (PCAs) can mitigate HFD-induced endotoxemia through their capacity to prevent chylomicron- dependent transcellular transport of LPS in Caco-2 monolayers and high fat-induced postprandial endotoxemia in mice. In summary, this thesis works provide evidence that EC can decrease HFD-associated endotoxemia, characterizing the underlying mechanisms. This action would be critical to the capacity of EC to mitigate HFD- and obesity-associated comorbidities.