MORPHOLOGICAL AND METABOLIC RESPONSES TO PHYSIOLOGICAL STRESS IN A MOUSE MODEL WITH ALBUMIN DEFICIENCY

Albumin is the primary carrier of free fatty acids (FFA) in the plasma. Plasma FFA is mainly released from white adipose tissue (WAT) by lipolysis and elevated plasma FFA concentration is recognized as a risk factor for metabolic syndrome. Our lab has considered albumin to be a target to reduce plasma FFA levels and flux. We have pioneered the use of the albumin knockout (Alb^-/-) mouse model to investigate health responses to reduced plasma FFA levels. We previously showed Alb^-/- mice had low FFA levels and flux, reduced ectopic lipid accumulation and improved insulin sensitivity. However, it was still unknown how this mouse model responds to different physiological stressors, including acute exercise, its intracellular FFA retention, and aging. It was also unknown how these responses are reflected in the animals’ remodeling of cellular and subcellular architecture. Thus, one of the novelties of this dissertation is the use of transmission electron microscopy to elucidate the ultrastructural changes in different organs as a result of various physiological challenges. To study a mouse without albumin, the foremost task is to determine the lack of albumin by a reliable assay. Therefore, the first chapter in this dissertation aimed to evaluate different assays that are commercially and clinically used to measure plasma/serum albumin levels. We found that enzyme-linked immunosorbent assay and mass spectrometry can accurately characterize albumin deficiency. The second chapter was conducted to study the metabolic changes in Alb^-/- mice by using acute exercise as a stressor. Results showed that Alb^-/- mice had lower hepatic glycogen levels and exhibited an enhanced ability to reduce hepatic lipid droplet (LD) abundance in response to exercise. We also revealed a potential relationship between hepatic glycogen and LD maintenance. The third study was a characterization of remodeling of WAT in reaction to intracellular FFA sequestration that occurs in albumin deficiency. Our results showed that when no albumin is present to facilitate FFA mobilization, WAT can chronically adapt to protect the adipocytes in both morphological and molecular manners. The morphological adaptations in Alb^-/- mouse WAT included lower caveolar density, higher micro-LD abundance, smaller size and rounder shape of mitochondria. In support of the ultrastructural phenotype, lipidomic analysis also demonstrated a significant difference between Alb^-/- and wildtype (WT) for triacylglycerol composition. The last chapter was a pilot study to reveal how Alb^-/- mice respond to aging. We found no major adverse effect of albumin deficiency on lifespan and physical functionality. Alb^-/- mice showed no statistically significant difference in life expectancy, but lower body weights during aging. Surprisingly, they exhibited better muscle strength and function when they reached the ‘elderly’ age, as compared with WT mice. Taken together, this dissertation depicts the morphological and metabolic responses to different physiological stressors in the Alb^-/- mouse model. The findings enhance our understanding of the ultrastructural and molecular changes that can occur in various cell types when they are metabolically challenged. The physiological and cellular plasticity responses described here could potentially be harnessed in the future to enhance tissue plasticity and modulate the response to a wide variety of stressors and metabolic challenges.