Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biotechnology Science and Engineering

Committee Chair

Sharifa T. Love-Rutledge

Committee Member

Bernhard Vogler

Committee Member

Luis R. Cruz-Vera

Committee Member

Teng-Leong Chew

Committee Member

Bradley Kraemer

Research Advisor

Sharifa T. Love-Rutledge

Subject(s)

Obesity--Complications, Insulin resistance, Glucose--Metabolism, Liver--Diseases, Metabolism--Animal models

Abstract

Obesity is an epidemic that affects over 40% of adults in America. Obesity can be divided into metabolically healthy and metabolically unhealthy obesity, with the latter being characterized by symptoms closely associated with metabolic syndrome, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). What causes the transition from metabolically healthy to metabolically unhealthy obesity is not fully known. Further, it is unclear how this transition correlates with the onset of co-morbid conditions. We propose that Ubiquitin D (FAT10) may play a role in transitioning into a metabolically unhealthy state in response to obesity. This dissertation evaluated two main research questions: 1) would LEW.1WR1 rats, predisposed to overexpress FAT10, develop symptoms of metabolic dysfunction such as insulin resistance, obesity, and MASLD over time? and 2) does increased FAT10 expression in hepatocytes cause changes that could negatively impact cellular metabolism? We report that LEW.1WR1 rats have insulin resistance as measured using Insulin tolerance tests. LEW.1WR1 rats developed glucose intolerance and worsening insulin resistance as they aged but did not develop ꞵ-cell expansion on a moderate sucrose diet. LEW.1WR1 rats on a chow diet developed MASLD based on validated histological scoring criteria and decreased fatty acid oxidation gene expression, which we believe is due to a significant increase in FAT10 gene expression in their livers. We then pursued whether increased FAT10 impacts hepatocytes with fluorescent microscopy and observed that increased expression causes disrupted mitochondrial area and volume, which could indicate megamitochondria or stress-induced mitochondrial hyperfusion. Our results show that LEW.1WR1 rats developed glucose intolerance, insulin resistance, and severe MASLD on a chow diet, indicating they may be a more human-like rodent model for developing metabolic disorders. Our research also showed that increased FAT10 expression induced mitochondrial morphology dysfunction, further supporting FAT10 as a target for early detection of metabolic diseases.

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