Date of Award

1-1-2022

Embargo Period

4-22-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Catrina Robinson

Second Advisor

Adviye Ergul

Third Advisor

Jane E. Joseph

Fourth Advisor

Carmela Reichel

Abstract

High-fat diet (HFD) in mice, a mouse model of diet-induced obesity, display cognitive deficits, which correlate with hyperinsulinemia and reduced levels of brain insulin. The binding of insulin to the insulin receptor leads to tyrosine auto-phosphorylation of the receptor, which is a necessary step for the initiation of insulin transport. Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues on the Insulin receptor. We hypothesize that diet-induced increases in PTP1B levels inhibits insulin receptor signaling contributing to cognitive impairment. To accomplish this, PTP1B levels, tyrosine phosphorylation, and cognition was assessed in mice placed on either a standard diet (STD) or HFD for 12-24 weeks of diet treated with either saline (control) or Claramine (10-180g), a specific and selective PTP1B inhibitor. After 12 weeks of diet, PTP1B levels were increased in HFD mice compared to STD mice. A single intraperitoneal dose of Claramine (180g) reduced PTP1B levels and increased tyrosine phosphorylation of the Insulin receptor in the hippocampus. HFD mice display cognitive deficits using a problem-solving task, the Puzzle Box; however, Claramine treatment delivered via mini osmotic pumps, improved cognitive deficits in HFD mice compared to STD mice. Postmortem hippocampal tissue analysis revealed no significant differences in PTP1B levels nor the expected increase in tyrosine phosphorylation in HFD mice treated with Claramine. Given that the hippocampus contains multiple cell types, we investigated the impact of hyperinsulinemia, to mimic HFD in vitro, on PTP1B, tyrosine phosphorylation of the Insulin receptor, and downstream insulin signaling in primary brain endothelial cells, one of the main cell types involved in mediating Insulin receptor transport from the periphery to the brain. PTP1B levels are increased in hyperinsulinemic cells and reduced in hyperinsulinemic cells treated with Claramine. While there are no significant differences in tyrosine phosphorylation there is a trending decrease in hyperinsulinemic cells with trending increase in hyperinsulinemic cells treated with Claramine. Overall, our data demonstrates that Claramine is an effective inhibitor of PTP1B in vivo and in primary endothelial cells and can improve diet-induced cognitive deficits; however, additional studies are warranted.

Rights

All rights reserved. Copyright is held by the author.

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