Masters Theses

Date of Award

8-2001

Degree Type

Thesis

Degree Name

Master of Science

Major

Comparative and Experimental Medicine

Major Professor

Dr. Roger C. Carroll

Committee Members

Dr. Naima Moustaid Moussa, Dr. John Erby Wilkinson

Abstract

Dominant mutations in the promoter region of the mouse agouti gene lead to a syndrome characterized by agouti yellow coat color, obesity, hyperinsulinemia, hyperglycemia, type II diabetes and increased linear growth. The mechanism of agouti modulation of the coat color development as well as obesity involves competitive antagonism of the ? -melanocortin stimulating hormone at its receptor.

Hyperplasia of the pancreatic ? cells in agouti mice precedes the development of obesity. Enhanced insulin secretion is induced in vitro by agouti effects on calcium influx into islet cells. Preliminary testing of insulin producing pancreatic cells has shown that exposure to high doses of an immunosuppressive drug tacrolimus (FK506) altered the secretion of insulin. The hypothesis of the present study is that FK506 treatment of transgenic mice, which either overexpress the agouti gene ubiquitously or in the adipose tissue, may alter expression of agouti mRNA and protein. Agouti mice also have an impairment of the immune system thus, another hypothesis to be tested was if immunosuppression by FK506 would amplify the agouti phenotype.

There was decrease in food intake and glucose levels in the aP2 mice with Tacrolimus (FK506). There was no detection of agouti mRNA or protein in adipose or pancreatic tissue of wild type mice and no significant effect of FK506 on agouti mRNA or protein expression in the aP2 mice. Toxic effects of FK506 at this dose in both mice were not significant.

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