Dissertation/Thesis Abstract

Peroxisome proliferator activated receptor-gamma P465L mutation in diabetes and atherosclerosis
by Pendse, Avani A., Ph.D., The University of North Carolina at Chapel Hill, 2010, 169; 3428395
Abstract (Summary)

The dominant-negative P467L mutation in peroxisome proliferator activated receptor-γ (PPARγ) was identified in insulin resistant patients with hyperglycemia and lipodystrophy. However, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. I hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, masked by hyperinsulinemia, to retain normal plasma glucose. I introduced in PpargP465L/+ mice, Ins2Akita mutation that causes islet apoptosis to lower plasma insulin. Unlike Ins2Akita/+ littermates, male PpargP465L/+Ins2Akita/+ mice have drastically reduced life-span. PpargP465L/+Ins2 Akita/+ females have aggravated hyperglycemia, smaller islets, reduced plasma insulin and impaired insulin sensitivity. Enhanced gluoconeogenesis, due to reduced plasma insulin, in PpargP465L/+Ins2 Akita/+ females compared to Ins2Akita/+ littermates, contributes to their fasting hyperglycemia. While liver and skeletal muscles remain sensitive, adipose tissue is resistant to insulin. PpargP465L/+Ins2Akita/+ mice have smaller fat depots composed of larger adipocytes suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia. The increasing prevalence of obesity and insulin resistance and its negative impact on atherosclerotic cardiovascular disease is of major concern. In the second part of my study, I hypothesized that the L/+ mutation will worsen atherosclerosis in Apoe-/- mice. Despite a consistent increase in blood pressure, PPARγP465L/+ mutation did not affect plaque size in Apoe-/- mice fed normal chow or high-fat-diet. Gene expression studies revealed significantly increased ABCA-1 and decreased CD-36 in PPARγP465L/+;Apoe-/- macrophages compared to Apoe-/- littermates, suggesting reduced lipid accumulation. Cultured PPARγP465L/+;Aoe-/- macrophages, had a significant reduction in DiI-labeled-VLDL uptake, compared to Apoe-/- macrophages. It is likely that balance between increased blood pressure with its pro-atherogenic potential and macrophage athero-protective phenotype results in an unchanged plaque. Bone marrow transfer experiments to investigate the role of PPARγP465L/+ mutation specifically in the macrophage showed a trend towards decrease in plaque size in mice reconstituted with PPARγP465L/+; Apoe-/- macrophages.

Thus, I have established the causative link between PPARγP465L mutation and insulin resistance phenotype, consolidating the crucial role of PPARγ in diabetes. PPARγP465L mutation, however, does not change the atherosclerotic plaque size in Apoe-/- mice, and warrants further investigation.

Indexing (document details)
Advisor: Maeda, Nobuyo
Commitee: Combs, Terry, Cordeiro-Stone, Marila, Homeister, Jonathon, Takahashi, Nobuyuki
School: The University of North Carolina at Chapel Hill
Department: Pathology
School Location: United States -- North Carolina
Source: DAI-B 72/01, Dissertation Abstracts International
Subjects: Genetics, Pathology, Physiology
Keywords: Adipose tissue, Atherosclerosis, Diabetes, Hepatocyte, Insulin resistance, P465L mutation, Peroxisome proliferator activated receptor, Ppar Gamma
Publication Number: 3428395
ISBN: 978-1-124-35000-4