Ultrastructural analysis of progressive endometrial hypercytolipidemia induced by obese (ob/ob) and diabetes (db/db) genotype mutations: structural basis of female reproductive tract involution

Abstract

The diabetes (db/db) and obese (ob/ob) genotype mutations induce a progressive, hypercytolipidemic condition within the endometrium of the female reproductive tract that promotes sterility and premature organ involution in C57BL/KsJ mice. The current studies focus on the ultrastructural changes that occur within the epithelial and stromal layers of the uterine endometrium during the progressive expression of these mutations, which induce a hyperglycemic-hyperinsulinemic metabolic state and promote tissue cytolipidemia and organoinvolution. Control (normal: +/−), diabetes (db/db) and obese (ob/ob) genotype groups were prepared for high resolution light (LM) and transmission (TEM) microscopic analysis of endometrial tissue samples collected from 4 (young)- to 20 (aged)-week-old mice, allowing for the progressive influences of the mutational aberrations on uterine structure to be evaluated. Compared to controls, both (ob/ob) and (db/db) mutations induced a dramatic increase in endometrial epithelial cytolipid vacuole accumulation, which increased in density between 4 and 20 weeks of age. Lipid vacuoles aggregated at the baso-polar regions of epithelial cells in response to the hyperglycemic-hyperlipidemic conditions typical of both (ob/ob) and (db/db) groups. Progressive cytoplasmic movement of the lipid pools induced a perinuclear isolation from surrounding cytoplasmic organelles. Apical lipid accumulations forced cytoplasmic organelles into peripheral cell compartments and altered the periepithelial stromal cell profile relative to controls. These studies define the progressive, intracellular accumulation of hypercytolipidemic pools which induce a transformation of normal endometrial cell types into adipocyte-like entities. The lipidemia-induced alterations in cell structure disrupt normal tissue continuity and function, culminating in organoinvolution and overt female reproductive sterility.