Cytolipotoxicity-induced involution of the female reproductive tract following expression of obese ( ob/ ob) and diabetes ( db/ db) genotype mutations: progressive, hyperlipidemic transformation into adipocytic tissues

Abstract

Both diabetes ( db/ db) and obese ( ob/ ob) single gene mutations induce a progressive, hyperglycemic–hyperinsulinemic endometabolic environment which promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice. The progressive expression of the induced diabetes–obesity syndrome (DOS) results in female reproductive sterility and eventual organoatrophy. In order to define the intra-cytoplasmic alterations induced by the progressive cytolipidemia on cellular vitality, utero-ovarian tissue samples were collected from both control ( +/?) and littermate-matched ob/ ob or db/ db C57BL/KsJ mice at either 4 weeks (initial-onset DOS phase), 8 weeks (progressive, overt DOS phase), or 16 weeks (chronic-DOS phase) of age for cytolipid distribution analysis. All db/ db and ob/ ob mutant groups exhibited phenotypic obesity and systemic hyperglycemia–hyperinsulinemia relative to age-matched littermate +/? groups. In all db/ db and ob/ ob age groups, a progressive hypercytolipidemia was noted relative to +/? groups. When analyzed for lipid channeling, a progressive perinuclear mapping pattern of cytolipid distribution was noted. The primary locus of initial db/ db and ob/ ob cytolipid deposition was localized to the baso-polar regions in endometrial epithelia samples, or to the interstitium-thecal layer border of ovarian follicular compartments, during the initial-onset DOS phase. Progressively, intra-cytoplasmic lipid mobilization promoted a consistent perinuclear channeling of lipid vacuoles, ultimately isolating nuclear loci from the peripherally displaced cytoplasmic organelles within uterine epithelial layers. In db/ db and ob/ ob ovarian tissue samples, a progressive, gradient-related lipid infiltration of interstitial, thecal and, ultimately, granulosa cell layers promoted an enhanced rate of follicular-lipidemic atresia relative to +/? groups. In each tissue layer, the cytolipidemia promoted a dramatic perinuclear lipid-isolation barrier from intra-cytoplasmic organelle domains. With age-related exacerbation of the DOS syndrome, cytoplasmic nuclear-organelle displacement and lipoisolation resulted in cellular atresia, promoting the eventual utero-ovarian organoatrophy which characterized the chronic-DOS phase in db/ db and ob/ ob C57BL/KsJ mutants. These results indicate that the cytoinvolution associated with reproductive tract atrophy in these genetically mutant, diabetic–obese models is promoted by the disruption of the normal cytoarchitecture of utero-ovarian tissue layers induced by the progressive lipid sequestration, accumulation and ultimate isolation-induced disruption of intra-cellular organelle compartmentalization.