Gonadal steroid modulation of the diabetes (db/db) mutation-induced hyperlipometabolic, hypogonadal syndrome: restoration of female reproductive tract cytochemical and structural indices.
The gonadal steroids, 17-B-estradiol (E2) and progesterone ( P), are recognized to stimulate cellular gluco- and lipo-metabolic compensatory cascades which counteract the deleterious influences of the diabetes (db/db) mutation (i.e., leptin membrane receptor defect) which promotes a progressive, hypercytolipidemia-induced premature involution of the female reproductive tract (FRT). The current studies define the therapeutic efficacy of E2 (1 microg/3.5 days) and P (1 mg/3.5 days) treatments (HRx) on utero-ovarian structural and cytochemical (gluco-/lipo-metabolic) maintenance, and the prevention of premature nuclear apoptosis and cytostructural disruption, following the expression of progressive db/db-induced hypercytolipidemia. Control (normal: +/+ and +/?) and diabetes (db/db) genotype groups of 8-week-old (i.e., overt phase of the db/db-hypogonadal syndrome) C57BL/KsJ mice were prepared for high resolution (HRLM) cytochemical and transmission electron ( TEM) microscopic analysis of cytolipidemia and nuclear apoptosis (TUNEL- labeled 3'-DNA fragmentation) indices from uterine and ovarian secondary (early antral) follicular tissue samples. Compared to HRx controls, the db/db mutation induced a dramatic increase in cytolipid vacuole volume and density within all ovarian follicular granulosa cells (GC) and uterine endometrial epithelial (UEE) layers. The co-localization of nuclear apoptotic 3'-DNA fragments within identified hyperlipidemic granulosa cells was coincident with the cytochemical and ultrastructural identification of lipid penetration through the nuclear envelope in db/db mutants. P-HRx moderated the severity of db/db-induced GC and UEE hypercytolipidemia, reducing the cytodensity of lipid vacuole accumulations and maintaining cytoplasmic organelle structure, organization, and nuclear membrane integrity. In contrast, E2-HRx resulted in a dramatic reduction in db/db cytolipidemia in both ovarian GC and UEE tissue compartments. Following E2-HRx, UEE cells demonstrated non-pycnotic nuclear profiles, reduced nuclear apoptosis TUNEL-labeling, increased cytoplasmic organelle density profiles and a pronounced cytoplasmic cisternal expansion indicative of active cellular nutrient/metabolite trafficking. Ovarian follicular GC populations demonstrated minimal cytolipidemia, a restored cytoarchitecture with prominent organelle compartments and reduced TUNEL-indexed nuclear lipoapoptosis. These results are the first cytochemical and ultrastructural indications that P- and E2-HRx compensate for the genetic db/db mutation-induced metabolic disturbances, which promote utero-ovarian hypercytolipidemia and the coincident nuclear lipoapoptosis culminating in the expressed diabetes hypogonadal syndrome. The capability of P-HRx to moderate the severity of utero-ovarian involution in db/db mutants, and of E2-HRx to restore and maintain viable GC and UEE cyto-chemical and -structural indices under normoglycemic conditions, suggests that chronic, low-dose cyclic P- and E2-HRx stimulate cellular gluco- and lipo-metabolic cascades which compensate for the lack of leptin signaling in these single-gene, obese-Type II diabetic mutants. The compensatory endometabolic maintenance of utero-ovarian cellular and nuclear architecture suggests that the gluco- and lipo-metabolic disregulation may be therapeutically prevented or reversed, restoring reproductive tract cytointegrity and function, reducing the manifestation of hypogonadal reproductive sterility and db/db compromise of the female reproductive tract.[1]References
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