Biomedical subjects

Bryan L Garris

Publications and source records attributed to Bryan L Garris.

12 recordsLinked to original sources

PubMed2005

Structural, metabolic and endocrine analysis of the diabetes (db/db) hypogonadal syndrome: relationship to hypophyseal hypercytolipidemia.

Expression of the diabetes (db/db) mutation in C57BL/KsJ mice results in functional suppression of the female pituitary-gonadal axis accompanied by premature utero-ovarian cytolipoatrophy. Cellular gluco- and lipo-metabolic disturbances promoted by the db/db systemic hyperglycemic-hyperinsulinemic state suppress pituitary gonadotropin release in response to gonadotropin-releasing hormone and gonadal steroid stimulation and results in a hypogonadal-infertility syndrome. Adult female C57BL/KsJ control (+/+ and +/? genotypes) and db/db littermates were monitored for associations in systemic and cellular alterations in luteinizing hormone (LH), follicle-stimulating hormone (FSH), gonadal steroid (binding) levels, and pituitary glucometabolic indices associated with db/db-enhanced lipid imbibition and cytostructural disruption. Obesity, hyperglycemia, and hyperinsulinemia characterized all db/db mutants relative to controls. Serum and pituitary progesterone and estradiol concentrations were suppressed in db/db mutants, in association with serum LH and FSH levels, but not with pituitary LH and FSH concentrations, which were comparable between groups. Pituitary insulin receptor binding and glucose utilization rates were suppressed in db/db groups relative to +/? indices. Structural and cytochemical analysis of anterior (AP), intermediate (IL), and neuro-(NP) hypophyseal lobes demonstrated prominent hypercytolipidemia in db/db mutants relative to controls. Prominent cytolipidemia was localized within well-granulated basophilic gonadotrophs and within IL and NP pituicytes. Vasolipidemia and interstitial cytoadiposity were prominent throughout all db/db pituitary lobes. Thus, disturbances associated with pituitary hypercytolipidemia are functional components of the expressed diabetes-associated hypogonadal syndrome in db/db mutants. Progressive alterations in hypophyseal cytoarchitecture are correlated with suppression of pituitary metabolic and endocrine indices, alterations that contribute to functional disruption of the pituitary-hypogonadal axis in C57BL/KsJ-db/db mice.

Adipocytes↗

PubMed2004

Estrogenic restoration of functional pancreatic islet cytoarchitecture in diabetes (db/db) mutant C57BL/KsJ mice: relationship to estradiol localization, systemic glycemia, and persistent hyperinsulinemia.

The diabetes (db/db) genotype mutation induces a hyperglycemic-hyperinsulinemic endometabolic state in C57BL/KsJ mice, manifesting a type 2 NIDDM diabetes-obesity syndrome (DOS) in this hyperphagic, leptin receptor (lf) defective model. The severity of the DOS induced by the single gene, homozygous-recessive mutation may be therapeutically moderated by gonadal steroids and pre-steroidal metabolites. The current studies define the estradiol (E2)-modulated phenotypic, systemic, cytochemical, and cellular metabolic responses to db/db mutation expression as compared to littermate control (+/?) indices. The db/db mutation induced dramatic age- and DOS severity-related increases in body weights, blood glucose, and serum insulin concentrations relative to +/? indices between 4-week-old (i.e., initial onset stage of DOS phenotype) and 16-week-old (i.e., chronic stage of DOS) groups. Chronic, low-dose (0.1 microg/3.5 days) E2 treatment (E2-HRx) significantly reduced the obesity mass and blood glucose levels of db/db mutants relative to oil-HRx groups. Similarly, E2-HRx maintained pancreatic glucose utilization rates and pancreatic tissue weights in db/db mutants to near +/? indices. Concurrent amelioration of db/db-enhanced pancreatic lipogenesis and islet hypercytolipidemia occurred following E2-HRx. Pancreatic islet lipo-deposition was markedly reduced in db/db mutants following E2-HRx, and the restoration of islet size and cellular insulin concentrations correlated with beta-cell cytoplasmic regranulation of insulin secretory vesicles. In chronic E2-HRx db/db groups, autoradiographic localization of (3)H-E2 was demonstrated in the nuclear compartments of regranulated, nonhypertrophic islet cell populations, including insulin-containing beta-cells. In chronic E2-HRx db/db mutants, beta-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets, with cytodistribution patterns and concentrations comparable to normal +/? indices. In contrast, E2-HRx maintained the systemic hyperinsulinemia characteristic of oil-HRx db/db mutants. The results of these studies indicate that the severity of the type 2 NIDDM endometabolic syndrome induced by the db/db genotypic mutation may be influenced by E2-HRx, including reduction of the islet hypercytolipidemia and hypertrophic atrophy which are indicators of impending pancreatic involution in this mutant model. The hypercytolipidemia-induced demise of beta-cell cytoarchitecture was reduced by E2-HRx, including the reestablishment of islet beta-cell cytogranulation. These data suggest that the severity of genomic db/db-mutation expression may be modified by E2-HRx, with the gonadal steroid probably acting as a nuclear-specific stimulatory transcriptional modulator of cellular glucometabolic cascades in the absence of leptin-directed homeostatic influences.

Acetyl-CoA Carboxylase↗

PubMed2004

Genomic modulation of diabetes (db/db) and obese (ob/ob) mutation-induced hypercytolipidemia: cytochemical basis of female reproductive tract involution.

Infertility and hypercytolipidemic utero-ovarian involution are recognized consequences of the diabetes-obesity syndrome (DOS) in C57BL mice with either obese (ob/ob) or diabetes (db/db) single gene mutations. We have evaluated the interdependent deleterious influences of both mutation types and differences in the genomic background on utero-ovarian dysfunction in C57BL mice. Control ( +/?) C57BL mice were matched with littermate ob/ob and db/db mutants expressed on either the /KsJ or /6 background. Both ob/ob and db/db mutations increased body weights of /KsJ and /6 background strains relative to +/? groups. In contrast, uterine and ovarian weights were depressed by ob/ob and db/db mutations relative to +/?, regardless of the background strain, but especially when expressed on the /KsJ background. Functionally, both ob/ob and db/db mutations induced hyperglycemic-hyperinsulinemic states coupled with depressed serum estradiol-17-beta and progesterone concentrations when expressed on a /KsJ background. Microscopic analysis of utero-ovarian tissue samples revealed marked hypercytolipidemia in the follicular granulosa and endometrial epithelial tissue layers of both ob/ob and db/db mutant groups relative to normal +/? cytoarchitecture. The db/db mutation consistently promoted more severe hypercytolipidemic profiles than the ob/ob mutation, regardless of background strain. Thus, the severity of utero-ovarian hypercytolipidemia following the expression of ob/ob and db/db mutations in C57BL mice is influenced, or moderated, by the genomic background on which the mutation is expressed.

Animals↗

PubMed2004

Diabetes (db/db) mutation-induced female reproductive tract hypercytolipidemia: estrogenic restoration of utero-ovarian indices.

The diabetes (db/db) mutation (leptin-receptor defect) induces a hyperglycemic-hyperinsulinemic endometabolic environment that promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice, resulting in reproductive sterility and eventual organoatrophy. The effectiveness of low-dose, 17-B-estradiol therapy (E2-HRx), initiated prior to the genetic expression of the overt diabetes-obesity syndrome (DOS) on preventing female reproductive tract involution was evaluated by analysis of cytochemical, endocrine and tissue lipo-metabolic indices relative to oil (O)-vehicle treated (HRx) control (+/?) and (db/db) groups. All HRx treatments started at 4 weeks of age (i.e., pre-overt DOS stage) and continued through 16 weeks of age (i.e., chronic DOS expression) when tissue parameters were evaluated. The DOS promoted a dramatic increase in phenotypic obesity, hyperglycemia and hyperinsulinemia in (db/db) groups, relative to (+/?) indices, throughout the experimental period. In contrast, utero-ovarian weights were dramatically reduced in (db/db) groups relative to (+/?). Chronic low-dose E2-HRx moderated these DOS-induced trends in (db/db) groups, maintaining lowered body weights and normoglycemic parameters while stimulating utero-ovarian weight indices. In addition, E2-HRx prevented the dramatic hypercytolipidemic condition which promotes utero-ovarian involution in (db/db) mice as evidenced by the maintenance of normal reproductive cytoarchitecture. The concurrent moderation of tissue lipase activity and stimulated glucose uptake rates by (db/db) utero-ovarian compartments, under persistent hyperinsulinemic influences, indicated that E2-HRx effectively reduced both the structural and endometabolic consequences of the DOS from promoting (db/db)-associated reproductive organoatrophy. These results indicate that the pathophysiological alterations induced by the (db/db) mutation may be ameliorated through low-dose steroidal therapy, the efficacy of which is suspected to occur via membrane metabolic cascade induction mechanisms or by direct nuclear transcription modulation in reproductive target cells. The subsequent re-establishment of insulin-coupled glucose utilization and suppressed caloric shunting towards lipogenesis promotes the normalization of utero-ovarian structural and metabolic homeostasis in C57BL/KsJ-db/db mutants.

Animals↗

PubMed2004

Hypophyseal lipoapoptosis: diabetes (db/db) mutation-associated cytolipidemia promotes pituitary cellular disruption and dysfunction.

Expression of the diabetes (db/db) mutation in C57BL/KsJ mice suppresses the female pituitary-gonadal axis via progressive cytolipidemic disruption of hypophyseal gonadotropin release, culminating in premature involution of the reproductive tract and manifest infertility. The current studies define the systemic, endocrine, cytochemical and structural apoptotic changes that result from pituitary hypercytolipidemia induced by db/db mutation expression in this Type II diabetes-obesity syndrome (DOS) model. Adult female C57BL/KsJ control (+/? genotype) and db/db littermates were monitored for systemic and cellular alterations in LH-, FSH- and gonadal steroid-secretion, and coincident pituitary apoptosis, as indexed by TUNEL labeled 3' nuclear DNA-fragmentation, associated with cytolipid depositions. Obesity, hyperglycemia and hyperinsulinemia characterized all db/db-mutants relative to +/? groups. Serum progesterone (P) and estradiol (E2) concentrations were suppressed in db/db mutants coincident with decreased plasma LH and FSH concentrations relative to +/? values. Cytochemical analysis of anterior (AP) pituitary cell subtypes indicated that db/db mutants demonstrated prominent hypercytolipidemia relative to +/? pituitary cytoarchitecture. Cytolipidemic vacuoles were localized within protein vesiculated db/db hypophyseal basophilic and acidophilic cell populations. Hypophyseal cytoadiposity in db/db AP cells was co-localized with prominent cellular apoptotic TUNEL labeling of nuclear 3'-DNA fragments in cells demonstrating vesicular depopulation and cytolytic vacuolization. These data represent the first demonstration of co-localized hypercytolipidemic and cytoapoptotic disruptive events occurring concurrently in a hypopituitary-hypogonadal syndrome model following expression of the Type II (NIDDM) diabetes-obesity syndrome in db/db-mutants. The coincident and progressive vascular-, interstitial- and cyto-lipidemic alterations in hypophyseal cytoarchitecture correlated with the concurrent apoptotic disruption of pituitary endocrine cytoarchitecture and supressed gonadal steroid synthesis, influences which collectively contribute to the premature involution of the pituitary-gonadal axis in C57BL/KsJ- db/db mice.

Animals↗

PubMed2004

Digital chemospectrophotographic identification of intracellular hyperlipidemia in diabetic endometrial epithelial cells: structural and metabolic basis of organoatrophy.

OBJECTIVE: Digital chemospectrophotographic (DCSP) microscopic analysis and evaluation methodology applicable for enhanced cytopathological analysis of diabetes-induced, cytohyperlipidemia-associated cellular involution in endometrial epithelial and stromal tissues that promotes reproductive dysfunction and organoatrophy. METHODS: Combined light microscopy (LM), transmission electron microscopy (TEM) and described DCSP evaluation of endometrial samples collected from control (+/?) and genetically diabetic (db/db) C57BL/KsJ, hyperglycemic-hyperinsulinemic (type II) mice, designed to enhance the intracellular localization of chemically specified triglyceride and free fatty acid depositions, on progressive reproductive tract atrophy and cellular involution indices. RESULTS: Compared to both the LM and TEM analysis of cytopathological changes associated with diabetes-induced endometrial involution and reproductive dysfunction, the application of DCSP provided enhanced pathovisual analysis of chemical-specific metabolic alterations and cytoplasmic structural changes which accompany cytohyperlipidemia-induced endometrial epithelial cell apoptosis and reproductive tract atrophy. CONCLUSIONS: DCSP analysis provides an enhanced analytical method for the evaluation of cytoplasmic changes associated with the expression of genomic-, endocrine- or metabolic-based disease states by providing intercytoplasmic specific chemical or metabolic substrate alterations to be identified from conventional pathocellular preparations without requiring the use of exogenous ligand binding or fluorescent methodologies, allowing for a more complete metabolic and cellular evaluation of cytoplasmic indices associated with organoatrophy.

Animals↗

PubMed2004

Cytochemical analysis of pancreatic islet hypercytolipidemia following diabetes (db/db) and obese (ob/ob) mutation expression: influence of genomic background.

Both diabetes (db/db) and obese (ob/ob) genotype mutations induce a hyperglycemic-hyperinsulinemic endometabolic state in C57BL mice, manifesting a type II NIDDM diabetes-obesity syndrome (DOS) in these leptin ligand/receptor-deficient models. The severity of the DOS induced by these single gene, homozygous-recessive mutations may be moderated by the background genome on which the mutation is expressed. The current studies define the phenotypic, systemic, cytochemical and cellular metabolic responses to db/db and ob/ob mutation expression when modified by /KsJ (severe DOS expression) or /6 (modified DOS expression) background strain influences as compared to littermate control (+/?) indices. Both db/db and ob/ob mutations induced dramatic increases in body weights, blood glucose and serum insulin concentrations relative to +/? indices when expressed on either the C57BL/KsJ (-/KsJ) or C57BL/6 (-/6) backgrounds. However, the -/KsJ background enhanced the severity of expression of these DOS indices relative to the -/6 strain. Similarly, the -/KsJ genome suppressed cellular glucose uptake rates, pancreatic tissue weights and insulin concentrations in both db/db and ob/ob mutants relative to /6 background strain influences or +/? indices. Concurrent enhancement of tissue and cellular lipogenic metabolism and islet cytolipid depositions were exaggerated when the mutations were expressed on the -/KsJ background relative to the -/6 genome. Pancreatic islet B-cell lipodeposition was markedly enhanced in ob/ob and db/db mutants expressed on either the -/KsJ or -/6 background. In both ob/ob and db/db models, B-cell insulin granulation was prominent in mildly hypertrophic pancreatic islets when the mutations were expressed on the -/6 background. In contrast, the severity of the DOS state expressed on the -/KsJ background resulted in pronounced B-cell atrophy, characterized by insulin degranulation, cellular hypertrophy and hypercytolipidemia associated with tissue involution, in both ob/ob and db/db mutants. Dramatic alterations in tissue norephinephrine (NE) and alpha-1-receptor populations in ob/ob and db/db mutants were exaggerated by the -/KsJ genome as compared to -/6 or control indices. The influences of the -/KsJ genome on the progressive expression of tissue NE counter-regulatory responses to enhanced cytolipidemic indices were inversely related, with cytochemical lipodeposition occurring under conditions of diminished adrenergic responses to the DOS indices. The results of these studies indicate that the severity of the type-II diabetes endometabolic syndrome induced by the ob/ob or db/db genotypic mutations is modified by the existing genome on which the mutations are expressed. These data suggest that the severity of genomic mutation expression may be modified depending on the capability of the background genome to counter-regulate the systemic, cellular or metabolic consequences of these mutations.

Animals↗

PubMed2003

Cytomorphometric analysis and surface ultrastructure of developing decidua.

A scanning electron microscopic (SEM) and morphometric analysis of the topographical changes occurring in the uterine luminal epithelial layer in association with decidual tissue (DT) formation in guinea pigs was undertaken in order to elucidate the surface ultrastructural characteristics which occur during the process of endometrial differentiation. Experimentally induced decidua formation was promoted by mechanical stimulation of the antimesometrial luminal surface during the period of maximal uterine sensitivity to stromal differentiation. DT-associated remodeling of the uterine epithelial layer was subsequently examined by light and SE microscopic analysis for apical epithelial and luminal contour alterations associated with decidua growth. Cytological changes in the luminal surface associated with DT induction included sparse microvillus growth from the apical epithelial surface, accompanied by the appearance of prominent apical membrane surface protrusions and endometrial gland openings as compared with non-DT-stimulated control samples. Decidua surface growth was characterized by a short, sparse epithelial microvillus pattern present over a highly contoured luminal uterine surface on which contoured gland openings were both numerous and prominent. These surface modifications contrasted with the flat, non-decidualized luminal surface contour which was covered by distinct, microvilli-laden, apical cell membranes, and defined by prominent intercellular membrane borders. The uterine surface at the time of maximal DT formation (i.e. growth) closely resembled that of a uterine luminal surface undergoing apoptosis and subsequent cellular reabsorption, characterized by disrupted cell surface membranes, sparse microvillus surfaces and prominent epithelial contours reflecting stromal tissue and vasculature involution. These data indicate that the alterations in the uterine luminal surface associated with DT formation are reminiscent of the endometrial changes associated with the initiation of early placentation, and may be used as a model for the analysis of the role of epithelial cell surface modifications associated with the induction and support of interstitial blastocyst implantation and early decidua formation.

Animals↗

PubMed2003

Diabetes (db/db) mutation-induced ovarian involution: progressive hypercytolipidemia.

Ovarian atrophy and reproductive tract incompetence are recognized consequences of the progressive expression of the overt, diabetes-obesity syndrome (DOS) in C57BL/KsJ (db/db) mutant mice. The present studies evaluated the progressive changes in ovarian cytoarchitecture, endocrine expression, and reproductive tract cytolipidemic parameters that promote reproductive failure and ovarian involution during the pre-onset, initial, progressive, and chronic expression stages of the DOS. Paired littermate control (normal: +/?) and diabetic (mutant: db/db) C57BL/KsJ females were selected for analysis of ovarian parameters at 2 weeks (pre-onset expression of DOS), 4 weeks (initial DOS expression), 8 weeks (progressive DOS: hyper-glycemic/lipidemic), and 16 weeks (overt/chronic DOS expression) of age. All 4- to 16-week-old (db/db) groups were obese, hyperglycemic, and hyperinsulinemic as compared with age-matched (+/?) controls. Prior to phenotypic expression of the DOS (2 week groups), ovarian interstitial cytolipidemia characterized the perifollicular and cortical regions of db/db tissue samples relative to +/? indices, while comparable body weight, blood glucose, as well as serum insulin and ovarian steroid hormone concentrations characterized both the +/? and db/db groups. Overt DOS expression in the 4-week-old db/db groups was characterized by body obesity, systemic hyperglycemia-hyperinsulinemia, and extensive hypercytolipidemia of ovarian folliculothecal compartments, as well as enhanced tissue lipase activities. By 8 weeks of age, progressive hypercytolipidemia characterized interstitial, thecal, and follicular granulosa cell layers of db/db tissue samples concurrent with suppressed ovarian steroid hormone production, enhanced lipid sequestration, and exacerbation of systemic hyper-glycemia/insulinemia. By 16 weeks of age, the chronic-DOS was characterized by extensive ovarian follicular involution, cortical perivascular hyperlipidemic infiltration, thecal cell atrophy, and follicular granulosa lipid imbibition. These data indicate that db/db mutation-induced ovarian structural and functional involution is a direct reflection of the cellular metabolic shift towards lipogenesis, indicated by the progressive cytoarchitectural transformation into adipocyte-like entities. The cytological indications of cellular metabolic compromise, which precede the phenotypic expression of the DOS indices, suggests that correction of these abnormal shifts in ovarian endocrine and cellular metabolism may restore, delay, or prevent the further compromise of ovarian function by db/db mutation expression.

Age Factors↗

PubMed2003

Diabetes-induced, progressive endometrial involution characterization of periluminal epithelial lipoatrophy.

The present studies detail the cytopathological alterations in uterine epithelial, basal lamina, and stromal endometrial subregions, and associated endocrine parameters that occur during the progressive exacerbation of the diabetes syndrome in this species of mouse. These alterations result in a cellular lipoatrophic condition that compromises uterine tissue integrity and promotes reproductive involution. Uterine tissue samples were obtained from litter-matched control (+/?) and diabetic (db/db) C57BL/KsJ mice at four designated stages of the progressive expression of the diabetes mutation. In db/db mice between the ages of 4 and 12 weeks, the uterine epithelial cellular architecture exhibited progressive deterioration, characterized by cytoplasmic lipid imbibition (accumulation), organelle disintegration, apical membrane ciliary regression, and peristromal lamina separation from basal membrane surfaces, as compared with control indexes. The cytoplasmic volume occupied by lipid inclusions dominated the epithelial cells in diabetic mice, presenting dense basal pole lipid vacuoles, with perinuclear-intracytoplasmic migration of the inclusions promoting an apical cytoplasmic lipid condensation of increasing volume 8-12 weeks after mutation expression. These cytoplasmic lipid accumulations occurred under altered metabolic and endocrine conditions characterized by hyperglycemic, hyperinsulinemic, hypertriglyceridemic, and enhanced noradrenergic indexes, which were exacerbated between 4- and 12-week stages. These structural changes were accompanied by enhanced adrenergic counterregulatory metabolic responses as well as elevated lipoprotein and triacylglycerol lipase activities. These data indicate that diabetes-associated uterine involution is characterized by a progressive cellular and peristromal lipoatrophy of epithelial cell cytology and metabolic parameters, promoting stromal separation and ultimate endometrial involution.

Animals↗

PubMed2002

Lipoatrophic diabetes-associated utero-ovarian dysfunction: influence of cellular lipid deposition on norepinephrine indices.

OBJECTIVE: Elucidation of the intracellular lipoatrophic diabetic state and the concomitant alterations in norepinephrine (NE) parameters characterizing female reproductive failure. METHODS: Quantitation of intrinsic NE levels in utero-ovarian and pancreatic tissue samples of C57BL/KsJ (+/?) control and (db/db) diabetic littermate mice was by high performance liquid chromatography (HPLC) and compared with the microspectrofluorometric histofluorescent (HF) localization of cellular and parenchymal NE. RESULTS: Diabetes-associated elevations in HPLC-detectable tissue NE concentrations occurred in all pancreatic and reproductive tract tissue samples as compared to control-matched samples, whereas concurrent HF analysis revealed suppressed perivascular and parenchymal NE depositions in diabetic mice. CONCLUSIONS: These data suggest that progressive hypertriglyceridemia/lipidemia may suppress the effectiveness of intrinsic elevations in tissue NE concentrations from effectively counterregulating the deleterious effects of the hyperglycemic, type-2 diabetic condition.

Animals↗

PubMedDate not supplied

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.

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.

Adipose Tissue↗