Interacting effects of the MAM model of schizophrenia and antipsychotic treatment: Untargeted proteomics approach in adipose tissue.

Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals.

Can fetal abdominal visceral adipose tissue and subcutaneous fat thickness be used for correct estimation of fetal weight? A preliminary study.

The aim of this study was to assess the accuracy of a new formula for the calculation of an estimated fetal weight (EFW) and to evaluate value of fetal visceral adipose tissue (VAT) and abdominal subcutaneous fat (SF) thickness on the prediction of birth weight. In this prospective study, fetal biometry, EFW, fetal VAT and SF thickness were measured in low-risk 37-41 gestational weeks pregnant women by ultrasonography. The linear regression analysis was performed to investigate the relationship between birth weight and obstetric measurements. It was found that the most important factors in the prediction of a birth weight were the abdominal circumference (AC), SF and VAT. The new formula for EFW was EFW=-2748.622+13.811*AC+56.795*SF+17.913*VAT According to the Hadlock 3 and the new formula, 92% and 95% of all fetal weight estimations were within 10% of actual birth weight, respectively. Measurement of VAT and SF thickness in prediction of fetal weight could reduce a weight estimation error. Impact statement What is already known on this subject? An accurate prediction of fetal weight during gestation provides useful information for assessing the fetal and newborn health status. As the detection of growth abnormalities is vital, there is a need for a reliable method of assessing birth weight during labour. Unfortunately, although different methods are available, a simple, quick and reliable method of assessing birth weight is still in debate. Fetal visceral adipose (VAT) tissue measurement is a new method which could be used for the correct estimation of fetal weight. Like adults, the VAT and subcutaneous fat tissue (SF) thickness could be correlated with the weight and body-mass index. What do the results of this study add? It was found that SF and VAT are important factors in the prediction of birth weight, like the abdominal circumference (AC). What are the implications of these findings for clinical practice and/or further research? The measurement of VAT and SF thickness in prediction of fetal weight could reduce a weight estimation error.

Xenotransplantation of human fetal adipose tissue: a model of in vivo adipose tissue expansion and adipogenesis.

Obesity during childhood and beyond may have its origins during fetal or early postnatal life. At present, there are no suitable in vivo experimental models to study factors that modulate or perturb human fetal white adipose tissue (WAT) expansion, remodeling, development, adipogenesis, angiogenesis, or epigenetics. We have developed such a model. It involves the xenotransplantation of midgestation human WAT into the renal subcapsular space of immunocompromised SCID-beige mice. After an initial latency period of approximately 2 weeks, the tissue begins expanding. The xenografts are healthy and show robust expansion and angiogenesis for at least 2 months following transplantation. Data and cell size and gene expression are consistent with active angiogenesis. The xenografts maintain the expression of genes associated with differentiated adipocyte function. In contrast to the fetal tissue, adult human WAT does not engraft. The long-term viability and phenotypic maintenance of fetal adipose tissue following xenotransplantation may be a function of its autonomous high rates of adipogenesis and angiogenesis. Through the manipulation of the host mice, this model system offers the opportunity to study the mechanisms by which nutrients and other environmental factors affect human adipose tissue development and biology.

Impact of embryo number and periconceptional undernutrition on factors regulating adipogenesis, lipogenesis, and metabolism in adipose tissue in the sheep fetus.

Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We hypothesized that maternal undernutrition during the periconceptional (PCUN: -60 to 7 days) and/or preimplantation (PIUN: 0-7 days) periods would result in a decrease in UCP1 expression and the abundance of insulin signaling molecules and an increase in the abundance of factors that regulate adipogenesis and lipogenesis in fetal perirenal adipose tissue (PAT) and that these effects would be different in singletons and twins. Maternal PCUN and PIUN resulted in a decrease in UCP1 expression in PAT, and PIUN resulted in higher circulating insulin concentrations, an increased abundance of pPKCζ and PDK4, and a decreased abundance of Akt1, phosphorylated mTOR, and PPARγ in PAT in singleton and twin fetuses. In singletons, there was also a decrease in the abundance of p110ß in PAT in the PCUN and PIUN groups and an increase in total AMPKα in PAT in the PIUN group. In twins, however, there was an increase in the abundance of mTOR in the PCUN group and an increase in PDK2 and decrease in total AMPKα in the PIUN group. Thus exposure to periconceptional undernutrition programs changes in the thermogenic capacity and the insulin and fatty acid oxidation signaling pathway in visceral fat, and these effects are different in singletons and twins. These findings are important, as the thermogenic capacity of brown fat and the insulin sensitivity of visceral fat are important determinants of the risk of developing obesity and an insulin resistance phenotype in later life.

Gubernaculum as icebreaker: do matrix metalloproteinases in rodent gubernaculum and inguinal fat pad permit testicular descent?

PURPOSE: Cryptorchidism is the most common male congenital abnormality. The rodent gubernaculum steers the testis from abdomen to scrotum postnatally by eversion and migration through the developing inguinal fat pad (IFP). We hypothesize that extracellular matrix remodeling in/around the gubernaculum is necessary for eversion and migration and is permitted by timed IFP maturation and aimed to examine regional development and matrix metalloproteinase (MMP) content. METHODS: Embryonic day 19 (E19) and postnatal days 0 and 2 (P0, P2) wild-type Sprague-Dawley rats (n = 10) were prepared for histologic examination (trichrome) and immunohistochemistry (membrane-type MMP-1 [MT1-MMP], MMP2) and analyzed using light/confocal microscopy. RESULTS: At E19, IFP contained fibroblasts and immature cells in an extensive collagenous extracellular matrix. Cells in the gubernaculum base were cytoplasmic-MT1-MMP-positive (inactive). At P0, the gubernaculum had everted, and adjacent cells were membranous-MT1-MMP-positive (active). At P2, the gubernaculum was migrating through the IFP, and adjacent cells were membranous-MT1-MMP-positive. Adipocyte maturation began cranially in the IFP and proceeded in a craniocaudal gradient until more uniformly mature at P2. CONCLUSION: The MT1-MMP-positive cells may remodel the gubernaculum for eversion and provide the collagenolysis necessary for migration, like an icebreaking ship, through the IFP, which matures to permit migration through collagen-rich tissue. Disruption of these processes may cause cryptorchidism.

The effect of flutamide on expression of androgen and estrogen receptors in the gubernaculum and surrounding structures during testicular descent.

BACKGROUND/PURPOSE: Inguinoscrotal testicular descent is controlled by androgens between embryonic days E16-19, but androgen receptor (AR) and estrogen receptor (ER) locations are unknown. We aimed to find AR, ERα, and ERß in the gubernaculum and inguinal fat pad (IFP) in normal rats and after flutamide treatment. METHODS: Sprague-Dawley timed-mated rats were injected with flutamide (75 mg/kg body weight/5% ethanol + oil) on E16-19 or vehicle alone. Male fetuses or pups (5-10/group) were collected at E16; E19; and postnatal (P) days 0, 2, 4, 8. Sections were prepared for hematoxylin and eosin or immunohistochemistry for AR, ERα, and ERß. Receptor labeling was quantitated as distinct nuclear labeling/100 µm(2) in gubernaculum and IFP. RESULTS: There was minimal gubernacular AR-labeling until E19, dramatically increasing postnatally. By contrast, at E16-E19 there was significant IFP AR immunoreactivity suppressed by flutamide (P < .05). No ERα expression was observed, but ERß was expressed in both gubernaculum and IFP, maximally at E16, but unchanged by flutamide. CONCLUSIONS: During the androgen sensitivity window (E16-19), the gubernaculum contains ERß but minimal ERα or AR, while the IFP, which is supplied by the genitofemoral nerve, contains abundant AR that are flutamide-sensitive. These results suggest that the IFP could be the site of androgenic action controlling gubernacular development.

Ontogeny and nutritional control of adipogenesis in zebrafish (Danio rerio).

The global obesity epidemic demands an improved understanding of the developmental and environmental factors regulating fat storage. Adipocytes serve as major sites of fat storage and as regulators of energy balance and inflammation. The optical transparency of developing zebrafish provides new opportunities to investigate mechanisms governing adipocyte biology, however zebrafish adipocytes remain uncharacterized. We have developed methods for visualizing zebrafish adipocytes in vivo by labeling neutral lipid droplets with Nile Red. Our results establish that neutral lipid droplets first accumulate in visceral adipocytes during larval stages and increase in number and distribution as zebrafish grow. We show that the cellular anatomy of zebrafish adipocytes is similar to mammalian white adipocytes and identify peroxisome-proliferator activated receptor gamma and fatty acid binding protein 11a as markers of the zebrafish adipocyte lineage. By monitoring adipocyte development prior to neutral lipid deposition, we find that the first visceral preadipocytes appear in association with the pancreas shortly after initiation of exogenous nutrition. Zebrafish reared in the absence of food fail to form visceral preadipocytes, indicating that exogenous nutrition is required for adipocyte development. These results reveal homologies between zebrafish and mammalian adipocytes and establish the zebrafish as a new model for adipocyte research.

Development of the human retroperitoneal fasciae.

INTRODUCTION: Although the renal fascia (RF), ureteral sheath, lateroconal fascia (LF) and hypogastric nerve are critical landmarks for retroperitoneal surgery, their laminar relationships require clarification. MATERIALS AND METHODS: Horizontal sections (hematoxylin-eosin staining) of human fetuses at two different developmental stages [9-12 (3 fetuses, crown-rump length, CRL 40-65 mm) and 20-25 weeks of gestation (9 fetuses, CRL 152-220 mm)] were compared. RESULTS: In the early-stage group, the pararenal space had already formed between the posterior RF and the transversalis fascia (TF). The anterior RF extended along the peritoneum and often fused with the latter. In the late-stage group, the posterior RF extended inferomedially toward the anterior aspect of the aorta and inferior vena cava. However, at the level of the renal hilus, the posterior RF was connected with vascular sheaths of the great vessels. The LF was seen developing as a fasciculation of the multilaminar structure in the pararenal space. However, on the posterolateral side of the colon after retroperitoneal fixation, the fusion fascia of the peritoneum could also be identified as LF. CONCLUSIONS: A common sheath for ureters and hypogastric nerves appeared to be likely on the inferior side of the kidney. The LF did not appear to be a primary structure such as the RF, but a result of secondary mechanical stress due to fatty tissue developing earlier along the TF than in the perirenal space. However, the suggested similarity between LF and fusion fascia in the plane occupied was a likely cause for misinterpreting the laminar configurations during surgery.