Gender-dependent physiological implications of combined PAI-1 and TIMP-1 gene deficiency characterized in a mouse model

2007 ◽  
Vol 293 (4) ◽  
pp. R1630-R1639 ◽  
Author(s):  
Jakob Harslund ◽  
Ole Lerberg Nielsen ◽  
Nils Brünner ◽  
Hanne Offenberg
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Mouse Model ◽  
Physiological Parameters ◽  
Male Mice ◽  
Female Mice ◽  
Leukocyte Counts ◽  
Blood Leukocyte ◽  
Pai 1

The endogenous proteinase inhibitors plasminogen activator inhibitor type 1 (PAI-1) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) are two distinct proteins with separate molecular pathways. However, a close relationship between PAI-1 and TIMP-1 has been proposed indicating some degree of functional overlap due to their involvement in ECM turnover, tissue remodeling, and cellular migration and signaling. To study the housekeeping physiological implications of PAI-1 and TIMP-1, we generated a combined PAI-1 and TIMP-1 gene-deficient mouse model. We present the results on generating this specific mouse model with particular emphasis on phenotypical characteristics, blood leukocyte counts, histology, and gene expression studies of PAI-1 and TIMP-1 in various organs. We observed a significant deviation in segregation of offspring only in male mice ( P < 0.01) predominantly caused by PAI-1 deficiency. In addition, the body weight in 3- and 20-wk-old male and 20-wk-old female mice was significantly different between genotypes ( P ≤ 0.0008). Furthermore, blood leukocyte counts were significantly different between genotypes in 20-wk-old male mice ( P ≤ 0.0002), whereas no significant differences were observed between genotypes in 20-wk-old female mice ( P ≥ 0.13). Quantifying the relative expression of PAI-1 and TIMP-1 revealed upregulation of PAI-1 ( P < 0.001) in male mice only. Our data highlight the complex roles of PAI-1 and TIMP-1 on physiological parameters such as segregation of offspring (embryonic development and survival), body weight (metabolism), blood leukocyte counts (immunity), and gene expression (regulatory redundancy). We conclude that PAI-1 and TIMP-1 seem to possess gender-dependent regulatory properties on various housekeeping physiological parameters and stress the potential implications in pathological conditions.

scholarly journals Sex-Specific Difference in Adipose Tissue and Blood Pressure in a New Mouse Model Expressing Human Soluble Prorenin Receptor in Adipocytes

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 56-56
Author(s):  
Kellea Nichols ◽  
Audrey Poupeau ◽  
Eva Gatineau ◽  
Gertrude Arthur ◽  
Ming Gong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Mouse Model ◽  
Fat Mass ◽  
Lean Mass ◽  
Soluble Form ◽  
Male Mice ◽  
Female Mice ◽  
Prorenin Receptor ◽  
Body Weights

Abstract Objectives Sex differences exist in obesity associated with cardiovascular disease; however, underlying mechanisms are not completely understood. Previous studies from our laboratory demonstrated that the prorenin receptor (PRR) and its soluble form (sPRR) contribute to adipogenesis and blood pressure control. The present study aimed to determine whether adipose-sPRR stimulated obesity is associated with hypertension and whether it is sex-dependent. Methods Transgenic mice on the C57BL/6 J background were generated expressing the human form of the soluble prorenin receptor (HsPRR) in a Cre-inducible manner. Male mice expressing Cre recombinase under the control of the adiponectin promotor were bred to heterozygote HsPRR/+ female mice to generate mice over-secreting sPRR (adi-HsPRR) and control littermate mice (CTL). The secretion of sPRR in the media doubled in primary adipocytes of adi-HsPRR mice compared to control mice (sPRR. CTL: 3729 ± 805 pg/ml; adi-HsPRR: 6170 ± 1237 pg/ml, P &lt; 0.05) validating the mouse model. Male (CTL = 4; adi-HsPRR = 8) and female mice (CTL = 10; adi-HsPRR = 10) were fed a low-fat (LF) diet or a high-fat diet (HF) for 20 weeks. Body weight was assessed weekly and EchoMRI was examined monthly. Results After 20 weeks on LF diet, adi-HsPRR male mice gained significantly more weight than CTL male mice (CTL: 25.1 ± 0.8 g; adi-HsPRR: 29.0 ± 0.8 g P &lt; 0.05), whereas no significant differences in body weights were observed in female mice. The body composition revealed a significant increase of fat mass, specifically in the epidydimal fat (CTL: 0.35 ± 0.04 g; adi-HsPRR: 0.61 ± 0.07 g, P &lt; 0.05), and lean mass of HsPRR male mice compared to CTL male mice. In contrast, female mice exhibited similar body weights (CTL: 20.6 ± 0.3 g; adi-HsPRR: 20.4 ± 0.4 g) and there was no differences of fat mass or lean mass between CTL and adi-HsPRR female mice. The sex-specific mechanism of sPRR on adipogenesis and blood pressure (by radiotelemetry) with LF and HF diet is currently under investigation. Conclusions Overall, sPRR stimulated body weight gain and fat mass expansion in male mice but not in female mice suggesting that female mice are protected from sPRR induced-hypertrophic effect. Funding Sources R01_HL142969–01 Yiannikouris, PI 07/15/2018–06/30/2022 NIH/NHLBI Title: The role of soluble prorenin receptor in hypertension associated with obesity Role: Ph.D Graduate Student.

scholarly journals NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

2018 ◽  
Vol 75 (6) ◽  
pp. 1042-1049
Author(s):  
Seongjoon Park ◽  
Erkhembayar Nayantai ◽  
Toshimitsu Komatsu ◽  
Hiroko Hayashi ◽  
Ryoichi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Fat Metabolism ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Age Related ◽  
Promising Target ◽  
Intracellular Mechanism

Abstract The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

scholarly journals Administration of Saccharin to Neonatal Mice Influences Body Composition of Adult Males and Reduces Body Weight of Females

Endocrinology ◽  
2014 ◽  
Vol 155 (4) ◽  
pp. 1313-1326 ◽  
Author(s):  
Sebastian D. Parlee ◽  
Becky R. Simon ◽  
Erica L. Scheller ◽  
Emilyn U. Alejandro ◽  
Brian S. Learman ◽  
...  
Keyword(s):  
Body Composition ◽  
Body Weight ◽  
Bone Mass ◽  
Composition Analysis ◽  
Male Body ◽  
Adult Males ◽  
Male Mice ◽  
Female Mice ◽  
Trabecular Bone Mass ◽  
High Concentrations

Nutritional or pharmacological perturbations during perinatal growth can cause persistent effects on the function of white adipose tissue, altering susceptibility to obesity later in life. Previous studies have established that saccharin, a nonnutritive sweetener, inhibits lipolysis in mature adipocytes and stimulates adipogenesis. Thus, the current study tested whether neonatal exposure to saccharin via maternal lactation increased susceptibility of mice to diet-induced obesity. Saccharin decreased body weight of female mice beginning postnatal week 3. Decreased liver weights on week 14 corroborated this diminished body weight. Initially, saccharin also reduced male mouse body weight. By week 5, weights transiently rebounded above controls, and by week 14, male body weights did not differ. Body composition analysis revealed that saccharin increased lean and decreased fat mass of male mice, the latter due to decreased adipocyte size and epididymal, perirenal, and sc adipose weights. A mild improvement in glucose tolerance without a change in insulin sensitivity or secretion aligned with this leaner phenotype. Interestingly, microcomputed tomography analysis indicated that saccharin also increased cortical and trabecular bone mass of male mice and modified cortical bone alone in female mice. A modest increase in circulating testosterone may contribute to the leaner phenotype in male mice. Accordingly, the current study established a developmental period in which saccharin at high concentrations reduces adiposity and increases lean and bone mass in male mice while decreasing generalized growth in female mice.

scholarly journals Lasting Effects on Body Weight and Mammary Gland Gene Expression in Female Mice upon Early Life Exposure to n-3 but Not n-6 High-Fat Diets

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e55603 ◽  
Author(s):  
Mirjam Luijten ◽  
Amar V. Singh ◽  
Caleb A. Bastian ◽  
Anja Westerman ◽  
M. Michele Pisano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Mammary Gland ◽  
Early Life ◽  
High Fat ◽  
Female Mice ◽  
Early Life Exposure ◽  
High Fat Diets ◽  
Fat Diets

scholarly journals Evaluation of the effective dose of amygdalin for the improvement of antioxidant gene expression and suppression of oxidative damage in mice

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9232
Author(s):  
Sarah Albogami ◽  
Aziza Hassan ◽  
Nibal Ahmed ◽  
Alaa Alnefaie ◽  
Afnan Alattas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Peroxidation ◽  
Superoxide Dismutase ◽  
Body Weight ◽  
High Dose ◽  
Male Mice ◽  
Antioxidant Gene ◽  
Oxidative Balance ◽  
Antioxidant Gene Expression ◽  
Medium Dose

Background Little is known regarding the toxic and therapeutic doses of amygdalin. Treatment regimens and schedules can vary between humans and animal models, and there have been reports of cyanide toxicity due to amygdalin use. Objective The aim of this study was to evaluate the effect of different doses of amygdalin on antioxidant gene expression and suppression of oxidative damage in mice. Methods Forty adult male mice were divided randomly into four groups (n = 10) as follows and treated orally for two weeks: a control group treated with saline solution, a group treated with amygdalin at 200 mg/kg body weight, a group treated with amygdalin at 100 mg/kg body weight, and a group treated with amygdalin at 50 mg/kg body weight. Liver and testis samples were collected for gene expression, biochemical and histopathological analyses. Results The mice treated with medium-dose amygdalin (100 mg/kg) showed upregulated mRNA expression of glutathione peroxidase (P < 0.01) and superoxide dismutase (P < 0.05) and significantly decreased lipid peroxidation (P < 0.05) in hepatic and testicular tissues compared to those in the untreated groups (controls), with mild histopathological effects. The mice treated with high-dose of amygdalin (200 mg/kg) showed downregulated mRNA expression of glutathione peroxidase and superoxide dismutase (P < 0.01) and significantly increased lipid peroxidation (P < 0.05) in both hepatic and testicular tissues compared to those in the untreated groups (controls), with an apparent effect at the histopathological level. No effects were observed in the mice treated with low-dose amygdalin (50 mg/kg) at the gene, protein and histopathological level. Conclusion Low-and medium-dose amygdalin did not induce toxicity in the hepatic and testicular tissues of male mice, unlike high-dose amygdalin, which had a negative effect on oxidative balance in mice. Therefore, amygdalin at a moderate dose may improve oxidative balance in mice.

scholarly journals CTRP12 ablation differentially affects energy expenditure, body weight, and insulin sensitivity in male and female mice

2020 ◽  
Vol 319 (1) ◽  
pp. E146-E162 ◽  
Author(s):  
Stefanie Y. Tan ◽  
Xia Lei ◽  
Hannah C. Little ◽  
Susana Rodriguez ◽  
Dylan C. Sarver ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Elevated Serum ◽  
Liver Weight ◽  
Homozygous Deletion ◽  
Whole Body ◽  
Male Mice ◽  
Female Mice

Secreted hormones facilitate tissue cross talk to maintain energy balance. We previously described C1q/TNF-related protein 12 (CTRP12) as a novel metabolic hormone. Gain-of-function and partial-deficiency mouse models have highlighted important roles for this fat-derived adipokine in modulating systemic metabolism. Whether CTRP12 is essential and required for metabolic homeostasis is unknown. We show here that homozygous deletion of Ctrp12 gene results in sexually dimorphic phenotypes. Under basal conditions, complete loss of CTRP12 had little impact on male mice, whereas it decreased body weight (driven by reduced lean mass and liver weight) and improved insulin sensitivity in female mice. When challenged with a high-fat diet, Ctrp12 knockout (KO) male mice had decreased energy expenditure, increased weight gain and adiposity, elevated serum TNFα level, and reduced insulin sensitivity. In contrast, female KO mice had reduced weight gain and liver weight. The expression of lipid synthesis and catabolism genes, as well as profibrotic, endoplasmic reticulum stress, and oxidative stress genes were largely unaffected in the adipose tissue of Ctrp12 KO male mice. Despite greater adiposity and insulin resistance, Ctrp12 KO male mice fed an obesogenic diet had lower circulating triglyceride and free fatty acid levels. In contrast, lipid profiles of the leaner female KO mice were not different from those of WT controls. These data suggest that CTRP12 contributes to whole body energy metabolism in genotype-, diet-, and sex-dependent manners, underscoring complex gene-environment interactions influencing metabolic outcomes.

Sex-specific effects of neonatal oral sucrose treatment on growth and liver choline and glucocorticoid metabolism in adulthood

2021 ◽  
Author(s):  
Cynthia Yamilka Ramírez-Contreras ◽  
Arya E Mehran ◽  
Melody Salehzadeh ◽  
Ei-Xia Mussai ◽  
Joshua W Miller ◽  
...  
Keyword(s):  
Body Weight ◽  
Preterm Infants ◽  
Serum Insulin ◽  
Control Diet ◽  
Male Mice ◽  
Long Term Effects ◽  
Female Mice ◽  
Specific Effects ◽  
Oral Sucrose

Hospitalized preterm infants experience painful medical procedures. Oral sucrose is the non‑pharmacological standard of care for minor procedural pain relief. Infants are treated with numerous doses of sucrose, raising concerns about potential long-term effects. The objective of this study was to determine the long‑term effects of neonatal oral sucrose treatment on growth and liver metabolism in a mouse model. Neonatal female and male mice were randomly assigned to one of two oral treatments (n=7‑10 mice/group/sex): sterile water or sucrose. Pups were treated 10 times/day for the first six days of life with 0.2mg/g body weight of respective treatments (24% solution; 1‑4μl/dose) to mimic what is given to preterm infants. Mice were weaned at age 3 weeks onto a control diet and fed until age 16 weeks. Sucrose-treated female and male mice gained less weight during the treatment period and were smaller at weaning than water-treated mice (p≤0.05); no effect of sucrose treatment on body weight was observed at adulthood. However, adult sucrose-treated female mice had smaller tibias and lower serum insulin-like growth factor-1 than adult water-treated female mice (p≤0.05); these effects were not observed in males. Lower liver S-adenosylmethionine, phosphocholine, and glycerophosphocholine were observed in adult sucrose-treated compared to water-treated female and male mice (p≤0.05). Sucrose-treated female, but not male, mice had lower liver free choline and higher liver betaine compared to water-treated female mice (p<0.01). Our findings suggest that repeated neonatal sucrose treatment has long-term sex-specific effects on growth and liver methionine and choline metabolism.

scholarly journals Sexually Dimorphic Responses to a High-Refined Carbohydrate Diet in a Nonalcoholic Fatty Liver Disease Mouse Model

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 16-16
Author(s):  
Michael Daniels ◽  
Chun Liu ◽  
Kang-Quan Hu ◽  
Xiang-Dong Wang
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Sexually Dimorphic ◽  
Male Mice ◽  
Carbohydrate Diet ◽  
Nonalcoholic Fatty Liver ◽  
Female Mice

Abstract Objectives Nonalcoholic fatty liver disease (NAFLD) incidence and prevalence have been reported to be higher in men than women, however, the effects of sexual dimorphism on NAFLD risk and progression have not been adequately examined. Our lab has previously shown that a liquid high-refined carbohydrate diet (HRCD) induced more severe hepatic steatosis compared to an isocaloric high fat diet in male mice. Also, HRCD-induced reduction in sirtuin 1 (SIRT1), an NAD-dependent deacetylase protein, has previously been implicated in NAFLD pathogenesis. Therefore, we investigated whether there were sexually dimorphic responses to a liquid high-refined carbohydrate diet (HRCD) in male and female, wildtype and SIRT1-deficient mice. Methods Male and female 10–12-week-old wildtype (SIRT1 +/+: n = 12; M = 6, F = 6) and mice carrying a heterozygous H355Y SIRT1 point mutation (SIRT1 +/y: n = 14; M = 7, F = 7) were both fed a HRCD (Lieber-DeCarli liquid diet supplemented with maltose dextrin; 47% energy from refined carbohydrate, Dyets, #710,260) for 5 weeks and 9 weeks. Hepatic gene expression was examined using qRT-PCR. Plasma ALT (alanine transaminase) and hepatic MDA (malondialdehyde) levels were determined using colorimetric assay kits. Hepatic steatosis scoring was conducted by analyzing Hematoxylin and Eosin (H&E) stains. Results 9 weeks of HRCD induced significantly less hepatic steatosis in female mice irrespective of genotype compared to male mice as determined by grading of H&E stains (P &lt; 0.05). Furthermore, liver expression of several fatty acid oxidation genes (CPT1, ACOX1) was significantly higher in females (P &lt; 0.05), which potentially suggests increased fatty acid oxidation. Additionally, female mice had significantly increased antioxidant gene expression (GPX4, SOD1, SOD2, Catalase) and significantly lower hepatic MDA (P &lt; 0.05), which indicate an increased capacity to mitigate oxidative stress. Lastly, plasma ALT levels were significantly lower in females compared to males after 9 weeks of HRCD (P &lt; 0.05). Conclusions Collectively, these data indicate that female mice are moderately protected against HRCD-induced NAFLD compared to male mice, potentially through increased hepatic fatty acid oxidation and superior mitigation of oxidative stress due to increased antioxidant system gene expression in the liver. Funding Sources HNRCA, USDA/ARS Grants.

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