Sex differences in cardio-pulmonary pathology of SARS-CoV2 infected and Trypanosoma cruzi co-infected mice

Coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; CoV2) is a deadly contagious infectious disease. For those who survived COVID-19, post-COVID cardiac damage poses a major threat for the progression of cardiomyopathy and heart failure. Currently, the number of COVID-related cases and deaths is increasing in Latin America, where a major COVID comorbidity is Chagas heart disease (caused by the parasite Trypanosoma cruzi). Here, we investigated the effect of T. cruzi infection on the pathogenesis and severity of CoV2 infection and, conversely, the effect of CoV2 infection on heart pathology during coinfection. We used transgenic human angiotensin-converting enzyme 2 (huACE2) mice infected with CoV2, T. cruzi, or coinfected with both in this study. Our study shows for the first time that white adipose tissue (WAT) serves as a reservoir for CoV2 and the persistence of CoV2 in WAT alters adipose tissue morphology and adipocyte physiology. Our data demonstrate a correlation between the loss of fat cells and the pulmonary adipogenic signaling and pathology in CoV2 infection. The viral load in the lungs is inversely proportional to the viral load in WAT, which differs between male and female mice. Our findings also suggest that adiponectin-PPAR signaling may differently regulate Chagas cardiomyopathy in coinfected males and females. We conclude that adipogenic signaling may play important roles in cardio-pulmonary pathogenesis during CoV2 infection and T. cruzi coinfection. The levels of adiponectin isomers differ between male and female mice during CoV2 infection and coinfection with T. cruzi, which may differently regulate inflammation, viral load, and pathology in the lungs of both the sexes. Our findings are in line with other clinical observations that reported that males are more susceptible to COVID-19 than females and suffer greater pulmonary damage.

Download Full-text

NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning

The Journals of Gerontology Series A ◽

10.1093/gerona/gly282 ◽

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.

Download Full-text

Carbonyl Reductase 1 Overexpression in Adipose Amplifies Local Glucocorticoid Action and Impairs Glucose Tolerance in Lean Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1639 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A806-A806

Author(s):

Rachel Bell ◽

Elisa Villalobos ◽

Mark Nixon ◽

Allende Miguelez-Crespo ◽

Matthew Sharp ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Fasting Glucose ◽

High Fat ◽

Male And Female ◽

Over Expression ◽

Female Mice ◽

Diet Induced Obesity

Abstract Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.

Download Full-text

Sexually dimorphic responses to fat loss after caloric restriction or surgical lipectomy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00710.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E316-E326 ◽

Cited By ~ 36

Author(s):

Haifei Shi ◽

April D. Strader ◽

Stephen C. Woods ◽

Randy J. Seeley

Keyword(s):

Adipose Tissue ◽

Energy Balance ◽

Caloric Restriction ◽

White Adipose Tissue ◽

Visceral Fat ◽

Subcutaneous Fat ◽

Distribution Patterns ◽

Male And Female ◽

Fat Loss ◽

Female Mice

White adipose tissue is the principal site for lipid accumulation. Males and females maintain distinctive white adipose tissue distribution patterns. Specifically, males tend to accumulate relatively more visceral fat, whereas females accumulate relatively more subcutaneous fat. The phenomenon of maintaining typical sex-specific fat distributions suggests sex-specific mechanisms that regulate energy balance and adiposity. We used two distinct approaches to reduce fat mass, caloric restriction (CR), and surgical fat removal (termed lipectomy) and assessed parameters involved in the regulation of energy balance. We found that male and female mice responded differentially to CR- and to lipectomy-induced fat loss. Females decreased energy expenditure during CR or after lipectomy. In contrast, males responded by eating more food during food return after CR or after lipectomy. Female CR mice conserved subcutaneous fat, whereas male CR mice lost adiposity equally in the subcutaneous and visceral depots. In addition, female mice had a reduced capability to restore visceral fat after fat loss. After CR, plasma leptin levels decreased in male but not in female mice. The failure to increase food intake after returning to ad libitum intake in females could be due to the relatively stable levels of leptin. In summary, we have found sexual dimorphisms in the response to fat loss that point to important underlying differences in the strategies by which male and female mice regulate body weight.

Download Full-text

Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi

Acta Tropica ◽

10.1016/j.actatropica.2016.05.007 ◽

2016 ◽

Vol 161 ◽

pp. 44-54 ◽

Cited By ~ 18

Author(s):

Fabiane M. Santos ◽

Ana L. Mazzeti ◽

Sérgio Caldas ◽

Karolina R. Gonçalves ◽

Wanderson G. Lima ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Diastolic Dysfunction ◽

Potential Effect ◽

Cardiac Damage ◽

Chagas Cardiomyopathy

Download Full-text

Response of the adipose tissue transcriptome to dihydrotestosterone in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00257.2007 ◽

2008 ◽

Vol 35 (3) ◽

pp. 254-261 ◽

Cited By ~ 11

Author(s):

Yonghua Zhang ◽

Ezequiel Calvo ◽

Céline Martel ◽

Van Luu-The ◽

Fernand Labrie ◽

...

Keyword(s):

Adipose Tissue ◽

Cell Function ◽

Kinase Inhibitor ◽

Control Group ◽

Peak Time ◽

Fat Cell ◽

Tissue Samples ◽

Male And Female ◽

Female Mice ◽

Retroperitoneal Adipose Tissue

Androgens have been postulated to be important modulators of adipose tissue metabolism and fat cell function. In the present study, we investigated the response of male and female mice retroperitoneal adipose tissue to the nonaromatizable androgen dihydrotestosterone (DHT). Adipose tissue samples were obtained in gonadectomized animals treated with vehicle (control group), or injected with 0.1 mg DHT 1, 3, 6, 12, 18, and 24 h prior to necropsy. Fourteen animals were pooled at each time point (total 196 animals). Transcripts that were significantly modulated were considered as androgen-responsive genes. Quantitative real-time RT-PCR was used to confirm results from the microarray analysis in a subset of 46 probe sets in male mice and 98 probe sets in female mice. Considering peak time vs. control, we confirmed 74.0 and 63.3% of the modulated genes by PCR in males and females, respectively. Four genes were significantly stimulated in a similar manner by DHT in both sexes, namely metallothionein 1, growth arrest and DNA-damage-inducible 45 gamma, cyclin-dependent kinase inhibitor 1A, and fk506-binding protein 5. All these genes appear to be involved in the regulation of adipocyte differentiation/proliferation and adipogenesis. In conclusion, this study, which evaluated the acute transcriptome response of adipose tissue to DHT in male and female mice, suggests that DHT consistently modulates genes involved in the regulation of adipogenesis in retroperitoneal adipose tissue of both male and female animals.

Download Full-text

A Comparison of Inflammatory and Oxidative Stress Markers in Adipose Tissue from Weight-Matched Obese Male and Female Mice

Experimental Diabetes Research ◽

10.1155/2012/859395 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 31

Author(s):

Karen J. Nickelson ◽

Kelly L. Stromsdorfer ◽

R. Taylor Pickering ◽

Tzu-Wen Liu ◽

Laura C. Ortinau ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Adipose Tissue ◽

Disease Risk ◽

Health Benefits ◽

Metabolic Phenotype ◽

Male And Female ◽

Female Mice ◽

Obese Male ◽

And Oxidative Stress

Expansion of intra-abdominal adipose tissue and the accompanying inflammatory response has been put forward as a unifying link between obesity and the development of chronic diseases. However, an apparent sexual dimorphism exists between obesity and chronic disease risk due to differences in the distribution and abundance of adipose tissue. A range of experimental protocols have been employed to demonstrate the role of estrogen in regulating health benefits; however, most studies are confounded by significant differences in body weight and adiposity. Therefore, the purpose of this study was to compare weight-matched obese male and female mice to determine if the sex-dependent health benefits remain when body weight is similar. The development of obesity in female mice receiving a high-fat diet was delayed; however, subsequent comparisons of weight-matched obese mice revealed greater adiposity in obese female mice. Despite excess adiposity and enlarged adipocyte size, obese females remained more glucose tolerant than weight-matched male mice, and this benefit was associated with increased expression of adiponectin and reductions in immune cell infiltration and oxidative stress in adipose tissue. Therefore, the protective benefits of estrogen persist in the obese state and appear to improve the metabolic phenotype of adipose tissue and the individual.

Download Full-text

The effect of fat removal on glucose tolerance is depot specific in male and female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00649.2006 ◽

2007 ◽

Vol 293 (4) ◽

pp. E1012-E1020 ◽

Cited By ~ 42

Author(s):

Haifei Shi ◽

April D. Strader ◽

Stephen C. Woods ◽

Randy J. Seeley

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Male And Female ◽

Female Mice ◽

Glucose Levels ◽

Dietary Condition ◽

Fat Removal ◽

Glucose Tolerance Tests ◽

Males And Females

Energy is stored predominately as lipid in white adipose tissue (WAT) in distinct anatomical locations, with each site exerting different effects on key biological processes, including glucose homeostasis. To determine the relative contributions of subcutaneous and visceral WAT on glucose homeostasis, comparable amounts of adipose tissue from abdominal subcutaneous inguinal WAT (IWAT), intra-abdominal retroperitoneal WAT (RWAT), male gonadal epididymal WAT (EWAT), or female gonadal parametrial WAT (PWAT) were removed. Gonadal fat removal in both male and female chow-fed lean mice resulted in lowered glucose levels across glucose tolerance tests. Female lean C57BL/6J mice as well as male and female lean FVBN mice significantly improved glucose tolerance, indicated by decreased areas under glucose clearance curves. For the C57BL/6J mice maintained on a high-fat butter-based diet, glucose homeostasis was improved only in female mice with PWAT removal. Removal of IWAT or RWAT did not affect glucose tolerance in either dietary condition. We conclude that WAT contribution to glucose homeostasis is depot specific, with male gonadal EWAT contributing to glucose homeostasis in the lean state, whereas female gonadal PWAT contributes to glucose homeostasis in both lean and obese mice. These data illustrate both critical differences among various WAT depots and how they influence glucose homeostasis and highlight important differences between males and females in glucose regulation.

Download Full-text

Sex-Dependent Effects of Eicosapentaenoic Acid and UCP1 Deficiency on Hepatic Steatosis in Diet-Induced Obese Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab055_003 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1193-1193

Author(s):

Kembra Albracht-Schulte ◽

Salvador Galindo ◽

Sarah Anjum ◽

Mandana Pahlavani ◽

Latha Ramalingam ◽

...

Keyword(s):

Adipose Tissue ◽

Eicosapentaenoic Acid ◽

Ambient Temperature ◽

Hepatic Steatosis ◽

Uncoupling Protein ◽

Expression Profiles ◽

Mitochondrial Protein ◽

Male And Female ◽

Female Mice ◽

Brown Adipose

Abstract Objectives Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic triglyceride (TG) accumulation, is associated with expansion of white adipose tissue (WAT). By contrast, brown adipose tissue (BAT) may prevent obesity and NAFLD through activity of mitochondrial uncoupling protein 1 (UCP1), which is involved in energy dissipation. Previous studies in our lab have shown that eicosapentaenoic acid (EPA) ameliorates obesity and hepatic steatosis in high-fat (HF) fed male, B6 mice at thermoneutral conditions, independent of UCP1. However, it is unknown whether similar effects of EPA and UCP1 deficiency will be observed at ambient temperature, and whether they differ by sex. Thus, the goal of this project was to investigate sex-dependent mechanisms of EPA in the livers of diet-induced obese, wild type (WT) and UCP1 knockout (KO) mice housed at ambient temperature. Methods WT and UCP1 KO B6 male and female mice were fed a HF diet (45% kcal fat; WT-HF, KO-HF) or HF diet supplemented with 36g/kg EPA (WT-EPA, KO-EPA) for 14 weeks. Body weight (BW), liver histology, and specific metabolic gene expression profiles were assessed. Results Although BW significantly varied by sex, diet, and genotype, UCP1 inactivation did not significantly increase BW compared to WT in either sex. Hepatic TG accumulation varied significantly by genotype with no significant differences seen with EPA supplementation in either sex. However, markers of lipogenesis were sex-dependently impacted by genotype and diet: there were no significant differences in markers of lipogenesis (Fasn and Acaca) with UCP1 KO or EPA supplementation in males; while these markers were reduced in female KO mice compared to female WT with no response to EPA. By contrast, lipogenic markers were reduced with EPA in female WT mice. Conclusions Our findings reveal an association between NAFLD and UCP1 deficiency, indicating the importance of this mitochondrial protein in limiting hepatic lipid accumulation, particularly in females. These findings also suggest a genotypic difference in response to dietary EPA supplementation on the livers of male and female mice, with beneficial effects reported in the female WT group. Funding Sources Funded by NIH/NCCIH grant #R15AT008879-01A1.

Download Full-text

Sex-Specific Differences in Fat Storage, Development of Non-Alcoholic Fatty Liver Disease and Brain Structure in Juvenile HFD-Induced Obese Ldlr-/-.Leiden Mice

Nutrients ◽

10.3390/nu11081861 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1861 ◽

Cited By ~ 3

Author(s):

Sophie A.H. Jacobs ◽

Eveline Gart ◽

Debby Vreeken ◽

Bart A.A. Franx ◽

Lotte Wekking ◽

...

Keyword(s):

Adipose Tissue ◽

Hepatic Steatosis ◽

Fat Mass ◽

Brain Structure ◽

Brain Function ◽

Liver Pathology ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Juvenile Obesity

Background: Sex-specific differences play a role in metabolism, fat storage in adipose tissue, and brain structure. At juvenile age, brain function is susceptible to the effects of obesity; little is known about sex-specific differences in juvenile obesity. Therefore, this study examined sex-specific differences in adipose tissue and liver of high-fat diet (HFD)-induced obese mice, and putative alterations between male and female mice in brain structure in relation to behavioral changes during the development of juvenile obesity. Methods: In six-week-old male and female Ldlr-/-.Leiden mice (n = 48), the impact of 18 weeks of HFD-feeding was examined. Fat distribution, liver pathology and brain structure and function were analyzed imunohisto- and biochemically, in cognitive tasks and with MRI. Results: HFD-fed female mice were characterized by an increased perigonadal fat mass, pronounced macrovesicular hepatic steatosis and liver inflammation. Male mice on HFD displayed an increased mesenteric fat mass, pronounced adipose tissue inflammation and microvesicular hepatic steatosis. Only male HFD-fed mice showed decreased cerebral blood flow and reduced white matter integrity. Conclusions: At young age, male mice are more susceptible to the detrimental effects of HFD than female mice. This study emphasizes the importance of sex-specific differences in obesity, liver pathology, and brain function.

Download Full-text

SUN-LB93 Mineralocorticoid Receptor Mediates Sex-Dependent Anticontractile Effect of Perivascular Adipose Tissue in Obese Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2254 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Jamaira A Victorio ◽

Israelle Netto Freitas ◽

Daniele Mendes Guizoni ◽

Ana Paula Davel

Keyword(s):

Sex Differences ◽

Adipose Tissue ◽

Sexual Dimorphism ◽

Protein Expression ◽

Vascular Function ◽

Mineralocorticoid Receptor ◽

Obese Mice ◽

Perivascular Adipose Tissue ◽

Male And Female ◽

Female Mice

Abstract Obesity, a condition of excessive fat mass and subclinical inflammation, reached epidemic proportions with higher prevalence in women compared to men worldwide. Expansion of the perivascular adipose tissue (PVAT) is observed in obesity and clinical studies indicate a positive correlation between PVAT amount and body mass index. PVAT, a fat depot surrounding most of the vessels, modulates vascular function by releasing PVAT-derived factors such as adipokines that exert anticontractile effect in health individuals. Despite sexual dimorphism on PVAT morphology, it is still unknown whether or not there is sex differences in the PVAT modulating vascular function in the setting of obesity. Aldosterone-mineralocorticoid receptor (MR) signaling pathway has been demonstrated to be adipogenic and proinflammatory in classical fat depots and treatment with MR antagonists (A) might reverse vascular dysfunction and remodeling in obese models, especially in female sex. Therefore, we aimed to evaluate the anticontractile effect of PVAT in male and female obese mice and hypothesized that MR signaling would be involved in possible sex differences in PVAT dysfunction in obesity. Male and female C57Bl6/J mice were fed a chow or a high-fat diet (HFD, 60% energy from fat) for 20 weeks. At the last 4 weeks of HFD, female and male mice were treated with the MRA spironolactone (Spi, 100 mg/kg/day). HFD feeding significantly increased body weight and visceral adipose tissue, which was not modified by Spi treatment in both sexes. Resistance mesenteric arteries were isolated with or without PVAT and mounted in a wire myograph to evaluate vascular contractile responses. Lean male and female mice PVAT had an anticontractile effect in the response to phenylephrine that was greater in females than males. The anticontractile effect of PVAT was significantly impaired in obese females but not modified in males. HFD-induced dysfunctional PVAT was prevented by Spi treatment in females. Next, we evaluated the protein expression of aldosterone-synthase CYP11B2, serum and glucocorticoid-regulated kinase 1 (SGK1), and epithelial sodium channel subunits (ENaCs) in isolated mesenteric PVAT of lean and obese male and female mice. There was an increased expression of CYP11B2, SGK1 and ENaCs only in obese female PVAT. Protein expression of adiponectin, a major PVAT-released adipokine was also increased in female mesenteric PVAT. In conclusion, the findings suggest sexual dimorphism in PVAT function in health and in obesity. Although anticontractile role of PVAT was exacerbated in lean female mice, female sex was more susceptible to develop PVAT dysfunction in the setting of obesity which was prevented by MR blockade. HFD-induced PVAT dysfunction in females was associated with increased expression of SGK1 and ENaCs. Therefore, data suggest MR activation as a mechanism mediating sex differences in PVAT dysfunction. FAPESP, CAPES.

Download Full-text