Gender-Dependent Up-Regulation of the VWF-Cleaving metalloprotease ADAMTS-13 in Mice with Obesity and Hypercholesterolemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3500-3500
Author(s):  
Anne Liu ◽  
Huaizhu Wu ◽  
Zhenyin Tao ◽  
Hiuwan Choi ◽  
Angela Bergeron ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
High Fat Diet ◽  
Active Form ◽  
Protective Measure ◽  
Male Mice ◽  
Wild Type ◽  
High Fat ◽  
Female Mice ◽  
Regular Diet ◽  
Apo E

Abstract The development of atherothrombosis is associated with hypercholesterolemia and systemic inflammation. Recent studies have shown that adipose tissue may directly promote inflammation. Since one of the hallmark events of atherosclerosis is the deposition of von Willebrand factor (VWF) on vascular endothelial cells, the release and proteolysis of ultra-large (UL) and hyperreactive VWF may play an important role in the development of thrombotic diseases. We therefore investigated how the synthesis of ADAMTS-13, the newly characterized metalloprotease that cleaves the hyperreactive ULVWF to smaller and less active form, may be regulated in mice with obesity and hypercholesterolemia. Wild-type C57BL/6 and Apo E −/− C57Bl/6 mice (18 in each group with equal gender distribution) were fed with regular Chow or western-type high fat diet for 6 months and then analyzed for ADAMTS-13 mRNA in the liver (by quantitative PCR), the primary site of ADAMTS-13 synthesis, and ADAMTS-13 activity under flow condition. We found that ADAMTS-13 mRNA was more than doubled for wild-type mice on high fat diet than those on regular diet (4.14±0.46 vs. 1.72±0.57 units, respectively, p < 0.01). The increase was 47.9% for Apo E−/− mice on high fat diet compared to mice on regular diet (2.61±0.31 vs. 3.86±0.72 units, respectively, p = 0.05). When the data were stratified for gender difference, the increase was primarily observed in male mice. For male mice, ADAMTS-13 mRNA on high fat diet was more than four and two folds of those on regular diet for wild-type and Apo E−/− mice, respectively. , For female mice, however, the increase was less than 40% and only detected in wild-type mice fed with high fat diet. Consistent with this observation, ADAMTS-13 activity in general was lower in female (61±12%) than males (81±10%, p < 0.05). For both wild-type and Apo E−/− mice, we detected no difference in ADAMTS-13 activity in males, but a significantly lower activity in the female Apo E−/− mice on high fat diet (19.6±10.5% vs. 49.1±9.2% for high fat and regular diets, respectively, p < 0.05). These results demonstrate that the synthesis of ADAMTS-13 is up-regulated in obese mice (wild-type on high fat diet) and mice with hypercholesterolemia (Apo E−/− mice on high fat diet). The increase may serve as a protective measure to encounter the likely increase in ULVWF release due to systemic inflammation and endothelial cell stimulation seen in these mice. Interestingly, male mice showed a much stronger up-regulation than females. The low rate of ADAMTS-13 synthesis may contribute to the lower ADAMTS-13 activity found in female mice, suggesting that the machinery of ULVWF proteolysis in female mice may be less responsive to obesity/hypercholesterolemia and systemic inflammation.

scholarly journals Androgen Receptor-Dependent and Independent Atheroprotection by Testosterone in Male Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5428-5437 ◽  
Author(s):  
Johan Bourghardt ◽  
Anna S. K. Wilhelmson ◽  
Camilla Alexanderson ◽  
Karel De Gendt ◽  
Guido Verhoeven ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Apolipoprotein E ◽  
High Fat Diet ◽  
Atherosclerotic Lesion ◽  
Male Mice ◽  
Wild Type ◽  
High Fat ◽  
Lesion Area ◽  
Major Pathway

The atheroprotective effect of testosterone is thought to require aromatization of testosterone to estradiol, but no study has adequately addressed the role of the androgen receptor (AR), the major pathway for the physiological effects of testosterone. We used AR knockout (ARKO) mice on apolipoprotein E-deficient background to study the role of the AR in testosterone atheroprotection in male mice. Because ARKO mice are testosterone deficient, we sham operated or orchiectomized (Orx) the mice before puberty, and Orx mice were supplemented with placebo or a physiological testosterone dose. From 8 to 16 wk of age, the mice consumed a high-fat diet. In the aortic root, ARKO mice showed increased atherosclerotic lesion area (+80%, P &lt; 0.05). Compared with placebo, testosterone reduced lesion area both in Orx wild-type (WT) mice (by 50%, P &lt; 0.001) and ARKO mice (by 24%, P &lt; 0.05). However, lesion area was larger in testosterone-supplemented ARKO compared with testosterone-supplemented WT mice (+57%, P &lt; 0.05). In WT mice, testosterone reduced the presence of a necrotic core in the plaque (80% among placebo-treated vs. 12% among testosterone-treated mice; P &lt; 0.05), whereas there was no significant effect in ARKO mice (P = 0.20). In conclusion, ARKO mice on apolipoprotein E-deficient background display accelerated atherosclerosis. Testosterone treatment reduced atherosclerosis in both WT and ARKO mice. However, the effect on lesion area and complexity was more pronounced in WT than in ARKO mice, and lesion area was larger in ARKO mice even after testosterone supplementation. These results are consistent with an AR-dependent as well as an AR-independent component of testosterone atheroprotection in male mice.

scholarly journals Sex and BNIP3 genotype, rather than acute lipid injection, modulate hepatic mitochondrial function and steatosis risk in mice

2020 ◽  
Vol 128 (5) ◽  
pp. 1251-1261
Author(s):  
Kelly N. Z. Fuller ◽  
Colin S. McCoin ◽  
Julie Allen ◽  
Shelby Bell-Glenn ◽  
Devin C. Koestler ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Interacting Protein ◽  
Female Mice ◽  
Complex Protein ◽  
Respiratory Outcomes

This is the first study focusing on hepatic mitochondrial respiratory outcomes in response to lipid overload via a high-fat diet (HFD) combined with intralipid injection. Novel findings include no effect of intralipid injection on mitochondrial outcomes of interest, despite increased circulating lipid concentrations. However, we report pronounced differences in hepatic mitochondrial respiration, complex protein expression, and H2O2 production by sex and BCL-2/adenovirus EIB 19-kDa interacting protein (BNIP3) genotype. Specifically, female mice had lower H2O2 emission globally and on an acute HFD, females had greater hepatic mitochondrial respiration than males, whereas BNIP3 knockout (KO) animals had greater mitochondrial coupling and complex protein expression than wild-type (WT) animals.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

scholarly journals Metabolic dysfunction in female mice with disruption of 5α-reductase 1

2017 ◽  
Vol 232 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Dawn E W Livingstone ◽  
Emma M Di Rollo ◽  
Tracy C-S Mak ◽  
Karen Sooy ◽  
Brian R Walker ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Stress Responses ◽  
High Fat Diet ◽  
Metabolic Dysfunction ◽  
Male Mice ◽  
High Fat ◽  
Female Mice ◽  
Normal Chow ◽  
Transcript Profiles

5α-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. However, it is unclear whether this is driven by changes in androgen and/or glucocorticoid action. Female mice with transgenic disruption of 5α-reductase 1 (5αR1-KO) were studied, representing a ‘low androgen’ state. Glucocorticoid clearance and stress responses were studied in mice aged 6 months. Metabolism was assessed in mice on normal chow (aged 6 and 12 m) and also in a separate cohort following 1-month high-fat diet (aged 3 m). Female 5αR1-KO mice had adrenal suppression (44% lower AUC corticosterone after stress), and upon corticosterone infusion, accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5αR1-KO mice aged 6 m fed normal chow demonstrated insulin resistance (~35% increased area under curve (AUC) for insulin upon glucose tolerance testing) and hepatic steatosis (~33% increased hepatic triglycerides) compared with controls. This progressed to obesity (~12% increased body weight) and sustained insulin resistance (~38% increased AUC insulin) by age 12 m. Hepatic transcript profiles supported impaired lipid β-oxidation and increased triglyceride storage. Female 5αR1-KO mice were also predisposed to develop high-fat diet-induced insulin resistance. Exaggerated predisposition to metabolic disorders in female mice, compared with that seen in male mice, after disruption of 5αR1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.

scholarly journals Estrogen Receptor Alpha Is Required to Protect Daily Metabolic Rhythms From Disruption by High-Fat Feeding in Female Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A808-A808
Author(s):  
Oluwabukola B Omotola ◽  
Julie S Pendergast
Keyword(s):  
Estrogen Receptor ◽  
High Fat Diet ◽  
Estrogen Receptor Alpha ◽  
Activity Rhythm ◽  
Wild Type ◽  
High Fat ◽  
Daily Rhythms ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Fat Feeding

Abstract The circadian system is a critical regulator of obesity in male mice, but its role in females is poorly understood. In our previous studies we found that estrogen regulates daily rhythms in female mice to confer resistance to diet-induced obesity, but the mechanism is unknown. Estrogen signals via the classical estrogen receptor alpha (ERα) to regulate metabolism and obesity. Therefore, in this study we tested the hypothesis that estrogen regulates daily metabolic rhythms in females via ERα. To do so, we studied daily rhythms in female global ERα knockout (ERα KO) with the circadian reporter, PERIOD2::LUCIFERASE, mice fed high-fat diet for 6 weeks. ERα KO female mice became obese and hyperglycemic when fed high-fat diet, while wild-type females were resistant to diet-induced obesity. Chronic high-fat diet feeding also reduced the amplitude of the daily rhythm of eating behavior in ERα KO, but not wild-type, female mice. In wild-type females, the amplitude of the locomotor activity rhythm increased during high-fat feeding. In contrast, high-fat feeding decreased the amplitude of the activity rhythm in ERα KO females. The temporal relationship between central and peripheral circadian tissue clocks was disrupted by high-fat feeding in ERα KO females since the phase of the liver PERIOD2::LUCIFERASE rhythm was advanced 4 hours by high-fat feeding in ERα KO mice compared to wild-type females. Taken together these results show that estrogen signals via ERα to protect daily metabolic rhythms from disruption by high-fat feeding in female mice.

scholarly journals Metabolic Burden of Erythropoietin Stimulated Erythropoiesis in Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2421-2421
Author(s):  
Constance Tom Noguchi ◽  
Heather Marie Rogers
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
Fat Mass ◽  
High Fat Diet ◽  
Male Mice ◽  
Wild Type ◽  
Hematopoietic Tissue ◽  
High Fat ◽  
Epor Expression

Erythropoietin (EPO) promotes erythroid differentiation and increases glucose uptake in erythroid progenitor cells in culture. The metabolic burden associated with EPO treatment in adult mice is suggested by a decrease in body weight concomitant with increased hematocrit. Wild type male mice (C57Bl/6, age 8 months) treated with EPO showed the expected increase in hematocrit accompanied by a fall in blood glucose level and a decrease in body weight and fat mass. However, the decrease in body weight is even more evident in obese mice on a high fat diet and has also been linked to non-hematopoietic response, particularly with EPO receptor (EpoR) expression in white adipose tissue. We examined the metabolic burden of EPO treatment (3000U/kg for 3 weeks) in young, lean male mice (3 months) placed on high fat diet at the time of EPO administration. The increase in hematocrit was accompanied by decreased blood glucose level and improved glucose tolerance. However, no difference in body weight was observed between mice treated with EPO and the saline treated group, suggesting that the EPO stimulated decrease in body weight is evident primarily in older animals with greater fat mass. To determine the contribution of EpoR expression in non-hematopoietic tissue to the metabolic EPO response, young male mice with EpoR restricted to erythroid tissue (TgEpoR) were placed on high fat diet and treated with EPO. The expected increased hematocrit was also accompanied by decreased blood glucose level and improved glucose tolerance, and no change in body weight between EPO and saline treatment. The similar responses observed in young wild type and TgEpoR mice suggest that the EPO stimulated increase in glucose metabolism is associated with increased erythropoiesis rather than a direct EPO response in non-hematopoietic tissue. TgEpoR mice exhibit an age dependent increase in fat mass even greater than that observed in wild type mice, and by 8 months TgEpoR mice are obese, glucose intolerant and insulin resistant compared with wild type mice. At 8 months, TgEpoR mice treated with EPO show the increase in hematocrit and, despite the increase in fat mass, there is only a minimal decrease in body weight compared with wild type mice. These data provide evidence that in addition to the age dependent association of EPO stimulated decrease in body weight and fat mass, this decrease in body weight is due largely to EPO response related to EpoR expression in non-hematopoietic tissue. Interestingly, young male mice with targeted deletion of EpoR in adipose tissue placed on a high fat diet and treated with EPO show the increase in hematocrit and improvement in glucose tolerance, and at 8 months, the increase in hematocrit with EPO treatment is accompanied by minimal change in body weight. The similar metabolic response of these mice with targeted deletion of EpoR in adipose tissue to TgEpoR mice indicate the contribution of EpoR expression in adipose tissue to the loss of body weight and fat mass. Therefore, the metabolic burden associated with EPO stimulated erythropoiesis appears to be reflected in improved glucose metabolism and glucose tolerance with minimal or no effect on body weight, is evident in young, lean mice, and is independent of EpoR expression in non-hematopoietic tissue. In older mice, non-hematopoietic metabolic EPO response is more readily apparent as reflected in loss of body weight/fat mass, which overshadows the erythropoietic metabolic response. In combination, the metabolic response to EPO treatment results from EPO stimulated increased erythropoiesis, improved glucose metabolism and glucose tolerance, and an age dependent decrease in body weight and fat mass associated with EpoR expression in non-hematopoietic tissue, particularly in white adipose tissue. Disclosures No relevant conflicts of interest to declare.

Glutaredoxin1 knockout promotes high-fat diet-induced obesity in male mice but not in female ones

2021 ◽  
Author(s):  
Xiao yu Zou ◽  
Muhammad Ijaz Ahmad ◽  
Di Zhao ◽  
Min Zhang ◽  
Chunbao Li
Keyword(s):  
High Fat Diet ◽  
Calorie Intake ◽  
Male Mice ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Diet Induced Obesity

This study aims to explore how high-fat diet and glutaredoxin1 (Glrx1) deficiency affect the development of obesity in male and female mice. High-fat diet induced great differences in calorie intake...

scholarly journals Sex-specific Metabolic Characterization of Serum and Liver of Mice with High-fat Diet

2020 ◽  
Author(s):  
Yi Zhou ◽  
Chen Li ◽  
Xinyi Wang ◽  
Qinbo Chen ◽  
Pengxi Deng ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Male Mice ◽  
High Fat ◽  
Metabolic Pattern ◽  
Male And Female ◽  
Female Mice

Abstract Background: Obesity exhibit sex differences is well established, but its metabolic mechanism remains unclear. Thus, investigation of metabolic pattern of male and female mice with high-fat diet (HFD) is of substantial importance for explore the potential mechanism linking gender differences in obesity.Methods: In the present study, we analyzed the metabolic changes in serum and liver of male and female mice with high-fat diet using nuclear magnetic resonance-based metabolomic approach.Results: Principle component analysis show that the metabolic pattern of serum and liver of male mice with HFD was significantly distinguished from the other groups. Furthermore, the accumulation of low-density lipoprotein/very low-density lipoprotein was found in the serum of male mice with HFD. Moreover, metabolomic results of liver reveal that tricarboxylic acid cycle and amino acid metabolism are increased in female mice with HFD.Conclusion: In conclusion, our results suggest that the differences in energy and amino acid metabolism of males and females were most likely influence the predisposition to obesity.

scholarly journals Disruption of CRTC1 and CRTC2 in Sim1 cells strongly increases high-fat diet intake in female mice but has a modest impact on male mice

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262577
Author(s):  
Jin Tanaka ◽  
Fuka Ishikawa ◽  
Tomoki Jinno ◽  
Motoki Miyakita ◽  
Haruka Miyamori ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
High Fat Diet ◽  
Chow Diet ◽  
Male Mice ◽  
High Fat ◽  
Double Knockout ◽  
Female Mice ◽  
Normal Chow ◽  
The Brain ◽  
Regulate Gene

cAMP responsive element binding protein (CREB)-regulated transcription coactivators (CRTCs) regulate gene transcription in response to an increase in intracellular cAMP or Ca2+ levels. To date, three isoforms of CRTC have been identified in mammals. All CRTCs are widely expressed in various regions of the brain. Numerous studies have shown the importance of CREB and CRTC in energy homeostasis. In the brain, the paraventricular nucleus of the hypothalamus (PVH) plays a critical role in energy metabolism, and CRTC1 and CRTC2 are highly expressed in PVH neuronal cells. The single-minded homolog 1 gene (Sim1) is densely expressed in PVH neurons and in some areas of the amygdala neurons. To determine the role of CRTCs in PVH on energy metabolism, we generated mice that lacked CRTC1 and CRTC2 in Sim1 cells using Sim-1 cre mice. We found that Sim1 cell-specific CRTC1 and CRTC2 double-knockout mice were sensitive to high-fat diet (HFD)-induced obesity. Sim1 cell-specific CRTC1 and CRTC2 double knockout mice showed hyperphagia specifically for the HFD, but not for the normal chow diet, increased fat mass, and no change in energy expenditure. Interestingly, these phenotypes were stronger in female mice than in male mice, and a weak phenotype was observed in the normal chow diet. The lack of CRTC1 and CRTC2 in Sim1 cells changed the mRNA levels of some neuropeptides that regulate energy metabolism in female mice fed an HFD. Taken together, our findings suggest that CRTCs in Sim1 cells regulate gene expression and suppress excessive fat intake, especially in female mice.

scholarly journals Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 543
Author(s):  
Allison C. Stone ◽  
Robert C. Noland ◽  
Randall L. Mynatt ◽  
Samuel E. Velasquez ◽  
David S. Bayless ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Lipid Oxidation ◽  
Fat Mass ◽  
High Fat Diet ◽  
Male Mice ◽  
High Fat ◽  
Female Mice ◽  
Glucose Levels ◽  
Glucose Clearance

Male mice lacking HuR in skeletal muscle (HuRm−/−) have been shown to have decreased gastrocnemius lipid oxidation and increased adiposity and insulin resistance. The same consequences have not been documented in female HuRm−/− mice. Here we examine this sexually dimorphic phenotype. HuRm−/− mice have an increased fat mass to lean mass ratio (FM/LM) relative to controls where food intake is similar. Increased body weight for male mice correlates with increased blood glucose during glucose tolerance tests (GTT), suggesting increased fat mass in male HuRm−/− mice as a driver of decreased glucose clearance. However, HuRm−/− female mice show decreased blood glucose levels during GTT relative to controls. HuRm−/− mice display decreased palmitate oxidation in skeletal muscle relative to controls. This difference is more robust for male HuRm−/− mice and more exaggerated for both sexes at high dietary fat. A high-fat diet stimulates expression of Pgc1α in HuRm−/− male skeletal muscle, but not in females. However, the lipid oxidation Pparα pathway remains decreased in HuRm−/− male mice relative to controls regardless of diet. This pathway is only decreased in female HuRm−/− mice fed high fat diet. A decreased capacity for lipid oxidation in skeletal muscle in the absence of HuR may thus be linked to decreased glucose clearance in male but not female mice.

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