Abstract MP27: Adipose-derived Human Soluble (Pro)renin Receptor Causes Resistance To Losartan Treatment In High-Fat Diet Male And Female Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Kellea Nichols ◽  
Audrey Poupeau ◽  
Eva Gatineau ◽  
Gertrude Arthur ◽  
Frederique B Yiannikouris
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
High Fat Diet ◽  
Partial Agonist ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Critical Gap ◽  
Prorenin Receptor ◽  
Obesity Hypertension

Obesity, affecting more that 37% of the US, contributes to hypertension. Despite the use of one or more anti-hypertensive treatments, 48% of the hypertensive population remains with resistant hypertension, which prompts the development for new therapeutic targets. We demonstrated that obesity increased the expression of prorenin receptor (PRR) in the adipose tissue and elevated plasma soluble PRR (sPRR). In addition, the infusion of mouse sPRR increased blood pressure in male mice fed high fat-diet (HF); indicating that adipose-derived sPRR could increase circulating sPRR and contribute to hypertension. However, there is a critical gap in the functional role of human sPRR in obesity-hypertension. In this study, we aim to define whether adipose-derived human sPRR contributes to obesity-hypertension. Human sPRR-Myc-tag transgenic mice were bred with mice expressing adiponectin/Cre to selectively express human sPRR in adipocytes (adi-HsPRR). Adi-HsPRR and control littermate (CTL) male and female mice were fed HF-diet for 20 weeks (N=8-15/group). Body weight was assessed weekly and body composition monthly. Blood pressure was measured by telemetry after 15 weeks of diet. Adipose-derived human sPRR did not significantly elevate body weight or fat mass (Male: CTL.18.3±1.0g; adi-HsPRR. 17.5±0.8g. Female: CTL. 15.6±1.5g; adi-HsPRR. 11.9±1.3g; p>0.05). Systolic blood pressure (SBP) significantly increased in HF-fed male and female mice however; adipose-derived human sPRR did not further elevate SBP (24h SBP. Male: CTL. 136.0±1.7 mmHg; adi-HsPRR: 133.4±1.5mmHg; Female: CTL. 131.9±2.8 mmHg; adi-HsPRR: 130.6±3.1 mmHg; p>0.05). Surprisingly, the anti-hypertensive effect of losartan (Los) to lower blood pressure was significantly reduced in adi-HsPRR male and female mice (Male: CTL. ΔSBP: -12.1±1.5 ΔmmHg; adi-HsPRR: -7.8±0.6 ΔmmHg; Female: CTL. ΔSBP: -13.4±1.1 ΔmmHg; adi-HsPRR: -5.7±2.3 ΔmmHg; p<0.05). In 3T3-L1 cells, sPRR significantly increased phosphorylation of ERK1/2, which was not completely blunted by Los indicating that human sPRR could act as a partial agonist of AT1R or activate ERK1/2 independently of AT1R. Our data suggests that adipose-derived sPRR does not stimulate AT1R-mediated contractility, instead impairs Los efficacy.

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

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.

scholarly journals Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

2019 ◽  
Vol 149 (1) ◽  
pp. 73-97 ◽  
Author(s):  
Eugene Nyamugenda ◽  
Marcus Trentzsch ◽  
Susan Russell ◽  
Tiffany Miles ◽  
Gunnar Boysen ◽  
...  
Keyword(s):  
High Fat Diet ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

P4-066: METABOLIC AND COGNITIVE EFFECTS OF HIGH FAT DIET IN MALE AND FEMALE MICE

2006 ◽  
Vol 14 (7S_Part_27) ◽  
pp. P1458-P1458
Author(s):  
Abigail E. Salinero ◽  
Lisa S. Robison ◽  
Brian M. Anderson ◽  
David Riccio ◽  
Kristen L. Zuloaga
Keyword(s):  
High Fat Diet ◽  
Cognitive Effects ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Bisphenol A Promotes Adiposity and Inflammation in a Nonmonotonic Dose-response Way in 5-week-old Male and Female C57BL/6J Mice Fed a Low-calorie Diet

Endocrinology ◽  
2016 ◽  
Vol 157 (6) ◽  
pp. 2333-2345 ◽  
Author(s):  
Minglan Yang ◽  
Maopei Chen ◽  
Jiqiu Wang ◽  
Min Xu ◽  
Jichao Sun ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Weight ◽  
Bisphenol A ◽  
Body Mass ◽  
Fat Mass ◽  
High Fat Diet ◽  
Inflammatory Factors ◽  
Chow Diet ◽  
High Fat ◽  
Male And Female

A growing body of epidemiological research show that Bisphenol A (BPA) is positively correlated with obesity and metabolic disorders. However, the mechanisms of BPA on adiposity remain largely unknown. In this study, we found that 5-week-old male and female C57BL/6J mice exposed to four dosages of BPA (5, 50, 500, and 5000 μg/kg/d) by oral intake for 30 days showed significantly increased body weight and fat mass in a nonmonotonic dose-dependent manner when fed a chow diet. The effect occurred even at the lowest concentration (5μg/kg/d), lower than the tolerable daily intake of 50 μg/kg/day for BPA. However, no significant difference in body weight and fat mass was observed in either male or female mice fed a high-fat diet, suggesting that BPA may interact with diet in promoting obesity risk. In vitro study showed that BPA treatment drives the differentiation of white adipocyte progenitors from the stromal vascular fraction, partially through glucocorticoid receptor. BPA exposure increased circulating inflammatory factors and the local inflammation in white adipose tissues in both genders fed a chow diet, but not under high-fat diet. We further found that BPA concentration was associated with increased circulating inflammatory factors, including leptin and TNFα, in lean female subjects (body mass index &lt; 23.0 kg/m2) but not in lean male subjects or in both sexes of overweight/obese subjects (body mass index &gt; 25.0 kg/m2). In conclusion, we demonstrated the nonmonotonic dose effects of BPA on adiposity and chronic inflammation in 5-week-old mice, which is related to caloric uptake.

Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers

2005 ◽  
Vol 288 (6) ◽  
pp. E1236-E1243 ◽  
Author(s):  
Elena Velkoska ◽  
Timothy J. Cole ◽  
Margaret J. Morris
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Adipose Tissue ◽  
Neuropeptide Y ◽  
Litter Size ◽  
High Fat Diet ◽  
Dietary Intervention ◽  
High Fat ◽  
Brown Adipose

Early life nutrition impacts on subsequent risk of obesity and hypertension. Several brain chemicals responsible for both feeding and cardiovascular regulation are altered in obesity. We examined effects of early postnatal overnutrition on blood pressure, brain neuropeptide Y (NPY), and adiposity markers. Rat pup litters were adjusted to either 3 or 12 male animals (overnutrition and control, respectively) on day 1 of life. After weaning, rats were given either a palatable high-fat diet or standard chow. Smaller litter pups were significantly heavier by 17 days of age. By 16 wk, the effect of litter size was masked by that of diet, postweaning. Small and normal litter animals fed a high-fat diet had similar increases in body weight, plasma insulin, leptin, and adiponectin concentrations, leptin mRNA, and fat masses relative to chow-fed animals. An increase in 11β-hydroxysteroid dehydrogenase-1 mRNA in white adipose tissue, and a decrease in uncoupling protein-1 mRNA in brown adipose tissue in both small litter groups at 16 wk of age, may represent a programming effect of the altered litter size. NPY concentration in the paraventricular nucleus of the hypothalamus was reduced in high fat-fed groups. Blood pressure was significantly elevated at 13 wk in high-fat-fed animals. This study demonstrates that overnourishment during early postnatal development leads to profound changes in body weight at weaning, which tended to abate with maturation. Thus the effects of long-term dietary intervention postweaning can override those of litter size-induced obesity.

scholarly journals The Influence of High-Fat Diet in Early Life on Intestinal Tumorigenesis in APC1638N Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 272-272
Author(s):  
Ting-Chun Lin ◽  
Ying Tang ◽  
Soonkyu Chung ◽  
Young-Cheul Kim ◽  
Zhenhua Liu
Keyword(s):  
Body Weight ◽  
Wnt Signaling ◽  
Tumor Size ◽  
High Fat Diet ◽  
Early Life ◽  
The Body ◽  
Tumor Incidence ◽  
High Fat ◽  
Intestinal Tumorigenesis ◽  
Female Mice

Abstract Objectives Colorectal cancer (CRC) is one of the most prevalent cancer worldwide. Evidence from epidemiological studies shows that the incidence rate of CRC among elders with age ≥ 50 years is gradually decreased, whereas the rate continuously rise in adults with age &lt; 50 years. Along with the rise of CRC in young adults, a significantly increasing trend in obesity is also observed in youth. The present study aims to investigate how the early-life nutrition influences the intestinal tumorigenesis later in mouse with an age equivalent to an age &lt; 50 years in human. Methods APC1638N mice (4 weeks of age) were fed a low-fat diet (N = 22; LF: 10% kcal from fat) or a high-fat diet (N = 23; HF: 60% kcal from fat) for 8 weeks, which is equivalent to child/adolescent age in humans. After that, all animals were switched to standard chow diet (LabDiet #5P76) and fed for additional 12 weeks before sacrifice. Tumors were examined and the expression tumorigenic Wnt-signaling downstream genes (Cyclin D1, c-Myc and Axin 2) in the intestine were assessed. Results Our results showed that compared to LF group, the body weight of both male and female mice significantly increased after 8-week HF feeding (P &lt; 0.05). After switching to the standard chow diet for further 12 weeks feeding, the increase of body weight in HF group remained, although the degree of magnitude reduced, and a statistical significance only shown in female mice (P &lt; 0.05). There were a higher tumor incidence (P = 0.051) and tumor multiplicity (P &lt; 0.05) in males than female.  No interactions between gender and diet were observed. The HF group had a higher tumor incidence (P = 0.088) and tumor size (P &lt; 0.05) when compared to the LF group. The expression of Wnt-signaling downstream gene, c-Myc, was significantly increased in the HF group at 24-week of age (P &lt; 0.01). Conclusions A short term of high-fat diet in early life tends to promote intestinal tumorigenesis in adults as indicated by a mild increase in tumor incidence and a significant increase in tumor size. Funding Sources This project was supported by the US Department of Agriculture Hatch funding (#1013548).

scholarly journals Container-aided Integrative QTL and RNA-seq Analysis of Collaborative Cross Mice Supports Distinct Sex-Oriented Molecular Modes of Response in Obesity

2019 ◽  
Author(s):  
Ilona Binenbaum ◽  
Hanifa Abu-Toamih Atamni ◽  
Georgios Fotakis ◽  
Georgia Kontogianni ◽  
Theodoros Koutsandreas ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Complex Traits ◽  
Hepatic Gene Expression ◽  
High Fat ◽  
Mouse Population ◽  
Male And Female ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Genetic Mechanisms

Abstract Background: The CC mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, the underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population. Results: We established an automated and reproducible integrative workflow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workflow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrate these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression differs significantly between obese and non-obese mice, with a significant sex effect, where male and female mice exhibit different responses and coping mechanisms. Conclusion: Integration of the data showed that different genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity differ in female and male mice. The clear distinction we observe in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.

scholarly journals Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice

2020 ◽  
Author(s):  
Geronimo Matteo ◽  
Myriam P Hoyeck ◽  
Hannah L Blair ◽  
Julia Zebarth ◽  
Kayleigh RC Rick ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
Low Dose ◽  
Dependent Manner ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Insulin Levels ◽  
Plasma Insulin Levels

AbstractObjectiveHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that acute high-dose TCDD exposure (20 μg/kg) decreased plasma insulin levels in both male and female mice in vivo; however, effects on glucose homeostasis were sex-dependent. The purpose of this study was to determine whether prolonged exposure to a physiologically relevant dose of TCDD impairs beta cell function and/or glucose homeostasis in a sex-dependent manner in either chow-fed or HFD-fed mice.MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks, and simultaneously fed a chow or 45% high-fat diet (HFD). Glucose metabolism was assessed by glucose and insulin tolerance tests throughout the study. Islets were isolated from females at 12 weeks for Tempo-Seq® analysis.ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. In addition, islet TempO-Seq® analysis showed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females.ConclusionsOur data suggest that TCDD exposure is more deleterious when combined with HFD-feeding in female mice, and that low-dose TCDD exposure increases diabetes susceptibility in females.

Sign in / Sign up

Export Citation Format

Share Document