scholarly journals SUN-237 Sex Differences in the Effect of Osteocalcin and Exercise on Memory and Cognition

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jordan Winberg ◽  
Jesse Rentz ◽  
Lina Darwish ◽  
Walter Swardfager ◽  
Jane Mitchell
Keyword(s):  
Problem Solving ◽  
High Fat Diet ◽  
Type Ii Diabetes ◽  
Treadmill Exercise ◽  
Bone Matrix ◽  
Behaviour Problem ◽  
Type Ii ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Abstract Osteocalcin is a protein produced in the osteoblasts of bone and found both in the bone matrix and in circulation1. Mouse studies have demonstrated that osteocalcin administration improves type II diabetes through increased insulin release and sensitivity2. Further, osteocalcin can cross the blood-brain barrier and has been shown to restore memory and cognition in mice3. To date, experiments testing the effects of osteocalcin in mice have almost exclusively been conducted in only one sex and could not account for sex as a biological variable. We hypothesized that osteocalcin and exercise would improve behavioral outcomes and aimed to record any difference in response between sexes. In this study, we compare the effects of daily osteocalcin treatment, with or without daily treadmill exercise, in male and female mice (C57BL/6) on a high-fat diet induced model of type II diabetes. Mice were fed high-fat diet for eight weeks, followed by eight weeks of daily osteocalcin injections and/or treadmill exercise. During the final two weeks of treatment behavioural testing for depressive-like behaviour, anxiety-like behaviour, problem-solving, and memory was completed, and the results obtained in male and female mice were compared. The high-fat diet increased depressive-like behaviour and impaired problem solving in both sexes. Significant interactions between sex and exercise and sex and diet were observed. High-fat diet increased anxiety-like behaviour in females, but not males, while exercise increased anxiety-like behaviour in males. Both treatments improved behavioural outcomes, though no difference could be attributed to the combination of treatments. Exercise and osteocalcin decreased depressive-like behaviour in both sexes. Osteocalcin improved problem solving in both sexes, but exercise only improved problem solving in females. The effects of osteocalcin were similar in both male and female mice, however exercise improved problem-solving only in female mice. This suggests that both sexes benefit from osteocalcin treatment and exercise may be more beneficial in females. The results indicate that osteocalcin and exercise have similar but not identical effects on behaviour that may be reflected in overlapping mechanisms of action. References: (1) Lee et al., Cell. 2007; 130(3): 456-469. (2) Ferron et al., Bone. 2012; 50(2): 568–575. (3) Khrimian et al., J Exp Med. 2017; 214(10): 2859-2873.

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

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 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.

scholarly journals Container-aided integrative QTL and RNA-seq analysis of Collaborative Cross mice supports distinct sex-oriented molecular modes of response in obesity

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
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 Collaborative Cross (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, 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 integrated 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 are different in female and male mice. The clear distinction we observed 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.

Bitter Taste Receptors, T2R138 and T2R16, are Induced in the Large Intestine of Male and Female Mice on a High Fat Diet in a Microbiota-Dependent Manner

2017 ◽  
Vol 152 (5) ◽  
pp. S156
Author(s):  
Filippo Caremoli ◽  
Jennifer Huynh ◽  
Venu Lagishetty ◽  
Jonathan Jacobs ◽  
Jonathan Braun ◽  
...  
Keyword(s):  
Large Intestine ◽  
High Fat Diet ◽  
Bitter Taste ◽  
Taste Receptors ◽  
Dependent Manner ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Bitter Taste Receptors
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