scholarly journals Female mice exposed to low-doses of dioxin during pregnancy and lactation have increased susceptibility to diet-induced obesity and diabetes

2020 ◽  
Author(s):  
Myriam P Hoyeck ◽  
Rayanna C Merhi ◽  
Hannah Blair ◽  
C Duncan Spencer ◽  
Mikayla A Payant ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Low Dose ◽  
Cell Function ◽  
Chemical Exposure ◽  
Chow Diet ◽  
Female Mice ◽  
Obesity And Diabetes ◽  
Pregnancy And Lactation ◽  
Dioxin Exposure

AbstractObjectiveExposure to persistent organic pollutants is consistently associated with increased diabetes risk in humans. We investigated the short- and long-term impact of chronic low-dose dioxin (aka 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) exposure during pregnancy and lactation on glucose homeostasis and beta cell function in female mice, including their response to a metabolic stressor later in life.MethodsFemale mice were injected with either corn oil (CO; vehicle control) or 20 ng/kg/d TCDD 2x/week throughout mating, pregnancy, and lactation, and then tracked for 6-10 weeks after chemical exposure stopped. A subset of CO- and TCDD-exposed dams were then transferred to a 45% high fat diet (HFD) or remained on standard chow diet for an additional 11 weeks to assess long-term effects of TCDD on adaptability to a metabolic stressor.ResultsDioxin-exposed dams were hypoglycemic at birth but otherwise had normal glucose homeostasis during and post-dioxin exposure. However, dioxin-exposed dams on chow diet were modestly heavier than controls starting 5 weeks after the last dioxin injection, and their weight gain accelerated after transitioning to a HFD. Dioxin-exposed dams also had accelerated onset of hyperglycemia, dysregulated insulin secretion, reduced islet size, increased MAFA- beta cells, and increased proinsulin accumulation following HFD feeding compared to control dams.ConclusionsOur mouse model suggests that chronic low-dose dioxin exposure may be a contributing factor to obesity and diabetes pathogenesis in females.

scholarly journals Female mice exposed to low doses of dioxin during pregnancy and lactation have increased susceptibility to diet-induced obesity and diabetes

2020 ◽  
Vol 42 ◽  
pp. 101104 ◽  
Author(s):  
Myriam P. Hoyeck ◽  
Rayanna C. Merhi ◽  
Hannah L. Blair ◽  
C. Duncan Spencer ◽  
Mikayla A. Payant ◽  
...  
Keyword(s):  
Low Doses ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Obesity And Diabetes ◽  
Pregnancy And Lactation ◽  
Increased Susceptibility

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 Impact of Pregnancy and Lactation on the Long-Term Regulation of Energy Balance in Female Mice

Endocrinology ◽  
2018 ◽  
Vol 159 (6) ◽  
pp. 2324-2336 ◽  
Author(s):  
Sharon Rachel Ladyman ◽  
Zin Khant Aung ◽  
David Ross Grattan
Keyword(s):  
Energy Balance ◽  
Female Mice ◽  
Pregnancy And Lactation

Impact of cyclosporine and low-dose steroid therapy on insulin sensitivity and beta-cell function in patients with long-term liver grafts

2001 ◽  
Vol 14 (1) ◽  
pp. 6-11
Author(s):  
T. Konrad ◽  
Bernd Markus ◽  
Carl Allers ◽  
Paolo Vicini ◽  
Gianna Toffolo ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Beta Cell ◽  
Steroid Therapy ◽  
Beta Cell Function ◽  
Low Dose ◽  
Cell Function

scholarly journals Leptin partially mediates the association between early-life nutritional supplementation and long-term glycemic status among women in a Guatemalan longitudinal cohort

2020 ◽  
Vol 111 (4) ◽  
pp. 804-813 ◽  
Author(s):  
Siran He ◽  
Ngoc-Anh Le ◽  
Manuel Ramirez-Zea ◽  
Reynaldo Martorell ◽  
K M Venkat Narayan ◽  
...  
Keyword(s):  
Early Life ◽  
Cell Function ◽  
Fasting Glucose ◽  
Mediation Effect ◽  
Glycemic Status ◽  
Glucose Lowering ◽  
Obesity And Diabetes ◽  
Increased Risk

ABSTRACT Background Early-life exposure to improved nutrition is associated with decreased risk of diabetes but increased risk of obesity. Leptin positively correlates with adiposity and has glucose-lowering effects, thus it may mediate the association of early-life nutrition and long-term glycemic status. Objectives We aimed to investigate the role of leptin in the differential association between early-life nutrition and the risks of obesity and diabetes. Methods We analyzed data from a Guatemalan cohort who were randomly assigned at the village level to receive nutritional supplements as children. We conducted mediation analysis to examine the role of leptin in the associations of early-life nutrition and adult cardiometabolic outcomes. Results Among 1112 study participants aged (mean ± SD) 44.1 ± 4.2 y, 60.6% were women. Cardiometabolic conditions were common: 40.2% of women and 19.4% of men were obese, and 53.1% of women and 41.0% of men were hyperglycemic or diabetic. Median (IQR) leptin concentration was 15.2 ng/mL (10.2–17.3 ng/mL) in women and 2.7 ng/mL (1.3–5.3 ng/mL) in men. Leptin was positively correlated with BMI (Spearman's ρ was 0.6 in women, 0.7 in men). Women exposed to improved nutrition in early life had 2.8-ng/mL (95% CI: 0.3, 5.3 ng/mL) higher leptin and tended to have lower fasting glucose (–0.8 mmol/L; –1.8, 0.2 mmol/L, nonsignificant) than unexposed women. There were no significant differences in leptin (–0.7 ng/mL; –2.1, 0.8 ng/mL) or fasting glucose (0.2 mmol/L; –0.5, 0.9 mmol/L) in men exposed to improved nutrition in early life compared with unexposed men. Leptin mediated 34.9% of the pathway between early-life nutrition and fasting glucose in women. The mediation in women was driven by improved pancreatic β-cell function. We did not observe the mediation effect in men. Conclusions Leptin mediated the glucose-lowering effect of early-life nutrition in women but not in men.

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

Endocrinology ◽  
2021 ◽  
Author(s):  
Geronimo Matteo ◽  
Myriam P Hoyeck ◽  
Hannah L Blair ◽  
Julia Zebarth ◽  
Kayleigh R C Rick ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
Low Dose ◽  
High Fat ◽  
Male And Female ◽  
Female Mice ◽  
Insulin Levels ◽  
Plasma Insulin Levels

Abstract Objective Human 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 a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. The current study assessed whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in chow-fed or high fat diet (HFD)-fed mice. Methods Male and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females for Tempo-Seq® analysis. Results Low-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. TCDD caused a modest increase in islet area in males but reduced % beta cell area within islets in females. RNAseq analysis revealed abnormal changes to endocrine and metabolic pathways in TCDDHFD females. Conclusions Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice, but promotes maladaptive metabolic responses in HFD-fed females.

scholarly journals Brain STAT5 Modulates Long-Term Metabolic and Epigenetic Changes Induced by Pregnancy and Lactation in Female Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2903-2917 ◽  
Author(s):  
Pryscila D S Teixeira ◽  
Angela M Ramos-Lobo ◽  
Isadora C Furigo ◽  
Jose Donato
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Effects ◽  
Epigenetic Changes ◽  
Ambulatory Activity ◽  
Control Female ◽  
Female Mice ◽  
Reproductive Experience ◽  
Pregnancy And Lactation ◽  
The Brain

Abstract Several metabolic and behavioral adaptations that emerge during pregnancy remain present after weaning. Thus, reproductive experience causes long-lasting metabolic programming, particularly in the brain. However, the isolate effects of pregnancy or lactation and the molecular mechanisms involved in these long-term modifications are currently unknown. In the current study, we investigated the role of brain signal transducer and activator of transcription-5 (STAT5), a key transcription factor recruited by hormones highly secreted during gestation or lactation, for the long-term adaptations induced by reproductive experience. In control mice, pregnancy followed by lactation led to increased body adiposity and reduced ambulatory activity later in life. Additionally, pregnancy+lactation induced long-term epigenetic modifications in the brain: we observed upregulation in hypothalamic expression of histone deacetylases and reduced numbers of neurons with histone H3 acetylation in the paraventricular, arcuate, and ventromedial nuclei. Remarkably, brain-specific STAT5 ablation prevented all metabolic and epigenetic changes observed in reproductively experienced control female mice. Nonetheless, brain-specific STAT5 knockout (KO) mice that had the experience of pregnancy but did not lactate showed increased body weight and reduced energy expenditure later in life, whereas pregnancy KO and pregnancy+lactation KO mice exhibited improved insulin sensitivity compared with virgin KO mice. In summary, lactation is necessary for the long-lasting metabolic effects observed in reproductively experienced female mice. In addition, epigenetic mechanisms involving histone acetylation in neuronal populations related to energy balance regulation are possibly associated with these long-term consequences. Finally, our findings highlighted the key role played by brain STAT5 signaling for the chronic metabolic and epigenetic changes induced by pregnancy and lactation.

scholarly journals Long-term metabolic consequences of acute dioxin exposure differ between male and female mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Myriam P. Hoyeck ◽  
Hannah Blair ◽  
Muna Ibrahim ◽  
Shivani Solanki ◽  
Mariam Elsawy ◽  
...  
Keyword(s):  
Male And Female ◽  
Female Mice ◽  
Dioxin Exposure

scholarly journals Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes

2020 ◽  
Vol 12 (528) ◽  
pp. eaau5956 ◽  
Author(s):  
Geetanjali Sharma ◽  
Chelin Hu ◽  
Daniela I. Staquicini ◽  
Jonathan L. Brigman ◽  
Meilian Liu ◽  
...  
Keyword(s):  
Weight Loss ◽  
Mouse Models ◽  
Glucose Homeostasis ◽  
Critical Role ◽  
Metabolic Dysfunction ◽  
Female Mice ◽  
Beneficial Effects ◽  
Reduced Body ◽  
Obesity And Diabetes ◽  
Postmenopausal Obesity

Human obesity has become a global health epidemic, with few safe and effective pharmacological therapies currently available. The systemic loss of ovarian estradiol (E2) in women after menopause greatly increases the risk of obesity and metabolic dysfunction, revealing the critical role of E2 in this setting. The salutary effects of E2 are traditionally attributed to the classical estrogen receptors ERα and ERβ, with the contribution of the G protein–coupled estrogen receptor (GPER) still largely unknown. Here, we used ovariectomy- and diet-induced obesity (DIO) mouse models to evaluate the preclinical activity of GPER-selective small-molecule agonist G-1 (also called Tespria) against obesity and metabolic dysfunction. G-1 treatment of ovariectomized female mice (a model of postmenopausal obesity) reduced body weight and improved glucose homeostasis without changes in food intake, fuel source usage, or locomotor activity. G-1–treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers but did not display feminizing effects on the uterus (imbibition) or beneficial effects on bone health. G-1 treatment of DIO male mice did not elicit weight loss but prevented further weight gain and improved glucose tolerance, indicating that G-1 improved glucose homeostasis independently of its antiobesity effects. However, in ovariectomized DIO female mice, G-1 continued to elicit weight loss, reflecting possible sex differences in the mechanisms of G-1 action. In conclusion, this work demonstrates that GPER-selective agonism is a viable therapeutic approach against obesity, diabetes, and associated metabolic abnormalities in multiple preclinical male and female models.

Sign in / Sign up

Export Citation Format

Share Document