Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats

Weigt, Carmen; Hertrampf, Torsten; Flenker, Ulrich; Hülsemann, Frank; Kurnaz, Pınar; Fritzemeier, Karl Heinrich; Diel, Patrick

doi:10.1016/j.jsbmb.2015.06.002

Cited by 33 publications

(25 citation statements)

References 78 publications

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“…We were able to make a precise measurement of non-fasting BGL as we have kept the measuring time consistent (around noon on the day of measurement) as well as fasting BGL as we followed the 15-h fasting protocol (18). In addition to a decreased BGL, we observed an increased glucose tolerance among NOD males following GEN exposure, which is in agreement with our previous studies in STZ - treated male B6C3F1 mice (11) and has been confirmed by others (37). …”

Section: Discussionsupporting

confidence: 93%

“…In our current study with NOD females, GEN exposure at 20 mg/kg produced a later onset of T1D but had no significant effects on glucose tolerance (37). This amount of GEN in a mouse is equivalent to a human clinical trial dose (approximately 100 mg/day) in terms of milligram/square meter of body surface that usually gives more accurate interspecies extrapolation (60).…”

Section: Discussionmentioning

confidence: 43%

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Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Huang¹,

Xu²,

Lefever³

et al. 2017

Toxicology and Applied Pharmacology

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Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20 mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG2b and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered β-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 43%

Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Huang¹,

Xu²,

Lefever³

et al. 2017

Toxicology and Applied Pharmacology

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“…Our findings corroborate the results of previous studies showing that the activation of ERα but not that of ERβ results in increased uterine weight 24, 25 . Uncontrolled uterine epithelial cell proliferation may lead to a pathological condition such as endometrial hyperplasia, which is a premalignant lesion of endometrial cancer 28 .…”

Section: Discussionsupporting

confidence: 92%

“…However, recent data suggest a possible tumour-suppressive role of ERβ 19–23 . Moreover, some studies indicate that activation of ERβ alone does not result in increased uterine weight 24, 25 . Therefore, selective activation of ERβ may be a safer approach to HRT than the common use of oestrogen, with respect to the risk of developing endometrial hyperplasia and cancer 26 .…”

Section: Introductionmentioning

confidence: 99%

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Sasayama

Sugiyama

Yonekubo

et al. 2017

Sci Rep

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Hormonal changes due to menopause can cause various health problems including weight gain and depressive symptoms. Multiple lines of evidence indicate that oestrogen receptors (ERs) play a major role in postmenopausal obesity and depression. However, little is known regarding the ER subtype-specific effects on obesity and depressive symptoms. To delineate potential effects of ERβ activation in postmenopausal women, we investigated the effects of a novel oestrogen receptor β-selective ligand (C-1) in ovariectomized mice. Uterine weight, depressive behaviour, and weight gain were examined in sham-operated control mice and ovariectomized mice administered placebo, C-1, or 17β-oestradiol (E2). Administration of C-1 or E2 reduced body weight gain and depressive-like behaviour in ovariectomized mice, as assessed by the forced swim test. In addition, administration of E2 to ovariectomized mice increased uterine weight, but administration of C-1 did not result in a significant increase in uterine weight. These results suggest that the selective activation of ERβ in ovariectomized mice may have protective effects against obesity and depressive-like behaviour without causing an increase in uterine weight. The present findings raise the possibility of the application of ERβ-ligands such as C-1 as a novel treatment for obesity and depression in postmenopausal women.

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“…Steroid hormones, steroids, and bile acids originate from cholesterol, the major discriminative constituent of PHFD and LHFD (Table 2). The annotated mass corresponding to 17β-estradiol, a cholesterol derivative reported to be associated with DIO resistance [29], [30], was detected at higher intensities in lean but not in obese GF mice, and no differences were observed in SPF mice (Figure 4C).…”

Section: Resultsmentioning

confidence: 99%

Dietary fat and gut microbiota interactions determine diet-induced obesity in mice

Kübeck

Bonet-Ripoll

Hoffmann

et al. 2016

Molecular Metabolism

182

128

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ObjectiveGut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice.MethodsGF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing.ResultsGF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17β-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes) as a characteristic feature of normal SPF mice fed lard.ConclusionsIn conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

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Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats

Cited by 33 publications

References 78 publications

Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Genistein prevention of hyperglycemia and improvement of glucose tolerance in adult non-obese diabetic mice are associated with alterations of gut microbiome and immune homeostasis

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Dietary fat and gut microbiota interactions determine diet-induced obesity in mice

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