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Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity.

ABSTRACT: The steroid receptor antagonist mifepristone is used as an anti-cancer agent, eliciting both cytostatic and cytotoxic effects on malignant cells. However, the metabolic effects of long-term treatment with mifepristone have remained unclear. The effects of mifepristone on insulin sensitivity and adiponectin secretion were evaluated both in in vivo and in vitro. First, we explored the effects of mifepristone, on metabolic functions in obese mice receiving a high-fat diet. When these mice were fed mifepristone, they exhibited a marked improvement in insulin sensitivity, attenuated hepatic injury, and decreased adipocyte size, compared with mice that received only the high-fat diet. Intriguingly, mifepristone-treated mice showed significantly elevated plasma adiponectin levels. Second, we tested the effects of mifepristone on differentiated 3T3-L1 adipocytes in vitro. When differentiated adipocytes were treated with mifepristone for 48 h, adiponectin was upregulated at both mRNA and protein levels. Collectively, these results reveal novel actions of mifepristone on metabolic functions, in vivo and in vitro, in which the drug exerts antidiabetic effects associated with an upregulation in adiponectin-secretion.

SUBMITTER: Hashimoto T

PROVIDER: S-EPMC3819252 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity.

Hashimoto Takeshi T Igarashi Junsuke J Hasan Arif U AU Ohmori Koji K Kohno Masakazu M Nagai Yukiko Y Yamashita Tetsuo T Kosaka Hiroaki H

PloS one 20131106 11

The steroid receptor antagonist mifepristone is used as an anti-cancer agent, eliciting both cytostatic and cytotoxic effects on malignant cells. However, the metabolic effects of long-term treatment with mifepristone have remained unclear. The effects of mifepristone on insulin sensitivity and adiponectin secretion were evaluated both in in vivo and in vitro. First, we explored the effects of mifepristone, on metabolic functions in obese mice receiving a high-fat diet. When these mice were fed ...[more]

PMID: 24223187

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Project description:AIMS/HYPOTHESIS:Treatment with the ?3?4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown. METHODS:DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed. RESULTS:In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPP-treated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment. CONCLUSIONS/INTERPRETATION:Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of ?4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle.

Project description:BackgroundLiraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE(-/-) mice with adiponectin (Acrp30) knockdown.MethodHFD-fed ApoE(-/-) mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes.ResultsThe combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1) and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals.ConclusionThese findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be partly mediated via increased FGF-21 and its receptors action.

Dataset Information

Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity.

Publications

Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity.

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