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Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Team 9 (E.R., H.C., J.-F.A., P.G.), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 858 et Université de Toulouse, Institut de Médecine Moléculaire de Rangueil, Institut Fédératif de Recherche (IFR) 31, and Team 2 (E.R., A.W., R.B.), INSERM Unité 858, Institut de Médecine Moléculaire de Rangueil, IFR31, 31432 Toulouse, France; and Service de Diabétologie (P.G.), Pôle Cardio-Vasculaire et Métabolique, Centre Hospitalier Universitaire de Toulouse, 31059 Toulouse, France

Address all correspondence and requests for reprints to: Professor Pierre Gourdy, Institut National de la Santé et de la Recherche Médicale Unité 858, Institut de Médecine Moléculaire de Rangueil, Boite Postale 84225, 31432 Toulouse Cedex 4, France. E-mail: gourdyp{at}toulouse.inserm.fr.

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor (ER), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ER-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ER-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ER pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

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