Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice.
Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor alpha (ERalpha), 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 17beta-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 ERalpha-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-alpha) 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 ERalpha-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 ERalpha pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.
Riant
Elodie
E
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.
Waget
Aurélie
A
Cogo
Haude
H
Arnal
Jean-François
JF
Burcelin
Rémy
R
Gourdy
Pierre
P
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D004041:Dietary Fats; D047628:Estrogen Receptor alpha; D018836:Inflammation Mediators; D007328:Insulin; D004958:Estradiol