Related Experiment Video
Updated: Jun 26, 2026
Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT)
Published on: January 7, 2018
Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice
Elodie Riant1, Aurélie Waget, Haude Cogo
1Institut 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.
Abstract:
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.
Insights
Estrogen receptor alpha (ERalpha) activation protects against high-fat diet-induced glucose intolerance and insulin resistance. Targeting this pathway may offer a therapeutic strategy for type 2 diabetes.
Area of Science:
- Endocrinology
- Metabolic Syndrome
- Molecular Biology
Background:
- Estrogens are known to influence glucose metabolism via estrogen receptor alpha (ERalpha).
- The therapeutic potential of targeting ERalpha for high-fat diet (HFD)-induced metabolic disturbances remains unclear.
Purpose of the Study:
- To investigate the role of ERalpha in mediating the protective effects of 17beta-estradiol (E2) against HFD-induced metabolic dysfunction.
- To determine if the ERalpha pathway can be a therapeutic target for HFD-induced insulin resistance and glucose intolerance.
Main Methods:
- Administration of 17beta-estradiol (E2) to wild-type and ERalpha-deficient ovariectomized mice fed either a normal chow diet or a HFD.
- Hyperinsulinemic euglycemic clamp studies to assess insulin resistance.
- Analysis of insulin signaling pathways (Akt phosphorylation) in skeletal muscle.
- Measurement of inflammatory cytokine and PAI-1 mRNA expression in liver and adipose tissue.
- Chimeric mouse models and comparison of sham-operated with ovariectomized mice.
Main Results:
- E2 administration protected against HFD-induced glucose intolerance and insulin resistance in wild-type mice, an effect abolished in ERalpha-deficient mice.
- E2 treatment improved insulin signaling in skeletal muscle and reduced insulin resistance by 50% during clamp studies.
- E2 treatment unexpectedly enhanced HFD-induced pro-inflammatory cytokine and PAI-1 mRNA expression in the liver and visceral adipose tissue.
- The pro-inflammatory effects of E2 in visceral adipose tissue were dissociated from its beneficial metabolic effects on glucose tolerance.
- Endogenous estrogen levels in HFD-fed mice were sufficient to protect against insulin resistance and glucose intolerance.
Conclusions:
- The estrogen receptor alpha (ERalpha) pathway is crucial for mediating the protective effects of estrogens against high-fat diet-induced metabolic disturbances.
- Targeting the ERalpha pathway presents a promising therapeutic strategy for managing and preventing type 2 diabetes associated with high-fat diets.
- Metabolic and inflammatory effects of estrogens can be dissociated, suggesting specific therapeutic interventions are possible.
