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

Abstract

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), 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 ERα-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-α) 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 ERα-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 ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

Adult Consequences of Post-weaning High Fat Feeding on the Limbic–HPA Axis of Female Rats

“…Estrogen is known to potentiate corticosterone levels (Kitay et al 1965) and protect against high fat diet-induced insulin resistance and glucose intolerance (Riant et al 2009). Plasma estrogen levels were not evaluated in our study, but it is known to increase proportionally with the fat content of diet in adult female rats (Leibowitz et al 2007).…”

“…Ovarian steroids, increasing after puberty, enhance adipogenesis (Mattsson and Olsson 2007), control glucose homeostasis (Ahmed-Sorour and Bailey 1981), and confer protection against high fat diet-induced insulin resistance (Riant et al 2009). Additionally, female sex hormones interfere with corticosterone actions in the brain at one or more levels of the HPA axis, by directly controlling corticotrophin releasing hormone (Patchev and Almeida 1996), adrenocorticotrophin (Wang et al 1998) and corticosterone secretion (Kitay et al 1965).…”

Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats

“…A high-sucrose diet has been shown to induce insulin resistance and other components of the metabolic syndrome in male rats and ovariectomised females, whereas females are unaffected (Horton et al 1997). Similarly, oestrogens have been shown to protect against high-fat diet-induced insulin resistance and glucose intolerance (Riant et al 2009), again suggesting that female hormones can protect against developing components of the metabolic syndrome. The obese Zucker diabetic fatty (ZDF/Gmi-fa) male rat has become a widely used animal model of type 2 diabetes (T2D), in contrast to the obese ZDF female that rarely develop the disease (Clark et al 1983).…”

Effects of treadmill exercise training on liver fat accumulation and estrogen receptor alpha expression in intact and ovariectomized rats with or without estrogen replacement treatment

“…Liver is one of the well-established target tissues for estrogens. Corroborating data indicate that estrogens influence glucose metabolism through the activation of the ERalpha (Riant et al 2009) and endurance training is associated with modification of ER transcripts levels in the liver and some of adaptations to endurance training in liver may be mediated by an ER-dependent mechanism (Paquette et al 2007a). Since receptor levels influence target tissue responsiveness to the hormonal milieu, there has been a great interest in the understanding of how the liver ERalpha, especially in the protein level, is regulated by estrogen and exercise.…”