Ovarian insufficiency impairs glucose homeostasis through activation of hypothalamic ceramide synthesis
Ovarian failure impairs insulin secretion by activating de novo synthesis of ceramides in the hypothalamus Estrogens are known to regulate body weight through their action on the hypothalamus to modulate food intake and energy expenditure. Hervé Le Stunff’s team from the NeuroPSI Institute, had previously shown that the synthesis of lipids, called ceramides, in the hypothalamus plays a central role in obesity induced by estrogen deficiency (Campana et al., 2018).
In a new study published in Metabolism, the team investigated the role of hypothalamic ceramides in the deregulation of glucose homeostasis and insulin secretion in ovariectomized female rats. Ovariectomy induces body weight gain associated with hypothalamic inflammation and impaired glucose homeostasis. Genetic inhibition of ceramide synthesis in the ventromedial nucleus of the hypothalamus (VMH) reverses hypothalamic inflammation and partially restores glucose tolerance induced by oophorectomy. Glucose-stimulated insulin secretion is increased in ovariectomized animals due to an increase in the second phase of insulin secretion, a hallmark of the early stage of type 2 diabetes (T2DM).
Inhibition of the synthesis of ceramides in VMH suppresses the increase in the second phase of insulin secretion. Finally, the researchers have shown that the genetic inactivation of the estrogen receptor ERalpha in VMH positively regulates the synthesis of ceramides. All of these results indicate that ovarian failure, observed at the time of menopause, leads to an increased synthesis of hypothalamic ceramides which will trigger an alteration in energy and carbohydrate homeostasis and therefore promote the appearance of T2DM.
Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis. Kelly Meneyrol, Ánxela Estévez-Salguero, Ismael González-García, Jeanne Guitton, Mohammed Taouis, Yacir Benomar, Christophe Magnan, Miguel López, Hervé Le Stunff.