Paraventricular vitamin D receptors are required for glucose tolerance in males but not females

Authors: BECK, JESSIE - Baylor College Of Medicine; DA SILVA TEIXEIRA, SILVANIA - Baylor College Of Medicine; HARRISON, KEISHA - Baylor College Of Medicine; PHYLLIPS, GABRIELLE - Baylor College Of Medicine; HE, YANLIN - Baylor College Of Medicine; SISLEY, STEPHANIE - Children'S Nutrition Research Center (CNRC)

Submitted to: Frontiers in Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/29/2022
Publication Date: 5/10/2022
Citation: Beck, J., Da Silva Teixeira, S., Harrison, K., Phillips, G., He, Y., Sisley, S. 2022. Paraventricular vitamin D receptors are required for glucose tolerance in males but not females. Frontiers in Endocrinology. 13. Article 869678. https://doi.org/10.3389/fendo.2022.869678.
DOI: https://doi.org/10.3389/fendo.2022.869678

Interpretive Summary: Vitamin D deficiency is linked to the development of type 2 diabetes but the exact mechanisms are unknown. Many clinical trials have failed to show improvement in glucose control after giving vitamin D, so it is important to understand the underlying mechanisms in order to design more effective therapies. We previously showed that vitamin D given directly into the brain can improve glucose levels in male rodents. In this study, we found that loss of the vitamin D receptor in a specialized part of the brain called the paraventricular hypothalamus (PVH) caused worsened glucose tolerance in male mice but not in female mice. We also found that the vitamin D receptor was needed for neurons to function properly in males but not females. However, vitamin D was able to activate the neurons the same in males and females. Thus, we find that there is a sex-specific effect for vitamin D receptors in the brain and that males require the vitamin D receptor to have normal glucose levels but females do not. This work highlights the need to understand vitamin D action in the brain and supports that it is very important in the role of vitamin D to control blood glucose levels.

Technical Abstract: When delivered directly into the brain, vitamin D, can improve glucose levels in male mice. Additionally, the loss of the vitamin D receptor (VDR) in male mice's paraventricular hypothalamus (PVH) results in impaired glucose tolerance. Data in humans shows that low vitamin D levels are detrimental to glucose homeostasis, an effect that may be more prominent in men. However, it is unknown if vitamin D action in the brain is required for normal glucose regulation in female mice. This study shows that in both viral and genetic models, male mice with obesity and PVH VDR loss have impaired glucose tolerance while female mice are unaffected. Weights were unaltered in both sexes by PVH VDR loss. Additionally, PVH VDR loss did not cause any glucose abnormalities in either sex when the mice were on a chow diet. Utilizing electrophysiology studies, we show PVH VDR loss resulted in decreased baseline firing frequency and resting membrane potential in males, but not females. Additionally, male mice with PVH VDR loss had impaired miniature excitatory postsynaptic currents (mEPSC), while females were unaffected. Interestingly, the PVH neurons of both sexes were activated by exogenous vitamin D (1,25-dihydroxyvitamin D3), an effect dependent upon the VDR. Thus, there is sexual dimorphism, for the actions of the PVH VDR on glucose regulation. PVH VDRs are necessary for normal glucose homeostasis in males but not females and this may be secondary to actions of the VDR on neuronal activity.