Vitamin D deficiency has been linked to diabetes but a causal relationship is not clear. We previously published hypothalamic vitamin D action is critical for glucose tolerance and insulin sensitivity in obese animals. We hypothesized vitamin D also enhanced insulin sensitivity within the brain. Indeed, 48 hours of 1,25D3 (aka calcitriol) increased phosphorylation of Akt in hypothalamic cells (GT1-7). This effect was not observed in the absence of insulin, indicating that vitamin D was enhancing insulin action rather than mediating phosphorylation independently. Phosphorylation of Akt is often mediated by phosphoinositide 3-kinase (PI3K). Wortmannin, a PI3K inhibitor, blocked the effects of vitamin D to enhance pAkt. This supports a PI3K-dependent mechanism of vitamin D action. Vitamin D increased mRNA concentrations of key components of the PI3K/Akt pathway, namely IRS2 and p85. p55 expression, a negative regulator of PI3K, was decreased. Vitamin D did not affect transcription of the insulin receptor, IRS1, Akt, or the vitamin D receptor. Together, these support vitamin D as a regulator of the PI3K pathway in hypothalamic neurons. Additionally, the PI3K pathway has previously been shown to be important in rapid effects of other nuclear hormones. Since we previously published vitamin D depolarizes hypothalamic neurons, we investigated whether the PI3K pathway was also necessary in rapid vitamin D actions. Indeed, vitamin D was unable to depolarize hypothalamic neurons in the presence of the PI3K inhibitor wortmannin. Together, these data support that the action of vitamin D in the brain to influence glucose homeostasis may be through altered insulin signaling in the brain and requires the PI3K pathway for effects. These results are important in light of the known association between vitamin D and insulin resistance. They suggest that although vitamin D enhances insulin sensitivity, its actions are dependent upon a functional PI3K pathway, which is likely altered in an obese, insulin-resistant individual.
S. Teixeira: None. Y. He: None. Y. Xu: None. S. Sisley: Consultant; Self; Alexion Pharmaceuticals, Inc..