# Brain VDR Regulate Glucose Balance

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2022 · $482,755

## Abstract

Our lack of understanding regarding how vitamin D regulates glucose prevents its use as an effective diabetes
therapy. We have shown that vitamin D can act in the brain to lower glucose levels and that loss of vitamin D
receptors (VDR) within the paraventricular hypothalamus (PVH) of the brain are critical for normal glucose
levels in obese, but not lean, animals. However, the neurocircuitry/function of VDRPVH neurons, the role of the
PVH VDR responding to dietary vitamin D, and mechanisms underlying effects in obese but not lean states are
unknown. This raises basic questions regarding how vitamin D receptors mediate glucose balance. We have
generated a genetic mouse model with Cre recombinase expression in VDR positive cells (VDRCre). This
provides an excellent model to determine the function, necessity, and downstream neuronal targets of VDRPVH
neurons. Additionally, utilizing other genetic tools, we can determine if VDR within the PVH are necessary for
changes in blood glucose by dietary vitamin D. Last, we can utilize these tools to determine the mechanisms
underlying weight-specific effects of vitamin D in the brain on glucose regulation. The objective of this grant is
to determine the mechanisms of vitamin D in the brain on glucose balance. We hypothesize that VDR regulate
glucose levels through distinct neuronal circuits and through genomic effects in PVH neurons. The central
hypothesis will be tested by three specific aims: 1) identifying neuronal mechanisms for PVH VDR positive
neurons; 2) determining if PVH VDR are required or sufficient for dietary-vitamin D changes in glucose
homeostasis; and 3) establishing mechanisms for the glucose-protective effect of vitamin D in an obese model.
In Aim 1, we will use chemogenetics, single-cell genomics, and immunohistochemistry to determine the
function, identity, and circuitry of VDRPVH neurons. In Aim 2, we will use different dietary manipulations of
vitamin D to test if PVH VDR are necessary for high-vitamin D induced glucose improvements. Additionally,
we will determine if central administration of active vitamin D can overcome deleterious effects of low dietary
vitamin D on glucose balance. In Aim 3, we will determine how obesity alters the transcriptomic and neuronal
activation response to active vitamin D (1,25D3). Additionally, we will determine if there are differences in VDR
expression or VDR+ neuronal number in obese vs. lean states. The research proposed is innovative, because
it investigates the function of a novel neuronal population (VDRPVH) on glucose tolerance, using a novel mouse
model. The proposed research is significant because it is expected to identify new paradigms to understand
vitamin D action, as well as possibly identifying a novel circuit in the PVH with critical glucose-regulating
properties. Results from this research may ultimately explain some of the variance in clinical trials utilizing
vitamin D as a therapy and provide critical information to advance the use o...

## Key facts

- **NIH application ID:** 10444524
- **Project number:** 1R01DK128117-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Stephanie Renee Sisley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $482,755
- **Award type:** 1
- **Project period:** 2022-04-05 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444524

## Citation

> US National Institutes of Health, RePORTER application 10444524, Brain VDR Regulate Glucose Balance (1R01DK128117-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10444524. Licensed CC0.

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