Vitamin D and Development Origins of Obesity and Insulin Resistance

early 80% of the Veterans are either overweight or obese, increasing their risk of hypertension, diabetes, and
cardiovascular disease. Accumulation of excess adiposity in this population begins at an early age, as nearly
20% of young active-duty veterans are obese, suggesting that this metabolic derangement starts early in life.
We aim to identify genetic programs induced by environmental conditions that increase veterans' susceptibility
to the development of obesity. We have collected convincing evidence suggesting that that a high incidence of
vitamin D (VD) insufficiency in young veterans and their offspring at birth could have significant long-term
consequences on their obesity risk. In mice, offspring from VD deficient dams become more obese with
increased insulin resistance (IR) and systemic inflammation by 6 weeks despite postnatal VD supplementation.
Furthermore, transplantation of fetal hematopoietic stem cells (HSCs) from VD-deficient embryos induces
higher weight and IR in VD-sufficient recipient mice during their life suggesting the involvement of persistent
epigenetic immune cell programming. We found that in utero VD deficiency suppresses HSC Jarid2 expression
activating the Mef2/PGC1D pathway, which persists in recipient bone marrow, resulting in adipose macrophage
miR106b-5p secretion, which promotes adipose IR. It is unclear, however, if VD supplementation in utero can
prevent the onset of this epigenetic program and if this program drives adipocyte proliferation and differentiation.
Importantly, our significant findings from the VDAART randomized controlled trial study in 529 pregnant women
supplemented from the first trimester with 4000IU/d suggest that children from VD supplemented mothers have
a 10% lower BMI starting at age 4. Moreover, maternal VD supplementation decreased the projected risk of
obesity at young adult life by 15-fold, suggesting that VD supplementation early in life reduces future risk of
metabolic disease. We hypothesize that VD supplementation early in pregnancy prevents epigenetic
suppression of Jarid2 and Mef2/PGC1D activation, thereby reducing miR106b-5p secretion from myeloid cells
and preventing adipose tissue differentiation. To test this hypothesis, we propose in Aim1a to determine if early
VD supplementation in VD deficient pregnant dams prevents induction of the HSC Jarid2/PGC1D/miR106b-5p
program and the transplantation of obesity and IR by HSCs into VD sufficient recipient mice. In Aim 1b and 1c,
we will determine if Jarid2-null HSCs can transplant obesity and IR to VD-sufficient recipients and if miR106b-
null VD-deficient HSCs lack the capacity to transplant obesity and IR, respectively. In Aim 2, we will 1)
characterize the mechanisms involved in the lowering of child BMI induced by VD supplementation during early
pregnancy by obtaining in our VDAART cohort measures of the obese phenotype (fat distribution, energy
expenditure, food intake) and 2) obtain blood samples to determine if circulating miR106b-5p levels correlates
with child BMI and fat percentage and if prenatal VD supplementation prevents monocyte
Jarid2/PGC1D/miR106b-5p activation and reduces adipocyte differentiation in vitro. The results of this proposal
will provide veterans' health providers with evidence for an early screening protocol with specific biomarkers
and related pathways that identify veterans at risk of obesity and diabetes.
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Grant Number: 5I01BX003648-08
NIH Institute/Center: VA
Principal Investigator: Carlos Bernal-Mizrachi