# Epigenetic programming of infant mesenchymal stem cells: mechanisms for obesity and diabetes risk in humans

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $424,893

## Abstract

PROJECT SUMMARY/ABSTRACT
Children born to mothers with obesity are at increased risk for developing obesity and diabetes later in life,
independent of lifestyle factors, such as physical activity or nutrition. While some children born to obese mothers
will not go on to develop obesity or insulin resistance, for those who do, little is known about how maternal
exposures (e.g., hyperinsulinemia) may influence child outcomes in humans. We use human, infant
mesenchymal stem cells (MSCs), cultured from umbilical cord tissue collected at birth, for investigating
mechanisms of obesity and diabetes risk in humans. Human and animal studies, as well as our own MSC data,
show strong association between maternal, MSC and infant metabolism. For example, MSCs from infants born
to obese vs. normal weight mothers have perturbations in lipid metabolism and energy sensing molecules
regulating lipid metabolism, such as AMP-activated protein kinase (AMPK), which we observed at the epigenetic
level (DNA methylation). Ob-MSCs also have impaired AMPK activation in response to metabolic stress in vitro,
which could compromise lipid partitioning and shifts in fuel utilization in response to metabolic stimuli. Moreover,
MSC lipid metabolism correlates with fat mass of the infants measured at birth. These observations make this a
novel model in which to investigate the epigenetic programming of human metabolic phenotypes in vitro. Our
unique, translational approach allows us to maintain human variability in a basic science model. Such integration
of mechanistic investigation with clinical samples will help us to achieve our long-term goal of understanding
mechanisms for the developmental programming of metabolism at the molecular level in humans. This project
will not only advance the field for understanding the molecular underpinnings of human developmental
programming, but may also identify modifiable maternal factors contributing to offspring phenotype supporting
implementation of critically needed obesity prevention strategies. Therefore, the central hypothesis for this
proposal is that perturbations in maternal metabolism induce infant MSC epigenetic signatures promoting
dysregulation of cellular fuel switching and mitochondrial dysfunction. This project leverages our unique resource
of MSCs already collected from >150 infants as part of a well characterized, longitudinal pre-birth cohort (Healthy
Start, R01DK076648). Thus, while Aims 1&2 will determine mechanisms for altered lipid partitioning and
mitochondrial dysfunction in MSCs from infants born to normal weight versus obese mothers, Aim 3 will expand
this knowledge to population science, validating our preliminary data in a larger cohort. Aim 1 will determine the
impact of maternal obesity-induced epigenetic signatures on offspring MSC fuel switching and lipid partitioning
in response to changes in nutrient supply. Aim 2 will determine whether epigenetic signature promotes
mitochondrial dysfunction and reduced su...

## Key facts

- **NIH application ID:** 9961571
- **Project number:** 5R01DK117168-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kristen Elizabeth Boyle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,893
- **Award type:** 5
- **Project period:** 2018-07-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961571

## Citation

> US National Institutes of Health, RePORTER application 9961571, Epigenetic programming of infant mesenchymal stem cells: mechanisms for obesity and diabetes risk in humans (5R01DK117168-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961571. Licensed CC0.

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