# Defining the role of IGF2 in regulating adipocyte progenitor proliferation and adipogenesis

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $51,320

## Abstract

PROJECT SUMMARY
Adipose dysfunction is a defining characteristic of metabolically unhealthy obesity. During obesity, excess
calories are stored in preexisting adipocytes. This cellular growth, otherwise known as adipocyte hypertrophy,
results in a pathological form of fat expansion that leads to inflammation, fibrosis, and insulin resistance. In
contrast, there is growing evidence indicating that fat expansion driven by an increase in adipocyte number
(hyperplastic growth) promotes metabolically healthy obesity. Our lab and others have recently shown that tilting
the balance in favor of hyperplastic fat expansion protects against maladaptive adipocyte hypertrophy and
obesity-induced metabolic disease. However, the specific cellular and molecular mechanisms that regulate
hyperplastic fat expansion remain unknown. To address this gap in knowledge, our lab has pioneered the
combined use of stable isotope tracing and quantitative mass spectrometry to precisely measure in vivo
adipogenesis, the process that drives hyperplasia through the differentiation of adipocyte progenitors into new
adipocytes, during various stages of development. Using this novel technique, we have characterized a
“hyperplastic-to-hypertrophic” adipose growth switch in humans and mice during which adipogenesis
precipitously declines. Differential expression analysis shows that this growth switch is accompanied by a stark
downregulation in the expression of insulin-like growth factor 2 (Igf2, IGF2) in both subcutaneous adipose tissue
and adipocyte progenitors (APs). Follow-up studies in ex vivo primary APs revealed that IGF2 promoted
adipogenesis and cell cycle gene expression, leading us to hypothesize that IGF2 stimulates AP proliferation,
enhances adipogenesis, and is capable of promoting hyperplastic fat expansion. This proposal will test this
hypothesis through the following Aims: (1) Determine whether IGF2 regulates adipocyte progenitor (AP)
proliferation ex vivo. We will use stable isotope tracing, EdU flow cytometry assays, and MTT cellular
proliferation assays to assess whether recombinant IGF2 treatment enhances proliferation of ex vivo primary
APs in basal conditions and during adipogenic differentiation, while also testing the modifying effect of cell cycle
inhibition. (2) Determine whether IGF2 regulates adipogenesis and fat expansion in vivo. We will use mouse
models of AP-specific IGF2 loss-of-function (AP-IGF2LOF) and gain-of-function (AP-IGF2GOF) to test whether IGF2
regulates hyperplastic fat expansion in vivo during both early postnatal development and in the context of high
fat diet-induced obesity. The results of this proposal will provide a better understanding of whether restoring
IGF2 action in adipocyte progenitors is a viable strategy for reprogramming hyperplastic fat growth and treating
obesity-induced metabolic disease. Completion of this proposal’s aims will also provide excellent training that is
consistent with my goal of a career as a cardiologist...

## Key facts

- **NIH application ID:** 10823601
- **Project number:** 1F30DK138641-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ankit Sharma
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $51,320
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823601

## Citation

> US National Institutes of Health, RePORTER application 10823601, Defining the role of IGF2 in regulating adipocyte progenitor proliferation and adipogenesis (1F30DK138641-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10823601. Licensed CC0.

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