# Cell cycle control of adipogenesis

> **NIH NIH R56** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $211,177

## Abstract

Recent evidence shows that creating new fat cells (adipogenesis) can counteract the
harmful metabolic effects of obesity, which have been shown to originate primarily from abnormal
enlargement (hypertrophy) and resulting dysfunction of existing fat cells. Thus, how to increase
adipogenesis over hypertrophy is of great interest. Previous work showed that preadipocytes in
vivo and in vitro must complete one or more cell cycles, a process referred to as clonal expansion,
before they can differentiate into adipocytes. One of the most striking genetic examples of
increased adipogenesis was demonstrated by manipulating this clonal expansion period by
knocking out the cell cycle inhibitors p21 and p27. Knockout of either p21 or p27 in mice results
in a 2-fold increase in adipogenesis and fat mass, but knockout of both results in a dramatic 6-fold
increase. Previous work suggests that p21 and p27 are regulated by very different mechanisms and
are active at different times during adipogenesis. In recent published work, we identified the
molecular mechanisms that could explain the increased adipogenesis observed in the p21-
knockout mouse. However, how p27 regulates adipogenesis and tissue mass and how p21 and p27
synergize are poorly understood. We hypothesize that the synergistic expression of p21 and p27
during adipogenesis is the primary mechanism that controls the number of cell divisions before
differentiation, and thus controls the number the adipocytes produced per preadipocyte. We will
test this hypothesis by using live-cell imaging approaches. We will first use methods to inducibly
express and rapidly degrade p27 to determine when and how p27 regulates cell cycle progression
during adipogenesis. We will then use live cell reporters for CDK4/6 and CDK2 activity to
understand when and how p27 and p21 synergize to regulate CDK4/6 and CDK2 activity and
control the number of adipocytes produced. Finally, we will use live-cell reporters and p27
knockout cell and mouse models to understand how p27 is regulated by upstream cell density and
extracellular matrix stiffness signals to open and close a proliferative window during adipogenesis.
The outcome of this work will be a framework how the clonal expansion period can be controlled
to significantly increase adipogenesis over hypertrophy while also ensuring that the progenitor
pool is maintained. Our results will likely have broad applicability not only to the maintenance of
adipose tissue, but also more generally for the maintenance and regeneration of neuronal, muscle,
and other terminally differentiated tissues.

## Key facts

- **NIH application ID:** 10476647
- **Project number:** 1R56DK131432-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Mary N Teruel
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $211,177
- **Award type:** 1
- **Project period:** 2021-09-16 → 2022-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476647

## Citation

> US National Institutes of Health, RePORTER application 10476647, Cell cycle control of adipogenesis (1R56DK131432-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10476647. Licensed CC0.

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