# Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $669,659

## Abstract

Abstract
Lipodystrophy is a disorder characterized by adipose tissue loss and redistribution, with
associated metabolic complications including diabetes. The most common form of monogenic
lipodystrophy is familial partial lipodystrophy type 2 (FPLD2), which is caused by a mutation in
the LMNA gene, encoding nuclear lamins A and C. The mechanisms for how adipose tissues
are lost, after developing normally through adolescence are unknown. To address this shortfall,
we selectively deleted Lmna in adipocytes (LmnaADKO) of mice. We observed a striking loss of
white adipose tissue in adult LmnaADKO mice, along with increased fat deposition in the liver,
elevated blood glucose levels in both fasting and fed states, increased circulating insulin levels
compared to the Lmnafl/fl controls. Analyses of young mice revealed development of white
adipose tissue in LmnaADKO mice, which is progressively lost coincident with puberty. These
phenotypes closely mirror those observed in human patients with FPLD2. To further investigate
the function of lamin A/C in adipose tissue and mechanisms by which adipocytes are lost, we
have now developed inducible LmnaiADKO mice as well as six knock-in mouse lines, each
containing a pathological variant that causes lipodystrophy. We hypothesize that lamin A/C is
required to maintain mature adipocyte characteristics, and we will ascertain molecular and
cellular mechanisms that underly loss of mature adipocytes in mouse models and human
patients. To test our hypotheses, we propose 1) to characterize seven lines of mice that contain
lipodystrophic variants across Lmna, and test whether mechanisms of adipocyte loss in these
mice reflect those found in inducible LmnaADKO mice, as well as in human patients with FPLD2.
2) to study effects of LMNA variant on adipocyte and nuclear morphology, gene expression,
cellular composition of adipose tissue depots, and chromatin architecture longitudinally in young
patients who do not have all signs of disease, and in healthy controls and parents with FPLD2.

## Key facts

- **NIH application ID:** 10981538
- **Project number:** 2R01DK125513-04A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ormond A MacDougald
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $669,659
- **Award type:** 2
- **Project period:** 2020-07-07 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981538

## Citation

> US National Institutes of Health, RePORTER application 10981538, Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans (2R01DK125513-04A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10981538. Licensed CC0.

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