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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $312,000

## 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 FPLD2 patients. Importantly, we also have
access to a highly motivated LMNA R482Q patient population, who are not yet exhibiting signs
of lipodystrophy. Analyses of their WAT will provide an unprecedented opportunity to advance
our understanding of this disease and its progression. We propose experiments in tissue from
these patients to pinpoint the earliest defects in WAT cellularity, including specific alterations in
adipocyte gene expression. To test our hypotheses, we propose the following specific aims:
SA1) determine in LMNAADKO mice whether loss of adipose tissues with lamin A/C deficiency is
due to impaired adipogenesis or is the result of increased adipocyte turnover, SA2) ascertain in
LMNAADKO mice whether loss of adipocytes occurs through intrinsic or extrinsic cellular
mechanisms, and SA3) evaluate in young FPLD2 patients, who are not yet showing overt signs
of lipodystrophy, the effects of LMNA mutation on morphology, gene expression, signaling
pathways and cellular composition of adipose tissue depots.

## Key facts

- **NIH application ID:** 10029064
- **Project number:** 1R01DK125513-01
- **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:** 2020
- **Award amount:** $312,000
- **Award type:** 1
- **Project period:** 2020-07-07 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029064

## Citation

> US National Institutes of Health, RePORTER application 10029064, Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans (1R01DK125513-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10029064. Licensed CC0.

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