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Mechanisms of adipocyte loss in mouse models of familial partial lipodystrophy 2

Award Number: F31DK135181
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 09/30/2025
AWARD TERMINATION DATE: 02/26/2026

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Mechanisms of adipocyte loss in mouse models of familial partial lipodystrophy 2 - PROJECT SUMMARY/ABSTRACT Lipodystrophies are rare diseases, characterized by a striking loss, redistribution, and dysfunction of adipose tissue, and accompanied by metabolic dysfunction. Familial partial lipodystrophy 2 (FPLD2) is the most common type of lipodystrophy, caused by mutations in LMNA, which encodes the nuclear lamina proteins lamin A/C. Lamin A/C is crucial for nuclear function and controls gene expression, but its role in adipocyte maintenance and function is incompletely understood. Our lab created a constitutive adipocyte specific Lmna knockout mouse model (LmnaADKO) to better characterize the roles of Lmna in adipocytes. LmnaADKO mice develop adipose tissues that are subsequently lost starting at 4 weeks of age; LmnaADKO mice have hepatic steatosis and reduced circulating leptin concentrations, closely recapitulating FPLD2. Analyses of LmnaADKO mice suggest that lamin A/C is required for adipocyte maintenance, substantially advancing our mechanistic understanding, since previous studies did not reveal how loss of Lmna function leads to lipodystrophy. To study mechanisms of how knockout of Lmna in adipocytes leads to subsequent loss of adipocytes, we generated mice in which Lmna can be inducibly knocked out with administration of tamoxifen (LmnaiADKO). This approach allows us to use adult mice, which have more adipose tissue, and to temporally synchronize adipocyte loss. In preliminary experiments, we have tested multiple mechanisms in vivo that could contribute to loss of adipocytes in LmnaiADKO mice. Altered adipogenesis seems unlikely, considering that functional white adipose tissue (WAT) develops in LmnaADKO mice and patients with FPLD2. We also did not observe signs of increased lipolytic capacity or increased acute cell death in WAT lacking Lmna in adipocytes. However, we did observe that adipocytes lacking Lmna are visibly smaller and misshapen compared to controls, suggesting adipocytes are losing their lipid stores, and are unable to maintain viability. Bulk RNA-seq and proteomics from LmnaiADKO WAT revealed downregulation of lipogenic pathways, and upregulation of inflammatory genes. We hypothesize that lamin A/C is required to maintain mature adipocyte characteristics, and that absence of functional lamin A/C leads to adipocyte loss through reduced lipogenic gene expression, driven by altered interactions between Lmna and chromatin. My project will test this hypothesis by (1) evaluating changes in lipogenic and mitochondrial genes in Lmna knockout adipocytes and performing DamID and FISH to study changes in chromatin-lamina interactions that may underlie changes in gene expression and (2) assessing decreased de novo lipogenesis in LmnaiADKO mice, in addition to restoring lipogenic gene expression to Lmna KO adipocytes to prevent WAT loss. Ultimately, these studies will reveal underlying molecular mechanisms of FPLD2, uncovering novel therapeutic targets for lipodystrophy patients while bolstering our understanding of fundamental adipocyte biology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$7,197 )
2026	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/26/2026	TERMINATION	-$7,197
2026	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/27/2026	TERMINATION	$0
														Subtotal = -$7,197

Issue Date FY: 2025 ( Subtotal = $21,799 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/17/2025	NON-COMPETING CONTINUATION	$21,799
														Subtotal = $21,799

Issue Date FY: 2024 ( Subtotal = $42,099 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/6/2024	NON-COMPETING CONTINUATION	$42,099
														Subtotal = $42,099

Issue Date FY: 2023 ( Subtotal = $40,819 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	6/16/2023	NEW	$0
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	6/7/2023	NEW	$0
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/7/2023	NEW	$40,819
														Subtotal = $40,819

Grand Total All Awards = $97,520

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Mechanisms of adipocyte loss in mouse models of familial partial lipodystrophy 2

Award Number: F31DK135181

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 09/30/2025

AWARD TERMINATION DATE: 02/26/2026

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