New research reveals that when fat tissue fails, the consequences ripple across the body.
Many people think negatively about body fat, but scientists now understand that adipose tissue is essential to health. It functions as an active organ that plays a central role in metabolism and supports many critical processes in the body.
Excess fat, as seen in obesity, is known to raise the risk of conditions such as diabetes and heart disease. Less obvious is that losing fat in the wrong way can be just as harmful. In rare disorders like familial partial lipodystrophy type 2 (FPLD2), the body loses and redistributes fat abnormally, which can also lead to diabetes and other metabolic problems.
A Paradox in Fat Biology
This paradox had long vexed Elif Oral, M.D., a clinician and Professor in the Division of Metabolism, Endocrinology, and Diabetes. Her work focuses on understanding why fat tissue breaks down in diseases such as lipodystrophy, with the goal of improving treatment options.
Working closely with patients who have FPLD2, Oral collaborated with Ormond MacDougald, Ph.D., Professor of Molecular & Integrative Physiology, graduate researcher Jessica Maung, Ph.D., and a broader research team to investigate the condition. Their efforts have begun to clarify what goes wrong inside fat tissue.
“A simple explanation is that all of the fat cells (adipocytes) have really catastrophic things happening in them,” said Maung. To study this, the researchers developed a mouse model in which the lamin A/C gene was selectively turned off in fat cells. This gene is known to be altered in people with FPLD2.
Their analysis of both the mouse model and patient tissue revealed major disruptions in gene activity. These changes prevent fat cells from properly storing and processing lipids. At the same time, both fat cells and nearby immune cells shift into a pro-inflammatory state. The mitochondria inside the fat cells also lose normal function.
Said Maung, “All of these effects come together to create this perfect environment for the tissue to be really unhealthy and eventually disappear.”
Consequences for Metabolic Health
When adipose tissue is no longer healthy, the body struggles to regulate fats and release key metabolic hormones. This breakdown can drive diseases such as diabetes and fatty liver disease.
“This is really underscoring the importance of healthy fats in keeping metabolism intact and functional,” said Oral. People think of Type 2 diabetes as a disease of beta cells, but it’s actually a disease of fat cells, too.”
The researchers believe these findings could guide the development of new treatments. By protecting fat tissue or restoring its function, future therapies may be able to prevent its loss and reduce metabolic complications.
“I think this work is an outstanding example of a collaboration between a translational clinical researcher and a basic science physiologist,” said MacDougald. “We also can’t overstate the importance of the patient population and their involvement in developing therapies and their dedication to understanding their disease.”
Reference: “Altered lipid metabolism and inflammatory programs associate with adipocyte loss in familial partial lipodystrophy 2” by Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral and Ormond A. MacDougald, 2 January 2026, The Journal of Clinical Investigation.
DOI: 10.1172/JCI198387
The study was funded by the National Institutes of Health.
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