Researchers uncover why a rare disease resulting in abnormal fat loss can also lead to diabetes

Many people may have a dim view of their fat tissue, yet scientists have come to recognize adipose as a necessary and metabolically active organ, carrying out many vital functions within the body.

In the case of obesity, too much fat can contribute to conditions such as diabetes and heart disease.

Intriguingly, for people with certain rare genetic and autoimmune disorders, such as familial partial lipodystrophy type 2, the abnormal loss and distribution of adipose tissue can also lead to diabetes and metabolic disease.

This paradox had long vexed Elif Oral, M.D., a clinician and Professor in the Division of Metabolism, Endocrinology and Diabetes.

She’s dedicated her research career to uncovering the underlying mechanism of pathological fat loss, to help patients with lipodystrophy syndromes.

With the generous help of patients with FPLD2, Oral along with Ormond MacDougald, Ph.D., Professor of Molecular & Integrative Physiology, graduate student researcher Jessica Maung, Ph.D., and their collaborative team have finally found some answers.

“A simple explanation is that all of the fat cells (adipocytes) have really catastrophic things happening in them,” said Maung.

The team created a mouse model in which they inducibly knocked out the lamin A/C gene in adipocytes, which is mutated in patients with FPLD2.

The team observed in both animal models and in patient donor tissue that dramatic gene expression changes lead to the fat cells being unable to carry out their normal lipid handling and storage functions.

In addition, the fat cells themselves and the immune cells within adipose tissue became pro-inflammatory.

Finally, mitochondria inside the fat cells became dysfunctional.

Said Maung, “All of these effects come together to create this perfect environment for the tissue to be really unhealthy and eventually disappear.”

In the absence of healthy adipose tissue, the normal maintenance of lipids and release of metabolic hormones goes awry, leading to metabolic diseases like 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 team hopes that these insights will help identify future therapeutic targets, enable targeting of adipose tissue to prevent it from disappearing, and correct metabolic dysfunction in this disease.

"This research finally shows us why our fat cells fail, not just that they do. The finding that metabolic disruption begins before visible fat loss even occurs is a gamechanger for how we think about early intervention. As both a patient and a research advocate, I see this study as a roadmap toward the targeted treatments our community desperately needs," said Sharon Halperin, Research Director of Lipodystrophy United, an advocacy and support organization.

“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.”

Additional authors: 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

Paper cited: “Altered lipid metabolism and inflammatory programs associated with adipocyte loss in familial partial lipodystrophy 2,” The Journal of Clinical Investigation. DOI: 0.1172/JCI198387

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