Why does lipedema affect some parts of the body and not others? Latest paper offers clues..
Associate Professor Ramin Shayan reviews his team's June 2026 paper published in Frontiers in Cell and Developmental Biology.
Ramin Shayan MBBS, PhD (Uni Melb), FRACS (Plastics)
Lipedema is a chronic condition affecting predominantly women, causing painful, disproportionate fat accumulation in the legs and sometimes arms — while the trunk remains largely unaffected. Despite its significant impact on quality of life, lipedema is frequently misdiagnosed as obesity or lymphoedema, and its underlying biology has remained poorly understood.
Our recent review published in Frontiers in Cell and Developmental Biology proposes a fundamentally new way of thinking about the disease — one that may finally explain its most puzzling feature: why fat accumulates where it does.
Fat is not the same everywhere.
The key insight driving this work is that fat tissue is not a uniform substance distributed passively around the body. Different fat depots — in the abdomen, thighs, arms, and lower limbs — can be thought of as biologically distinct “mini-organs,” each with their own cellular composition, developmental history, immune environment, and responses to hormonal signals. Just as the liver and kidney are different organs despite both being abdominal, abdominal fat and thigh fat are fundamentally different tissues.
This matters for lipedema because it suggests the disease may not arise from a global problem with fat metabolism, but from something intrinsic to the biology of lower limb fat tissue specifically — a vulnerability that is built in at the cellular level.
A complex ecosystem under stress
The review synthesises current evidence showing that lipedema involves coordinated disruption across multiple cell types within affected fat depots. Fat stem cells — which normally regulate how fat tissue grows and renews itself — appear to become overactive, driving the formation of abnormally enlarged fat cells. Immune cells, particularly a type called macrophages, infiltrate the tissue and shift into states associated with remodelling and fibrosis rather than classical inflammation. Blood vessels become leaky and structurally abnormal. Lymphatic vessels, which drain fluid from tissues, progressively lose function. The structural scaffolding of the tissue — the extracellular matrix — becomes stiffer and more fibrotic over time.
Critically, these changes do not occur in isolation. They appear to reinforce one another in a self-perpetuating cycle: leaky blood vessels increase fluid load on the lymphatics, fibrosis impairs lymphatic drainage, immune signals amplify fat cell dysfunction, and mechanical stress from expanding tissue drives further remodelling. The result is progressive disease that becomes increasingly difficult to reverse.
Why here and not there?
The central unresolved question — why lipedema selectively targets specific fat depots despite the entire body being exposed to the same hormonal environment. The answer may lie in the intrinsic differences between fat depots at the cellular and molecular level.
Lower limb fat depots appear to possess distinct fat stem cell populations, different patterns of developmental gene expression, and unique immune and vascular architectures compared with abdominal fat. These differences may mean that when the body undergoes hormonal shifts — at puberty, during pregnancy, or at menopause — lower limb fat responds in a fundamentally different and maladaptive way. The same hormonal signal that has no adverse effect on abdominal fat may trigger pathological remodelling in genetically or developmentally predisposed lower limb tissue.
This framework also helps explain why lipedema is so resistant to diet and exercise: if the problem is not caloric excess but intrinsic dysfunction within a specific tissue ecosystem, weight loss alone cannot correct it.
New technologies, new opportunities
A major focus of the review is the opportunity presented by two powerful new technologies: single-cell transcriptomics, which allows scientists to read the activity of every gene in thousands of individual cells simultaneously, and spatial transcriptomics, which maps those cellular states onto the physical architecture of the tissue. Together, these tools are enabling the construction of a comprehensive “fat atlas” — detailed cellular maps of fat tissue across different body regions in health and disease. Stay tuned for our next paper on this.
Applied to lipedema, these approaches could finally distinguish between cells that are genuinely diseased and cells that are simply behaving normally for their anatomical location — a distinction that has confounded earlier research. They could identify which cell populations are the primary drivers of disease, which signalling pathways connect them, and where in the tissue the pathological process is concentrated.
What remains to be done
Despite the recent advances in the field, there are limitations of the current evidence. Most existing lipedema studies compare affected tissue to controls without carefully matching the anatomical site — meaning observed differences may partly reflect normal regional variation rather than true disease biology. Comprehensive fat atlases spanning multiple subcutaneous depots in healthy individuals across different hormonal states do not yet exist, and without them, disease-specific signatures are difficult to validate.
Future research will need to build these reference maps, apply single-cell and spatial technologies to carefully matched lipedema and control tissue, and determine whether the disease reflects a universal adipose dysfunction expressed regionally, or a fundamentally depot-intrinsic disorder arising from the unique biology of lower limb fat.
The bigger picture
We have flagged a conceptual shift in how lipedema may be understood — from a disorder of too much fat, to a disorder of the wrong kind of fat tissue behaviour in the wrong place. That shift has implications for further work as it points toward biologically targeted diagnostics and therapies tailored to the specific cellular dysfunction in affected tissue, rather than generic approaches to fat reduction.
For the millions of women living with lipedema worldwide, we hope that this is a meaningful step forward.
