Uncovering a cellular and molecular basis for lipoedema

“There is no group more desperate than patients with lipoedema”, moderator Dr Christine Moffatt, clinical professor of skin integrity and emeritus at Nottingham University Hospital in the UK, opened the 8th online event of the global MOH series, which was co-moderated by Sylvain Gaillard, corporate medical affairs manager at Sigvaris Group in Switzerland. The first speaker, Dr Ramin Shayan, specialist plastic and reconstructive surgeon and director of O’Brien Institute Department at St Vincent’s Institute in Fitzroy, Victoria, Australia, shared his view on lipoedema from the plastic surgeon’s perspective.

In lipoedema patients, abnormal fat deposits lead to obesity that is refractory to weight loss. Dr Shayan distinguished between wanted fat required for padding, energy, temperature balance, and hormone regulation and unwanted fat. His research focuses on switching off the growth of unwanted fat and switching on the growth of wanted fat. The long-term objective is to develop therapeutic drugs to restore form, function and wellness. While current treatments are limited and non-curative, one of the aims of reconstructive surgery is to help heal the body. The overall goal is to enhance patient’s quality of life by treating stigmatisation, fat-shaming, self-esteem problems, emotional distress and depression. However, surgical methods are costly, time-consuming and not feasible for all patients.

According to Dr Shayan, biomarkers and a molecular mechanism that can be targeted are the keys to unravelling lipoedema. His research group employed a comprehensive ‘omics’ platform to analyse tissue across modalities in order to identify the stem cells driving the disease.

Dr Tara Karnezis, lead of Lipoedema Lab, presented the results on the identification of Bub1, a mitotic checkpoint protein involved in unregulated cell growth, as a potential therapeutic avenue to target cancer stem cells. A combined omics approach highlighted more fat stem cells in lipoedema fat than in obese fat. Lipoedema stem cells are functionally distinct, display a different fat formation potential, show enhanced growth and a distinct gene signature compared to normal fat. Genes involved in proliferation included Bub1, which is expressed in lipoedema stem cells. “Bub1 is critical for lipoedema stem cell growth, which in turn is more sensitive to Bub1 inhibition than normal fat,” Dr Karnezis summarised the rationale for focussing on Bub1. Future plans include validation of Bub1 as a biomarker, to validate Bub1 in a prospective clinical study in an animal model, to design a novel Bub1 inhibitor and to expand this knowledge into obesity and other metabolic diseases.

During the subsequent expert discussion, joined by panellists Drs Asmaa Alderaa (Saudi-Arabia) and Stanley Rockson (US), Dr Moffatt emphasised the need to be cautious and self-regulating with conclusions drawn in this field, because of the inherent prejudices associated with the disease. Dr Shayan stressed the importance of expectation management in the context of surgery and recommended adjustable compression garments after surgery.

Take Home Messages:

• Lipoedema is a disease of unmet need. Current treatments are limited and non-curative.
• In the absence of diagnostic tools and markers, diagnostic and staging is difficult.
• Surgical methods are costly, time-consuming and not feasible for all patients.
• The mitotic checkpoint protein Bub1 appears to play a key role in lipoedema and offers a therapeutic avenue.
• Future research plans include validation of Bub1 as a biomarker and designing a novel Bub1 inhibitor.