Investigating the Molecular Mechanism of Fat Accumulation in Lipedema and its Response to Thermogenic Stimuli

Abstract ID 92884 Poster Board 401 Obesity is a condition that can be avoided by either consuming fewer calories or burning more. The general misconception around adipose tissue is that it can only store calories and not burn them. However, adipose tissue itself is comprised of three types of fat cells, wherein it is only the white adipose tissue located in the abdominal visceral areas of mammals and humans that solely store lipid droplets. Brown adipose tissue is metabolically active and burns fat. It is aptly named, due to the high number of iron-containing mitochondria present within these cells giving them their brown color. The brown adipose tissue exists only in a small amount within the neck and shoulder area of human adults. The third type of fat that forms the basis of our research interest is an inducible type of white fat that remodels into thermogenic brown-like/beige adipose tissue upon exposure to external stimuli such as cold temperature, chronic exercise, and certain diets. This fat is located within the abundant subcutaneous depots present in the leg and hip region. Upon thermogenic stimulation, similar to the brown adipose tissue, the inducible beige fat can burn calories, thus, it is an attractive target to combat obesity. Lipedema is a disease of fibrotic loose connective tissue characterized by the presence of increased nodular and fibrotic adipose tissue mainly in the hips, buttocks, and limb region, which may be severely painful and impair mobility. Even though lipedema fat mainly resides in subcutaneous white fat depots, it is often resistant to burn by dietary or exercise-based interventions. Our question for this project is what are the underlying causes of lipedema fat resistance and how to tackle them? We hypothesize that the unique cellular and secreted protein profiles and their signaling properties as well as mitochondrial dynamics contribute to lipedema fat resistance. We will study the mechanisms underpinning lipedema fat resistance and investigate whether excess lipedema fat may be converted to thermogenic beige adipose tissue preventing the progression of the disease into the latter stages. To investigate the above, we will apply unbiased high throughput mass spectrometry-based proteomics and single-cell live imaging techniques. We will acquire the profiles of cellular, secreted, and mitochondrial proteins as well as the mitochondrial dynamic, and function which would be compared among adipose stem cells (ASCs) of lipedema, obese, and lean control groups. Currently, we have been able to induce differentiation in adipose stem cells (ASCs) of lean, obese, and lipedema groups. To induce thermogenesis, both acute and chronic browning strategies targeting different signaling pathways were applied. According to preliminary qPCR results, we see that lean and lipedema cells follow a similar trend in terms of undergoing thermogenesis whereas obese cells appear to have a rather white fat-like phenotype. Oxygen consumption rate (OCR) measured in biological replicates of lipedema, obese, and lean control ASCs corroborated a similar pattern. Next, we plan to apply unbiased high throughput mass spectrometry-based proteomics and single-cell live imaging techniques to better understand the pathophysiology of lipedema. This work was supported by the Lipedema Foundation Award #LF34-21.