Targeting Mitochondrial Dysfunction in Lipedema: A Pharmacological Approach to Enhance Metabolic Flexibility
Poster Number
14A
Faculty Mentor Name
Atefeh Rabiee
Research or Creativity Area
Pharmacy
Abstract
Lipedema is a chronic, often misdiagnosed disorder marked by painful, nodular fat accumulation resistant to diet and exercise, predominantly in females. The affected subcutaneous white adipose tissue (SWAT) retains inducible “beige” potential for thermogenesis yet resists lipid mobilization. We hypothesize that this recalcitrance stems from dysregulated protein expression and mitochondrial dysfunction. By employing mass spectrometry-based proteomics and secretome profiling, we aim to identify the specific pathogenic protein alterations and secreted factors that drive lipid retention. These insights informed our screen of pharmacological agents designed to bypass this functional resistance and stimulate beige adipocyte thermogenesis.
To overcome this functional resistance, we screened pharmacological agents known to stimulate beige adipocyte thermogenesis, a well-established therapeutic target in obesity. We evaluated mechanisms primarily involving beta-adrenergic-mediated cAMP–PKA signaling, alongside other key regulatory cascades, including AMPK, mTOR, and TGF-beta/BMP. The selected candidate compounds—curcumin, capsaicin, quercetin, berberine, baicalin, retinoic acid, mirabegron, formoterol, liraglutide, semaglutide, and AICAR—were chosen based on their reported roles in modulating thermogenic signaling networks and mitochondrial metabolism.
In vitro studies using primary lipedema-derived adipocytes demonstrated that selected compounds significantly reduced both lipid droplet size and number following 24-hour acute treatment, as assessed by Oil Red O staining. These effects were further supported by real-time lipolytic activity measured by CellCyte X live-cell imaging. Ongoing multimodal analyses—including gene and protein expression (qPCR, Western blot), cellular morphology, mitochondrial dynamics (fission and fusion markers), and oxygen consumption rate measurements (RESIPHER)—are being conducted to identify lead candidates and refine optimal dosing strategies. Collectively, these findings aim to inform the development of mechanism-based therapeutic approaches for lipedema by integrating molecular insights with translational potential.
Collectively, these findings provide critical mechanistic insight into the metabolic dysregulation underlying lipedema and underscore the therapeutic potential of targeted pharmacological interventions to restore thermogenic activity and metabolic flexibility in affected adipose tissue.
Purpose
This study investigates whether impaired thermogenic activation in lipedema adipose tissue is driven by dysregulated protein expression and mitochondrial dysfunction, which together limit lipid mobilization despite retained beige adipocyte potential. The rationale is based on the observation that lipedema subcutaneous adipose tissue exhibits resistance to conventional metabolic stimuli, suggesting underlying molecular defects in thermogenic signaling pathways. To address this, we employed mass spectrometry–based proteomic and secretome profiling to identify pathogenic alterations, followed by targeted pharmacological screening of compounds that activate key thermogenic pathways (including β-adrenergic–cAMP–PKA, AMPK, mTOR, and TGF-β/BMP signaling). Using primary lipedema-derived adipocytes, we assessed lipid remodeling, lipolysis, and mitochondrial function through multimodal assays. This approach is expected to reveal critical molecular drivers of thermogenic dysfunction and identify effective pharmacological candidates capable of restoring metabolic flexibility, thereby informing mechanism-based therapeutic strategies for lipedema.
Results
Proteomic and secretome analyses revealed significant dysregulation of proteins and pathways related to thermogenesis, mitochondrial function, and adipocyte metabolism in lipedema tissue.
Pharmacological screening showed that select compounds reduced lipid droplet size and number after 24-hour treatment (Oil Red O), with increased lipolytic activity confirmed by live-cell imaging. However, responses varied across compounds and samples, with some showing minimal or no effect.
Preliminary qPCR and Western blot data indicate modulation of thermogenic and mitochondrial markers by select treatments, while others showed no significant changes. Early mitochondrial analyses suggest treatment-dependent alterations, and OCR measurements are ongoing.
Significance
Lipedema remains an underdiagnosed and poorly understood adipose disorder with no effective, mechanism-based therapies, creating a critical gap in women’s metabolic health. This work is important because it addresses a fundamental paradox in lipedema biology—retained beige adipocyte potential but impaired thermogenic activation—by identifying the molecular and mitochondrial mechanisms that drive this dysfunction.
By integrating proteomics with functional pharmacological screening, this study provides a novel, mechanism-driven framework to restore thermogenic activity in lipedema adipose tissue. The findings have direct translational potential, as they may guide the development of targeted therapies that improve metabolic flexibility and reduce pathological fat accumulation.
Beyond lipedema, this work advances broader understanding of adipose tissue plasticity, mitochondrial dysfunction, and thermogenic resistance, which are central to obesity and type 2 diabetes. These insights may inform future therapeutic strategies, influence clinical awareness and diagnosis, and support evidence-based interventions in metabolic disease. The outcomes are relevant to researchers, clinicians, and public health stakeholders, with potential to shape both scientific direction and patient care.
Location
University of the Pacific, DeRosa University Center
Start Date
24-4-2026 11:00 AM
End Date
24-4-2026 2:00 PM
Targeting Mitochondrial Dysfunction in Lipedema: A Pharmacological Approach to Enhance Metabolic Flexibility
University of the Pacific, DeRosa University Center
Lipedema is a chronic, often misdiagnosed disorder marked by painful, nodular fat accumulation resistant to diet and exercise, predominantly in females. The affected subcutaneous white adipose tissue (SWAT) retains inducible “beige” potential for thermogenesis yet resists lipid mobilization. We hypothesize that this recalcitrance stems from dysregulated protein expression and mitochondrial dysfunction. By employing mass spectrometry-based proteomics and secretome profiling, we aim to identify the specific pathogenic protein alterations and secreted factors that drive lipid retention. These insights informed our screen of pharmacological agents designed to bypass this functional resistance and stimulate beige adipocyte thermogenesis.
To overcome this functional resistance, we screened pharmacological agents known to stimulate beige adipocyte thermogenesis, a well-established therapeutic target in obesity. We evaluated mechanisms primarily involving beta-adrenergic-mediated cAMP–PKA signaling, alongside other key regulatory cascades, including AMPK, mTOR, and TGF-beta/BMP. The selected candidate compounds—curcumin, capsaicin, quercetin, berberine, baicalin, retinoic acid, mirabegron, formoterol, liraglutide, semaglutide, and AICAR—were chosen based on their reported roles in modulating thermogenic signaling networks and mitochondrial metabolism.
In vitro studies using primary lipedema-derived adipocytes demonstrated that selected compounds significantly reduced both lipid droplet size and number following 24-hour acute treatment, as assessed by Oil Red O staining. These effects were further supported by real-time lipolytic activity measured by CellCyte X live-cell imaging. Ongoing multimodal analyses—including gene and protein expression (qPCR, Western blot), cellular morphology, mitochondrial dynamics (fission and fusion markers), and oxygen consumption rate measurements (RESIPHER)—are being conducted to identify lead candidates and refine optimal dosing strategies. Collectively, these findings aim to inform the development of mechanism-based therapeutic approaches for lipedema by integrating molecular insights with translational potential.
Collectively, these findings provide critical mechanistic insight into the metabolic dysregulation underlying lipedema and underscore the therapeutic potential of targeted pharmacological interventions to restore thermogenic activity and metabolic flexibility in affected adipose tissue.
