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Several imaging modalities have been used to assess lymphatic function, including fluorescence microscopy, near-infrared fluorescence (NIRF) imaging, and Doppler optical coherence tomography (DOCT). They vary in how the mouse is positioned, the invasiveness of the experimental setup, and the volume of contrast agent injected. Here, we present how each of these experimental parameters affects functional measurements of collecting lymphatic vessels. First, fluorescence microscopy showed that supine mice have a statistically lower contraction frequency compared with mice sitting upright. To assess the effect of different injection volumes on these endpoints, mice were injected with 4, 10, or 20 μl of dye. The lowest frequencies were observed after 20-μl injections. Interestingly, lymph-flow DOCT revealed that although there was lower contraction frequency in mice injected with 20 μl versus 4 μl, mice showed a higher volumetric flow with a 20-μl injection. This indicates that contraction frequency alone is not sufficient to understand lymphatic transport. Finally, NIRF revealed that removing the skin reduced contraction frequency. Therefore, this study reveals how sensitive these techniques are to mouse position, removal of skin, and dye volume. Care should be taken when comparing results obtained under different experimental conditions.

Whereas the blood microvasculature constitutes a biological barrier to the action of blood-borne insulin on target tissues, the lymphatic microvasculature might act as a barrier to subcutaneously administrated insulin reaching the circulation. Here, we evaluate the interaction of insulin with primary microvascular endothelial cells of lymphatic [human dermal lymphatic endothelial cells (HDLEC)] and blood [human adipose microvascular endothelial cells (HAMEC)] origin, derived from human dermal and adipose tissues, respectively. HDLEC express higher levels of insulin receptor and signal in response to insulin as low as 2.5 nM, while HAMEC only activate signaling at 100 nM (a dose that blood vessels do not normally encounter). Low insulin acts specifically through the insulin receptor, while supraphysiological insulin acts through both the IR and insulin growth factor-1 receptor. At supraphysiological or injection site-compatible doses pertinent to lymphatic microvessels, insulin enters HAMEC and HDLEC via fluid-phase endocytosis. Conversely, at physiologically circulating doses (0.2 nM) pertinent to blood microvessels, insulin enters HAMEC through a receptor-mediated process requiring IR autophosphorylation but not downstream insulin signaling. At physiological doses, internalized insulin is barely degraded and is instead released intact to the extracellular medium. In conclusion, we document for the first time the mechanism of interaction of insulin with lymphatic endothelial cells, which may be relevant to insulin absorption during therapeutic injections. Furthermore, we describe distinct action and uptake routes for insulin at physiological and supraphysiological doses in blood microvascular endothelial cells, providing a potential explanation for previously conflicting studies on endothelial insulin uptake.

Background Lipedema is a common painful subcutaneous adipose tissue (SAT) disorder in women affecting the limbs. SAT therapy is a manual therapy to improve soft tissue quality. Objective Determine if SAT therapy improves pain and structure of lipedema SAT. Design Single arm prospective pilot study. Setting Academic medical center. Patients Seven women, 46 ± 5 years, weight 90 ± 19 kg, with lipedema. Intervention Twelve 90-min SAT therapy sessions over 4 weeks. Outcomes Dual X-ray absorptiometry (DXA) scans, SAT ultrasound (Vevo 2100), leg volumetrics, skin caliper assessment, tissue exam, weight, resting metabolic rate, pain assessment, lower extremity functional scale (LEFS) and body shape questionnaire (BSQ) at baseline and end of study. Results Weight, resting metabolic rate and BSQ did not change significantly. Limb fat over total body fat mass (p = 0.08) and trunk fat over total body mass trended down from baseline (p = 0.08) by DXA. Leg volume and caliper assessments in eight of nine areas (p < 0.007), LEFS (p = 0.002) and average pain (p = 0.007) significantly decreased from baseline. Fibrosis significantly decreased in the nodules, hips and groin. Ultrasound showed improved SAT structure in some subjects. Side effects included pain, bruising, itching, swelling and gastroesophageal reflux disease. All women said they would recommend SAT therapy to other women with lipedema. Limitations Small number of subjects. Conclusion SAT therapy in 4 weeks improved tissue structure, perceived leg function, and volume although shape was not affected. While side effects of SAT therapy were common, all women felt the therapy was beneficial.

Background: Breast cancer treatment-related lymphedema (BCRL) arises from a mechanical insufficiency following cancer therapies. Early BCRL detection and personalized intervention require an improved understanding of the physiological processes that initiate lymphatic impairment. Here, internal magnetic resonance imaging (MRI) measures of the tissue microenvironment were paired with clinical measures of tissue structure to test fundamental hypotheses regarding structural tissue and muscle changes after the commonly used therapeutic intervention of manual lymphatic drainage (MLD)., Methods and Results: Measurements to identify lymphatic dysfunction in healthy volunteers (n = 29) and patients with BCRL (n = 16) consisted of (1) limb volume, tissue dielectric constant, and bioelectrical impedance (i.e., non-MRI measures); (2) qualitative 3 Tesla diffusion-weighted, T1-weighted and T2-weighted MRI; and (3) quantitative multi-echo T2 MRI of the axilla. Measurements were repeated in patients immediately following MLD. Normative control and BCRL T2 values were quantified and a signed Wilcoxon Rank-Sum test was applied (significance: two-sided p < 0.05). Non-MRI measures yielded significant capacity for discriminating between arms with versus without clinical signs of BCRL, yet yielded no change in response to MLD. Alternatively, a significant increase in deep tissue T2 on the involved (pre T2 = 0.0371 ± 0.003 seconds; post T2 = 0.0389 ± 0.003; p = 0.029) and contralateral (pre T2 = 0.0365 ± 0.002; post T2 = 0.0395 ± 0.002; p < 0.01) arms was observed. Trends for larger T2 increases on the involved side after MLD in patients with stage 2 BCRL relative to earlier stages 0 and 1 BCRL were observed, consistent with tissue composition changes in later stages of BCRL manifesting as breakdown of fibrotic tissue after MLD in the involved arm. Contrast consistent with relocation of fluid to the contralateral quadrant was observed in all stages., Conclusion: Quantitative deep tissue T2 MRI values yielded significant changes following MLD treatment, whereas non-MRI measurements did not vary. These findings highlight that internal imaging measures of tissue composition may be useful for evaluating how current and emerging therapies impact tissue function.

Lymphatic vessels are lined by lymphatic endothelial cells (LECs), and are critical for health. However, the role of metabolism in lymphatic development has not yet been elucidated. Here we report that in transgenic mouse models, LEC-specific loss of CPT1A, a rate-controlling enzyme in fatty acid β-oxidation, impairs lymphatic development. LECs use fatty acid β-oxidation to proliferate and for epigenetic regulation of lymphatic marker expression during LEC differentiation. Mechanistically, the transcription factor PROX1 upregulates CPT1A expression, which increases acetyl coenzyme A production dependent on fatty acid β-oxidation. Acetyl coenzyme A is used by the histone acetyltransferase p300 to acetylate histones at lymphangiogenic genes. PROX1-p300 interaction facilitates preferential histone acetylation at PROX1-target genes. Through this metabolism-dependent mechanism, PROX1 mediates epigenetic changes that promote lymphangiogenesis. Notably, blockade of CPT1 enzymes inhibits injury-induced lymphangiogenesis, and replenishing acetyl coenzyme A by supplementing acetate rescues this process in vivo.

BACKGROUND: People with lipedema or Dercum's disease (DD) can have a similar distribution of excess painful nodular subcutaneous adipose tissue (SAT), making them difficult to differentiate. METHODS: Case series of 94 patients with DD, 160 with lipedema and 18 with both diagnoses (Lip+DD) from a single clinic in an academic medical center to improve identification and differentiation of these disorders by comparison of clinical findings, prevalence of type 2 diabetes (DM2), hypermobility by the Beighton score and assessment of a marker of inflammation, Total complement activity (CH50). RESULTS: Differences between groups were by Student's t-test with α of 0.05. The Lipedema Group had significantly greater weight, body mass index (BMI), gynoid distributed nodular SAT and fibrotic and heavy tissue than the DD Group. Hypermobility was significantly higher in the Lipedema (58±0.5%) than DD Group (23±0.4%; P<0.0001). DM2 was significantly greater in the DD (16±0.2%; P=0.0007) than the Lipedema Group (6±0.2%). Average pain by an analog scale was significantly higher in the DD (6±2.5%) than the Lipedema Group (4±2.1%; P<0.0001). Fatigue and swelling were common in both groups. Easy bruising was more common in the Lipedema Group, whereas abdominal pain, shortness of breath, fibromyalgia, migraines and lipomas were more prevalent in the DD Group. The percentage of patients with elevated CH50 was significantly positive in both groups. CONCLUSIONS: The significantly lower prevalence of DM2 in people with lipedema compared with DD may be due to the greater amount of gynoid fat known to be protective against metabolic disorders. The high percentage of hypermobility in lipedema patients indicates that it may be a comorbid condition. The location of fat, high average daily pain, presence of lipomas and comorbid painful disorders in DD patients may help differentiate from lipedema.

EXECUTIVE SUMMARY Lipedema is a chronic condition that occurs almost exclusively in women and manifests as symmetrical buildup of painful fat and swelling in the limbs, sparing the hands and feet. A critical issue is the poorly understood disease biology, which for diagnosed patients results in limited treatment options that, at best, ameliorate the symptoms of lipedema. Individuals who suffer from the disease are further impacted by the absence of diagnostic tools, the lack of public and medical awareness of lipedema, and the stigma associated with weight gain. As a result, the true number of women with lipedema, or its epidemiology, is unknown. Braving these challenges is an active, numerous, and engaged patient community eager to participate in lipedema research. Supported by equally devoted caregivers and researchers, the lipedema field presents an immense opportunity for scientific and medical advancements. To capitalize on this potential, the Lipedema Foundation and the Milken Institute’s Center for Strategic Philanthropy convened leading stakeholders to discuss the current state of lipedema science and identify the key philanthropic research opportunities to advance the field. Little is known about how and why lipedema develops in a patient. Although the disease is reported to occur during puberty and other periods of hormonal changes, why this happens is not understood. The painful fat and swelling in some patients can be so debilitating that their mobility is impaired; yet what drives these symptoms is unknown. Psychosocial issues are also prevalent in women with lipedema, contributing to health burden and complexity of disease management. Furthermore, many patients develop the disease alongside obesity; however, diet, exercise, and weight loss surgery have limited effect on lipedema fat. Although the lack of disease biology is staggering, philanthropic investments in research can leverage the desire of patients to participate in studies to improve their and the entire field’s understanding of lipedema. The convergence of multiple scientific topics around lipedema indicates that addressing these gaps in research will also improve the understanding of hormone, pain and edema, mental health, and metabolic biology. There are no diagnostic tools or tests for lipedema. Diagnosis of lipedema involves a clinical assessment and discussion of the individual’s medical history, a process that is difficult to scale within the current healthcare system. The absence of diagnostic tools to streamline or confirm a clinical diagnosis is a key unmet need, which if addressed by philanthropy, has the potential to dramatically change the trajectory of the disease. Investing in research efforts to advance novel imaging technologies to diagnose lipedema is a promising research avenue that would simultaneously benefit individuals who suffer from the disease and healthcare providers unfamiliar with the condition. The public and medical community are not aware of lipedema. Lipedema was initially described in 1940, yet little knowledge about the disease has permeated the general public, with a concomitant lack of mention in the educational curriculum of medical trainees. Addressing this challenge will require philanthropic efforts to define the disease from a basic, clinical, and diagnostic perspective. A key philanthropic opportunity is support for a lipedema patient registry linked to a tissue biorepository. This effort has the potential to generate and support the needed disease research, while engaging patients as partners in understanding the science of lipedema.